The Toxicity of Plutonium, Americium and Curium. A Report Prepared Under Contract for the Commission...
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The Toxicity of
PLUTONIUM, AMERICIUM AND CURIUM
A Report Prepared Under Contract for the Commission of the European Communities within its Research and
Development Programme on "Plutonium Recycling in Light Water Reactors''
J. C. Nenot Commissariat a PEnergie Atomique, Departement de Protection, CEN, Fontenay-aux-Roses, France
J. W. Stather National Radiological Protection Board, Harwell, Didcot, United Kingdom
Published for the
COMMISSION OF THE EUROPEAN COMMUNITIES
by
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First edition 1979
British Library Cataloguing in Publication Data
Nenot, J C The toxicity of plutonium, americium and curium. 1. Americium - Toxicology 2. Curium -Toxicology 3. Plutonium-Toxicology I. Title II. Slather, J W III. Commission of the European Communities 615.9'25'44 RA1231.R2 79-40429
ISBN 0-08-023440-2
EUR 6157 E N , FR
In order to make this volume available as economically and as rapidly as possible the authors' typescripts have been reproduced in their original forms. This method unfortunately has its typographical limitations but it is hoped that they in no way distract the reader.
Printed in Great Britain by Page Bros. (Norwich) Ltd.
SUMMARY
The objective of the report is to provide a biological basis for an
assessment of the radiological health problems resulting from human
exposure to plutonium, americium and curium.
Only limited data are available on the metabolism of these actinides
in man and there has been no recorded incidence of serious long-term
effects, such as cancer or hereditary effects, which might be related
to their incorporation into the body. Long term follow-up studies of
workers occupationally exposed to plutonium and other actinides will
eventually provide valuable data for improving the basis upon which stan-
dards of protection are determined. Current knowledge of the metabolism
and effects of plutonium, americium and curium is derived mainly from
animal experiments that have been conducted during the last 3 0 years in
many laboratories throughout the world.
Actinides may enter the body either by inhalation, by ingestion or
through wounds. The intact skin is an effective barrier to their entry
into the body. After inhalation of actinide dusts the amount deposited
in the three regions of the respiratory tract (nasopharynx, tracheo-
bronchial region, pulmonary region) depends on the particle size dist-
ribution and is not significantly influenced by the chemical form. Within
the first few days after exposure a fraction of the deposited activity
is rapidly cleared from the respiratory tract. This is due to transport
of particles to the oesophagus by the ciliated epithelium of the upper
regions of the respiratory tract and to absorption of soluble actinides
into the blood. The fraction of the deposited material which remains
in the alveolar region of the lung after the first few days is cleared
slowly. Clearance involves transport to the oesophagus in specialised
phagocytic cells named macrophages, transport to lymphatic tissue, and
slow transfer to the blood. Experimental studies have shown that for
plutonium dioxide the slow component is cleared exponentially with a
half-time of retention of about 5 0 0 days. For soluble forms of plutonium,
such as the nitrate and citrate, and for all compounds of americium and
curium, the half-time of retention is about 5 0 days. Absorption from tho
gastro-intestinal tract is low. The amount absorbed is estimated to
be about 1 x lO""2^ for soluble plutonium compounds, 1 x 1 0 ~ ^ % for plutonium
dioxide and 5 x 10~2% for all forms of americium and curium.
The behaviour of actinides at wound sites depends not only upon the
physico-chemical properties of the material deposited but also on
ix
X
biological factors such as the depth and site of deposition, the type of
tissue and the dispersion within the tissue. In general soluble forms
are cleared more readily than insoluble forms, subcutaneous deposits more
readily than intramuscular deposits and americium and curium more readily
than plutonium.
Upon reaching the circulation, plutonium, americium and curium are
accumulated in various tissues. For radiological protection purposes the
three sites of deposition that need to be considered are the skeleton,
liver and gonads. The skeleton and liver together accumulate about 90%
of the activity entering the blood (about U%% in the skeleton and k$% in
the liver) while approximately 3 x 1 0 ~ ^ % is accumulated by the testes and
1 x 1 C r ^ % by the ovaries. The human skeleton and liver are estimated to
retain actinides with half times of 1 0 0 years and i\0 years, respectively.
Animal studies suggest that there is no loss of activity from the gonads.
Acute or medium-term effects are due to very high radiation doses
which will only occur in extreme accidental situations. The level of
activity deposited in the pulmonary region of the lung which might cause
death of half an exposed population within one year is estimated to be
about 1 0 0 uCi ( 3 . 7 MBq). The main delayed effect found in experimental
animals has been the development of cancer which has occurred predominantly
in the lung and in the skeleton. Effects have generally been observed
at levels of activity in humans much greater than those equivalent to max-
imum permissible body burdens in man. The frequency of lung cancers
occurring after the inhalation of actinides increases with the dose up
to a maximum and then decreases at higher doses as a result of cell
sterilization and death. Most pulmonary cancers observed in experimental
animals have occurred in the peripheral regions of the lung. Actinides
deposited in the skeleton have induced bone cancers but various animal
species differ in their response, the dog exhibiting the highest
sensitivity. In addition to lung and bone cancers a small number of
liver cancers have been observed, and in animals exposed to readily
transportable forms of actinides some cancers have also occurred in other
soft tissues. No evidence of hereditary effects resulting from the
incorporation of actinides in the gonads has been demonstrated in any
of the animal species studied.
In evaluating the radiation effects that may occur in a population
exposed to actinides, estimates of risk coefficients are required for
xi
radiation induced cancers and for radiation induced hereditary diseases.
As the histological types of cancer seen in experimental animals may
differ from those commonly seen in man and as there are species differences
in radio sensitivity, only human data have been used for calculating risk
coefficients for late somatic effects of radiation. There are no data
on the development of cancers in humans as a result of incorporation of
plutonium, amercium or curium isotopes. Estimates of risk have therefore
been based mainly on the results of epidemiological studies on humans
exposed to external radiation. Some information is also available on
the development of bone and liver cancers as a result of intakes of other
alpha emitters. The recommended rounded values (based on the use of
a quality factor of 2 0 for alpha radiation) for the number of deaths per
1 0 ^ man gray (alpha) are: 1+00 from lung cancers, 1 0 0 from bone cancers,
1+00 from leukaemia, 1 0 0 from liver cancers and 1+00 from gastrointestinal
tract cancers; for serious hereditary diseases a total of 111+0 cases per
1 0 ^ man gray can be predicted over many generations. To assess the
biological consequences of intake of actinides these risk coefficients
must be weighted by the doses accumulated by the various tissues.
Furthermore the risk coefficients for radiation induced cancers are based
on the assumption that the full risk to the tissues is expressed. Because
of the long latent period for cancer induction this will only apply to
doses received early in life. The genetically significant dose is that
accumulated up to age about 3 0 .
At present the methods available for removing accidental intakes of
actinides from the body are only moderately successful. If insoluble
materials are inhaled, bronchopulmonary lavage is the only potentially
effective treatment. If activity is deposited at a wound site the most
satisfactory treatment is excision of as much of the contaminated tissue
as possible. For removing soluble forms of plutonium, americium and
curium, injection of the chelating agent DTPA is presently the best
method; it effectively clears actinides from the blood and extracellular
fluids and is rapidly excreted in the urine.
ACKNOWLEDGEMENTS The authors would like to acknowledge the valuable help given by many
of their colleagues during the preparation of this report. The authors
also wish to thank Miss R. A. Steggles for typing the manuscript.
xii
Chapter 1
I N T R O D U C T I O N
The Commission of the European Communities has initiated a programme
to evaluate the merits of using plutonium in light water reactor fuels.
As part of this programme, it is necessary to consider the implications
of handling materials containing increased quantities of plutonium,
americium and curium. This report provides a synthesis of current
knowledge on the metabolism and biological effects of these actinides
in animals and man, from which an assessment of radiological health
problems can be made. Relevant data are included from the many recent
studies that have been conducted both in the Member States of the
European Community and elsewhere.
In order to assess the consequences of humay, exposure to these
actinides it is necessary first to identify their routes of entry into
the body, second to understand the factors influencing their distribution
and retention in tissues, third to determine the tissues at risk and
fourth to define doss-response relationships for the critical tissues.
There is only a limited amount of information on the metabolism of
these actinides in humans although some data are available on the distri-
bution of plutonium in human autopsy samples. Published studies on the
behaviour of actinides in man. involve exposure to unknown physico-chemical
forms in most cases, often at unspecified times, and in many cases chelating
agents have been usfd which may have influenced their metabolism. Animal
studies are therefore necessary to elucidate those factors influencing
the metabolism of actinides in the body. A major limitation to the
value of many animal studies, however, is that the amounts of actinides
used hare been greatly in excess of those levels likely tc be encountered
in cases of human exposure. Since the behaviour of actinides in the body
is influenced by the mass deposited, studies on animals exposed to
relatively low doses have been considered wherever possible.
No detrimental biological effects in man can be unequivocably
attributed to exposure to actinides. Extensive animal studies have
shown that biological effects occur predominantly at the point of entry
(lungs or wound site) in regional lymphatic tissue draining the sites of
deposition and in the skeleton and liver following deposition in these
organs from the blood. Effects have generally been observed at levels of
activity in tissues much greater than those equivalent to maximum perm-
1
2
issible body burdens in man.
Depending upon the radiation dose to tissues both early and late
somatic damage could be anticipated in exposed individuals. Early
somatic effects are assumed to require a threshold ose before any damage
occurs and are unlikely except as a result of a mass.ive intake following
a major accident. The main late somatic effect is expected to be cancer,
although life-shortening may also occur as a result of non-specific
radiation effects. Cancer induction is assumed to be linearly related
to the close with no threshold. The histological types of radiation-
induced cancer that occur in experimental animals often differ from those
commonly seen in man and there exe species differences in radiosensitivity.
Only human data have therefore been used for calculating risk coefficients
for radiation induced cancer in the lung, bone, bone marrow, liver and
gastrointestinal tract. These estimates of risk have been based mainly
on the results of epidemiological studies on humans exposed to external
radiation but some information is also available on humans exposed to
incorporated alpha-emitters.
Radiation damage to the germ cells can result in spontaneous
abortion or hereditary disease. Hereditary effects may therefore be
expected to occur in the descendants of exposed individuals. No evidence
of genetic damage resulting from the incorporation of actinides in the
gonads has been demonstrated either in man or in animal studies. Estimates
of risk coefficients for radiation induced hereditary disease have been
extrapolated from studies on animals exposed to external radiation.
In the event of accidental contamination of humans by actinides,
therapeutic procedures may be used in an attempt to increase their rate
of elimination from the body. Current developments for treating intakes
of actinides have therefore been discussed.
Chapter 2
PHYSICAL AND CHEMICAL PROPERTIES OF BIOLOGICAL IMPORTANCE
1 • Introduction
Plutonium, americium and curium are produced in both thermal and
breeder reactors. The main civilian use of plutonium is in breeder
reactors and it may also be used as fissionable material in thermal
reactors. It has other uses in industry and medicine such as for power
sources and cardiac pacemakers. Americium and curium have few uses
although americium-21+1 has been used for transmission scanning studies in
tissues, in neutron sources, in smoke detectors, and in a-active foils with
applications in static eliminators.
2 . Plutonium
The chemistry of plutonium has been described by Katz and Seaborg
( 1 9 5 7 ) , Cleveland ( 1 9 7 0 ) and Taylor ( 1 9 7 3 a ) . It is a silvery white metal
which melts at 6 3 9 . 5°C and oxidises readily on warming in moist air. In
finely divided form the metal may be pyrophoric. When plutonium metal is
burnt in oxygen or when oxygen containing compounds such as Pu(lV) oxalate
or Pu(lY) peroxide are heated in vacuo to about 1000°C plutonium dioxide is
formed. Plutonium dioxide is a highly refractory material which melts at
2200-2 l+00°C and is difficult to dissolve by normal methods.
There are 1 5 known isotopes of plutonium having atomic weights between
2 3 2 and 2 l+6. Of these only 2 3 6 - 2 1 + 3 are of any biological interest either
as a result of their production in nuclear power programmes or because of
other uses. Table 2 . 1 shows the main physical properties of these isotopes.
The isotopes Pu - 2 3 9 and Pu-2l+1 are fissile and therefore of special
interest for fuel in both thermal and breeder reactors. In 1 9 7 5 the
estimated production of plutonium in the Countries of the European Community
was 3 « 0 tons and it was anticipated that this would rise to 5 - 7 tons by 1 9 8 0
(Haijtink, 1 9 7 6 ) . Pu - 2 3 9 and Pu-2l+0 emit an L X-ray of uranium in k% and
1 1 % of disintegrations respectively with an energy of about 1 7 keV. These
X-rays can penetrate a few centimetres of tissue thus allowing Pu - 2 3 9
(4Pu-2l+0)* to be detected in the lung or a wound site. The other a emitting
isotopes of plutonium also emit L X-rays in varying amounts. Pu - 2 3 8 is
used as a heat source in thermo-electric power generators such as cardiac
pacemakers and Pu - 2 3 6 and Pu - 2 3 7 are used.in tracer studies. Because of
*In the remainder of this report Pu - 2 3 9 + 21+0 are referred to as Pu - 2 3 9
Table
2.1
Physical properties of the manor isotopes of Plutonium, Americium and Curium
Isotope
Radioactive,
Half-live
W
(years)
Principal Mode
of Decay
Mean alpha
energy W
(MeV)
Specific Activity
^Ci g"
1
Mass per
Li
Ci
(«)
Relative
Mass
a
Plutonium-
236
2.8
5 E
0
0 a
5.7
5 5
.32
E
08
1.8
8 E
-09
1.1
5 E
-02*
Plutonium-
237
1.2
5 E
-01
E. C •
1.2
1 E
1
0 8.
28
E-1
1 5.
08
E-0
6
Plutonium-
2 38
8
.78
E 0
1 a, X-rays
5-2*
6 1
.71
E
07
5.82
* E
-08
3-58
E
-03
Plutonium
-239
2.
2*39
E
02*
a, X-rays
5.1
5 6
.13
E 0
2*
1.6
3 E
-05
1.0
0 E
0
0
Plutonium-
2i*0
6
.53
7 E
0
3 a
5.1
5 2
.28
E
05
U.3
8 E
-06
2.6
9 E
-01
Plutonium-
22*1
1
.50
2 E
01
P 9.
90
E
07
1.0
1 E
-08
6.1
9 E
-02*
Plutonium
-22*
2 3.
87
E
05
a U
.89
3.82
E
0
3 2
.62
E-0
2+
1.6
1 E
01
Plutonium
-22*
3 5
.66
E-01
* (3
2.60
E
12
3.82
* E
-13
2.3
6 E
-08
Americium-
22+1
2*
. 58
E
0
2 a, y-rays
5.2*
9 3
.25
E
06
3.08
E
-07
1.8
9 E
-02
Americium-
21*3
7.
2*0
E
03
a
5.2
7 1
.99
E
05
5.0
2 E
-06
3.08
E
-01
Curium-
21*2
2*
. 1*7
E
-01
a
6.1
0 3
.31
E
09
3.02
E
-10
1.8
5 E
-05
Curium-
214*
1
.79
E 0
1 a
5.80
8.
20
E
07
1.2
2 E
-08
7.2*
8 E
-02*
E.C.
-
Electron capture
a
-
In comparison with
1
^Ci of plutonium
-239 which is taken as
1
Reference:
A
- Harte
(1
97
6)
5
it,n short half-life ( 5 hrs) and low P energy ( 0 . 6 MeV) plutonium-21+3
is of little radiological importance.
Plutonium can exist in solution mainly in four valence states: Pu(lll),
Pu(lV), Pu(V) and Pu(Vl) and in some conditions as Pu(VIl). The individual
oxidation states can be stabilised by appropriate oxidising, reducing or
complexing agents. In concentrated acidic solutions a number of oxidation-
reduction reactions can occur leading to the formation of an equilibrium in
which the different oxidation states can co-exist.
There is little information on the oxidation state of plutonium in
biological systems. In neutral solutions the formation of the Pu(lV) state
is favoured and biological fluids contain ligands and complexing entities
that tend to stabilise the Pu(lV) state. Stable plutonium complexes can be
formed with citrate, ascorbate, amino acids and proteins. The stability of
these complexes decreases in the order Pu(lV) > Pu(lll) > Pu(Vl) > Pu(V).
It is, therefore, probable that most if not all plutonium in biological
systems is in the Pu(lV) state.
Of particular biological importance is the property of plutonium ions
in solution to rapidly hydrolyse and form polymers at high concentrations.
The tendency to hydrolyse decreases in the order Pu(lV) > Pu(Vl) > Pu(lll)
> Pu(v). Hydrolysis of Pu(lV) can result in the formation of relatively
insoluble polymers, a process which is only slowly reversible. The forma-
tion of plutonium polymers in the body leads to their phagocytic uptake by
macrophages and other cells that can accumulate particulate material.
Compounds of Pu(lll) and Pu(Vl) hydrolyse less rapidly at physiological pH
and can potentially be more readily absorbed from the gastrointestinal
tract, lung or other sites.
3 - Americium and Curium
The chemistry of the transplutonium elements americium and curium has
been reviewed by Katz and Seaborg ( 1 9 5 7 ) , Pascal ( 1 9 7 0 ) and Taylor ( 1 9 7 3 b ) .
Americium metal is silvery white, malleable and ductile and melts at
9 9 U + 7°C. It oxidises slowly in the air. Curium is a silvery, hard,
brittle metal with a melting point of 1 3 5 0 + 60°C. It oxidises rapidly
in the presence of oxygen. The oxides of both americium and curium are
more soluble than plutonium dioxide.
There are 1 3 known isotopes of americium ( 2 3 2 , 23I+ , 2 3 7 - 2 1 + 7 ) . Am-2l+1
is the most abundant isotope and is produced from Pu-2l+1 by P decay. It
6
subsequently decays by a emission also giving rise to a Y-ray with an energy
of 60 keV (1+0% of disintegrations) and if incorporated in the body can be
readily detected outside. Am-22|3 is the only other isotope of americium
produced in any quantity. Of the 12 known isotopes of curium only C111-2I4.2
and Cm—21+1+ are produced in significant amounts.
The main physical properties of these isotopes of americium and curium
are shown in Table 2.1. In solution the trivalent state is the most stable
oxidation state and the only one of importance in biological systems. The
general features of hydrolysis and complex ion formation are similar to
those found for plutonium. The trivalent transplutonics are however less
readily hydrolysed because of their lower ionic charge and larger ionic
radii (Am III = 99 pm, Cm III = 98 pm, Pu IV = 9 0 pm; Durbin, 1 9 6 2 ) . The
most important feature of their solution chemistry is that they form only
weak complexes with serum proteins and other ligands (Taylor, 1973*0 •
1|. General data relevant to problems in Radiological Protection
The relative amounts of the most important isotopes of plutonium,
americium and curium produced either in a thermal reactor (PWR) or in a
breeder reactor fuelled with plutonium from an SGHWR reactor are given in
Table 2 . 2 . Both inventories show that high levels of both americium and
curium isotopes are produced as well as plutonium. This is in contrast to
the fuel inventory after low burn-up times of say 1 0 0 0 MWD/Te when Pu - 2 3 9
+ 21+0 are the main isotopes produced (Dolphin, et al., 1 9 7 U ) • Although the
Cm-2i|2 isotope accounts for most of the alpha activity in fuel rods at the
end of long irradiation times it decays rapidly with a half-life of 1 6 3 days
to Pu-238.
Plutonium is used in fuel mainly in the oxide form. The chemical
separation procedures used in the reprocessing of fuel elements involve
their dissolution in nitric acid and subsequent separation of plutonium
from uranium and other fission products by extraction in organic solvents.
Plutonium i._ precipitated as the oxalate and then converted to the oxide.
In the preparation of plutonium metal an intermediate stage is the formation
of the fluoride compound. Accidental releases from chemical separation
plants may therefore involve numerous chemical forms of plutonium which
appear in various process streams during the separation procedures. The
higher actinides are normally removed during reprocessing but the release
of Pu-21+1 gives rise to Am-2l+1.
Actinides commonly enter the body by ingestion or inhalation as
particles. Depending upon the source of the release actinides may be taken
7
Table 2 . 2
Relative activities of isotopes in freshly discharged fuel3.
A b Inventory for PWR
at 3 3 , 0 0 0 MWD, Te"1
B c Inventory for CFR
with SGHWR plutonium at 8 0 , 0 0 0 MWD, Te~ 1
plutonium-236 1 . 1 0 E - 0 3 2 . 3 5 E-01+
Plutonium-2 3 7 < 3 . 1 U E -06 3 . 8 3 E - 0 3
Plutonium-238 8 . 5 5 E 0 0 2 . 9 U E 0 0
Plutonium-239 1 . 0 0 E 0 0 1 . 0 0 E 0 0
Plutonium-2l|0 1 . 5 0 E 0 0 2 . 1 5 E 00
Plutonium-2l+1 3 . 3 0 E 0 2 2 . 3 2 E 0 2
Plutonium-2U2 I+.3U E - 0 3 8 . 9 2 E - 0 3
Americium- 21+1 2 . 7 0 E - 0 1 6 . 9 1 E - 0 1
Americium-2l+3 5 . 6 9 E - 0 2 1+.00 E - 0 2
Curium-21+2 1 . 0 5 E 0 2 1 . 0 3 E 01
Curium-21+1+ 7 - 6 8 E 00 3 . 8 7 E 0 0
a In comparison with plutonium-239 taken as 1
b Pressurised Water Reactor (PWR)
c Commercial Fast Reactor (CFR)
d Steam Generating Heavy Water Reactor (SGHWR)
Reference: A. Bell ( 1 9 7 3 )
B. Kelly et al, ( 1 9 7 7 )
Relative activities of the major isotopes of plutonium, americium
and curium in irradiated fuel
8
in either as individual elements or in association with other active or
inactive materials. Following the inhalation of particles consisting of
mixtures of actinides and other elements the transportability of the
different actinides in the lung seems to depend largely on the element
present in greatest mass (Chapter 1+). Table 2.1 shows the relative masses
of the major isotopes of plutonium, americium and curium for unit amounts
of activity taking 1 jiCi (37 kBq) of plutonium-239 as 1. Thus in a dust
particle that contains oxides of both plutonium-239 (90% of the alpha
activity) and americium-21+1 ( 1 0 % of the alpha activity) the relative masses
of the two isotopes are kl& s 1 respectively and the low solubility of
plutonium dioxide limits the transport of americium from sites of deposition
in the body.
Another important physical parameter that influences the behaviour of
actinide particles in the body is their size. Table 2.3 shows both the
total number of atoms of Pu-239 in various sizes of spherical particles of
the oxide as well as the number of atoms at the surface. In particles
greater than 100 nm in diameter less than 2% of the atoms are at the
surface. These particles do not dissolve readily in biological fluids.
However, for 1 nm particles 89% of the atoms are at the surface where they
can be readily solubilised by biological ligands (this is discussed in
Chapter !+)•
9
Table 2.3
The theoretical relationship between particle size and number of
surface atoms in plutonium-239 dioxide spheres8.
Diameter in [xm
No. of atoms at surface (N T)
Total No. of atoms (N T)
Percentage of atoms at surface
0 . 0 0 1 2 1 . 5 21+. 1 89 0 . 0 0 2 8 6 11+6 5 8
0 . 0 0 3 191+ 1+56 k3 0 . 0 0 5 5 3 8 1 9 3 2 28
0 . 0 1 0 2 1 5 2 11+367 1 5
0 . 0 2 5 1.31+5 X 21.1+5 x 1oh 6
0 . 0 5 0 5 . 3 8 0 X 1 0 6 1 6 8 . 9 x ^oh
3 0 . 1 0 0 2 . 1 5 2 X 1 0 * 1 3 U . 1 x 1 0 ^ 2
a Assumes plutonium-239 dioxide crystal lattice structure
(Cleveland, 1 9 7 0 )
Reference: Smith et al ( 1 9 7 7 )
Chapter 3
HUMAN EXPERIENCE
1 . Introduction
In the United States it has been estimated that by 1 9 7 1 + about 1 7 * 0 0 0
persons had worked in the plutonium industry from the beginning of the
Manhattan project in 1 9 U 3 (Gillette, 1 9 7 U ) • There is no information on the
number of people that have worked with plutonium or the higher actinides
world wide. Accidental intakes of plutonium by humans have been recorded
since the discovery of plutonium in 1 9 U 2 . Despite this there is relatively
little information available on either the metabolism or effects of
plutonium in man that can be used to predict the potential consequences of
human exposure. The available human data frequently result from accidental
exposures, often at unspecified times and to compounds of unknown physico-
chemical form. The data is difficult to interpret because many
workers are also exposed to external radiation and possibly to other
internally incorporated radionuclides. Human metabolic data on the trans-
plutonium elements is even more fragmentary.
2 . Routes of Entry
The two principal routes of accidental entry of actinides in
occupationally exposed persons are either by inhalation or through cuts,
abrasions or other wounds. In a survey of 2 0 3 USAEC contractors1 personnel
with internal deposits of plutonium, Voelz ( 1 9 7 5 ) reported that 1 31 had
been contaminated by inhalation, 1+8 through wounds and 8 by both routes.
In 1 6 cases the cause of contamination was unknown.
Accidental intakes by inhalation have provided some information on
the retention of both plutonium and americium in the human lung. Lung
retention data have normally been obtained by chest counting. A limitation
of the technique is that measurements of actinides in the chest by external
counting do not distinguish between activity in lung and that in other
thoracic tissues such as lymph nodes. The limit of detection is between
5 and 1 0 nCi ( 1 8 5 and 3 7 0 Bq) of plutonium-239 or about 0 . 2 nCi ( 7 . 1 + Bq)
of americium-2l+1 depending upon the amount of absorbing tissue over the
rib cage of the individual. Americium-21+1 is detected more readily due to
the emission of 60 keV gamma-rays which are less readily absorbed in the
chest wall than the plutonium x-rays.
Plutonium dust particles that are accidentally inhaled frequently
contain some americium-2l+1. If the amount of americium in the inhaled
11
12
particles can be determined from samples of the dust collected on air
filters or from the source material then the amount of plutonium in the
chest can be inferred from the level of americium measured,
The number of incidents involving accidental inhalation of plutonium
or other actinides in man for which detailed in vivo and excretion
measurements have been made is small, Plutonium deposited in the upper
regions of the respiratory system is cleared with a half-time of 0 . 5 to
0 , 8 days (Ramsden et al, 1 9 7 0 ; Watts, 1 9 7 5 ) • Plutonium deposited in the
lower regions of the respiratory system is cleared more slowly. The
long term c -mponent of retention, obtained by measurements of activity
in the chest, in a man accidentally exposed to plutonium haa been reported
to be 2 9 0 days (Ramsden et al, 1 9 7 0 ) and in a second man 2'.|0 days
(Johnson et al, 1 9 7 2 ) . Watts ( 1 9 7 5 ) reviewed published data on the
clearance of insoluble plutonium-239 compounds from the lung. She
re-exanined the original data reported by Ramsden et al ( 1 9 7 C ) and showed
that the long term clearance from the chest could be represented by a two
component function with half-times of 1 7 and 6 5 0 days. The retention
data reported by Johnson et al ( 1 9 7 2 ) could be fitted by two components
with half-times of 2k and 3 2 0 days.
Oxides of americium are cleared more rapidly from the lung. Sanders
( 1 9 7 U & ) reported that in a man that had accidentally inhaled mixed oxides
of americium-2Ul and curium-2I4I4. the lung content of both nuclides after
the first seven days was cleared with a half-time of 2 8 days. This
difference between oxides of plutonium and the higher actinides has also
been found in animal experiments (Chapter U ) .
Fry ( 1 9 7 6 ) reported the long-term retention of americium-21+1 in the
chest of a subject who had inhaled the oxide was at least 9 0 0 days.
However, in vivo measurements were not started until about 21+0 days
after the accident and it seems likely that much of the activity measured
in the chest was in tissues other than the lung.
The other main route of entry of actinides into the body in occupa-
tionally exposed persons is through wounds. The majority of cases of
human exposure to transuranium elements through wounds have involved
plutonium either alone or in combination with americium. In most instances
either the oxide or metal has been involved (Pilleron et al, 1 9 6 1 ; ;
Lagerquist et al, 1 9 6 5 ; Schofield and Lynn, 1 9 7 3 ; Testa and Dellesite,
1 9 7 3 ; Johnson and Lawrence, 1 9 7 U ) • Cases of human contamination by
plutonium nitrate (Lafuma, 1 9 6 3 ; Schofield, 1 9 6 9 ; Jolly et al, 1 9 7 2 ) and
13
plutonium oxalate (Schofield et al, 1 9 7 U ) have also been reported. Accident
cases are frequently treated by surgical exision and/or chelation therapy
and often the nature of the material involved is not known. There may
also have been a history of accidental inhalation exposures. The data
available on humans are therefore not suitable for describing the be-
haviour of actinides that have entered the body through cuts or wounds
and use must be made of data from animal experiments (Chapter k)»
Transfer of actinides to man can also occur as a result of inhalation
or ingestion of actinides in the environment. Recently Bennett ( 1 9 7 ^ ) has
shown that estimated organ burdens of plutonium-239 in the United States
population are adequately accounted for by considering the inhalation
intake alone. The contribution to organ burdens by the ingestion route
was less than that from inhalation by about a factor of 1 0 0 0 .
3 . Distribution in Tissues
A number of studies have been reported on the tissue distribution of
plutonium in human autopsy samples arising from both occupational exposure
and fallout. The objective of measuring levels of activity in tissues
from occupationally exposed persons is to determine the body content of
plutonium or other actinides at death and subsequently to relate these to
the previous history of exposure and bioassay results. This should both
help to improve the accuracy of bioassay programmes and test the adequacy
of control procedures.
There are now more than 7 0 0 autopsy cases that have been studied for
plutonium concentrations (Campbell et al, 1 9 7 3 ; Lagerquist et al, 1 9 7 3 ;
Nelson et al, 1 9 7 2 ; Newton et al, 1 9 6 8 ; Norwood et al, 1 9 7 3 , 1 9 7 5 ;
Schofield and Dolphin, 1 9 7 U ; Maclnroy, 1 9 7 6 ; Popplewell, 1 9 7 7 ) , many of
the reported cases are from the general population but there are records
of more than $0 persons accidentally exposed at work. A major difficulty
in the assessment of organ or total body content from measurements on
autopsy samples is the necessity to extrapolate from measurements on a
relatively small sample of tissue. This is a particular problem with bone
when often only some vertebrae and ribs are removed. The tissues normally
analysed are lung, tracheo-bronchial lymph nodes, liver, kidney, gonads
and bone. Results from other tissues have normally shown much lower
concentrations. The results shown in Table 3 . 1 are for 2 2 autopsy
analyses with the highest concentration of plutonium. They have been
chosen on the basis that at least one tissue analysed has a concentration
of plutonium of 2 0 0 0 disintegrations per minute per kilogram. The results
Table 3*1
Distribution of plutonium in autopsy tissues of occupationally exposed workers
Time from possible
first exposure
to death
(years)
Concentration of plutonium in tissues
dis min"' kg"
1
Cause of Death
Reference
Time from possible
first exposure
to death
(years)
Lung
TBLN
Liver
Skeleton
Kidney
6
59
80
21 3
0 60
20
20
Cardiac embolism
pulmonary
A
NR
2800
16600
21+8
2
3 20
Suicide
A
12
1+07
0 3U
00
93
50
72
00
600
Complications of
heart surgery
A
25
351
3756
0 97
50
0 58
Coronary infarction
A
21
1U65
2 9
79
0 32
09
21+2
15
Coronary thrombosis
B
1+
2508
55
0 78
88
NA
Bronchitis
B
1 88
0 5
39
0 12
91+
21
3 15
Accident
B
9 39
60
330
867
181+8
1+1+
Coronary thrombosis
B
<1
2838
NA
672
130
NA
Coronary thrombosis
B
-39
00
NA
3900
0 1+
700
600
N.G.
C
-9
76
00
850
310
171
28
N.G.
D
-31
+100
11600
297
28
1+
N.G.
D
13
633U
8
50
96
98
36
23
89
1+7
N.G.
E
15
25
22
1+6000
U3U
3 NA
50
N.G.
E
15
8538
1
50
89
6 2866
612
7-1
N.G.
E
19
377
2681
+5
70
2 31
+ <MRL
N.G.
E
lU
Table
3
.1 (continued)
Time from possible
first exposure
to death
(years)
Concentration of plutonium in tissues
dis min"' kg"
1
Cause of Death
Reference
Time from possible
first exposure
to death
(years)
Lung
TBLN
Liver
Skeleton
Kidney
Cause of Death
Reference
25
NA
85
72
59
87
NA
N.G.
E
31
+ .
8U65
5
63
75
0 NA
3550
NA
Living
E
27
297
2298
<1
12
1
N.G.
E
29
375
10
35
2 53
8 85
10
N.G.
E
20
290
3678
Ik
18
1
N.G.
E
25
69
95
5 78
79U
9 38
U6
11
17
57
N.G.
E
+
Specimens obtained at biopsy
TBLN
Tracheobronchial lymph nodes
NA
Tissue not available
MRL
Minimum reporting level
Skeleton
Average concentration of results reported
NG
Cause of death not given
NR
Not recorded
References
A
Norwood et al,
19
73
B
Schofield and Dolphin,
19
7U
C
Popplewell,
1
97
7 D
Lagerquist et al,
19
73
E
Maclnroy,
19
76
Organ weights of Reference Man
ICRP Publication
2
3, 1
97
5
Lungs
TBLN
Liver
Skeleton
Kidneys
1000 g
15 g
1800 g
10
00
0 g
310
g
15
16
show that the concentration is highest in the tracheo-bronchial lymph
nodes in 13 of the cases and this reflects the fact that most exposures
were to plutonium oxide often more than 1 0 years prior to death.
The variation in the distribution of plutonium shows that each case
is unique. To relate these measurements to the previous history of
exposure and bioassay measurements, the chemical form, solubility and
particle size of the material involved must be know as well as its route
of entry, and the time and duration of exposure. Much of this information
is frequently not available and as a consequence the results of tissue
analyses have only a limited value.
Levels of fall-out plutonium have also been measured in human tissues.
This activity arises mainly from the estimated 3 2 5 k 0 i ( 1 2 PBq) of
plutonium-239 disseminated over the earth!s surface by weapons testing.
Smaller amounts of plutonium-238, plutonium-2l+1 and plutonium-21+2 have
also been produced by weapons testing (Bennett, 1 9 7 6 ) . Amercium-2l+1 is
the daughter isotope of plutonium-21+1. The amercium-2Ul : plutonium-239
activity ratio is currently about 0 . 2 5 in soil and will eventually
increase to 0 .1+ (Krey et al, 1 9 7 6 ) . Thus in addition to plutonium some
information on the tissue distribution of fall-out americium may even-
tually become available.
Data have been published by Maclnroy ( 1 9 7 6 ) on the distribution of
plutonium in human tissues from the general population. In a total of
2 0 0 or more specimens analysed the average concentrations of plutonium
1 1
found in tissues were: for lung 0 . 2 7 pCi kg" ( 1 0 mBq kg" ), liver 0 . 5 7 pCi — 1 — 1 1 1
kg"" ( 2 1 mBq kg" ), lymph nodes 1 . 3 5 pCi kg"* ( 5 0 mBq kg" ) and vertebrae —1 —1
0 . 2 3 pCi kg ( 8 . 5 mBq kg ). Levels in the kidneys and gonads were less
than the minimum recorded level ( 0 . 0 1 1 + pCi ( 0 . 5 mBq) per sample analysed).
The values for lung, liver and vertebrae are all within a factor of 2 or 3 .
Although measurements of total lymph node concentrations mask variation
between individual nodes the concentration of plutonium in them is about
5 times that found in the lungs. The variations found between the
different tissues are considerably less than those found in occupationally
exposed workers. 1+. Excretion
Estimates of the systemic body content of plutonium are normally made
from measurements of the daily excretion of plutonium in the urine.
Analysis of the data is based upon measurements made in the United States
IT
of urinary excretion of plutonium in 1 8 patients of relatively short life
expectancy who were intravenously injected with known amounts of plutonium
citrate or nitrate (Langham et al, 9 5 0 ; Langham, 1 9 5 7 ) . The studies were
under-oaken between 1 9 U 5 and 1 9 U 7 and 0 . 0 1 ; to 5 - 9 H c i 0 -5 t o 2 1 8 k B (l) o f
plutonium were injected. In the original analysis of data on 1 6 of the
patients Langham et a l , ( l 9 5 0 ) noted that? severe limitation m their use was
that only k cases were followed beyond H4O days after injection and only
two beyond 2 0 0 days (a series of U consecutive samples were collected from
the 5 2 3 r d and 1 6 1 0 t h day in one case - HP6 and from 1 6 1 0 days in the second
case - HP3). The data were therefore adjusted by including excretion data
from laboratory personnel accidentally contaminated with plutonium to
extend the excretion curve to 1 7 5 0 days. The adjusted expression was
Yua = 0 . 2 0 X~°'lk
where Yua is the percent of the injected dose excreted in a single
day and X is the time of observation in days post-injection.
Durbin ( 1 9 7 2 ) has recently reviewed the data from these studies and
discussed the limitations in its use. Apart from the short periods of
sample collection the data were collected after intravenous injection of
plutonium citrate or nitrate and this is not a normal route of occupational
exposure. In I4 cases hexavalent plutonium was injected which appears to be
more readily excreted than tetravalent plutonium. Also many of the
patients were severely ill with abnormal metabolism.
Durbin ( 1 9 7 2 ) used the plutonium excretion data given by Langham et al,
( 1 9 5 0 ) to obtain a five component exponential curve for urinary excretion
of plutonium thought to be representative of an adult human in reasonably
good health.
The plutonium excretion data reported by Langham et al, ( 1 9 5 0 ) have
also been modified by Beach and Dolphin (I96I4.) to take account of movement
from the lung as follows:
Y u = (b - 1 ) 0 . 1 6 Jr~b (x- tr0-68 d-\r
where Y^ is the urinary excretion rate expressed as a percentage of
the plutonium intake, is a function of time representing the transfer
of plutonium from the lung to the body, t is in days since contamination
and b is a constant.
To use this formula, a value of the function representing transfer
into the body, b, must be assigned if possible from knowledge of the intake
conditions.
18
Although these formulae are adequate for representing the excretion of
plutonium for short times after exposure the results from autopsy analysis
and from observation on occupationally exposed persons have shown that
their use at late times can lead to an over-estimation of the systemic
burden of plutonium, by up to a factor of 5 or more, (Lagerquist et al,
1 9 7 3 ; Maclnroy, 1 9 7 6 ; Popplewell, 1 9 7 7 ) .
Recently it has been found that of the 1 8 individuals given injections
of plutonium in 1 9 U 5 - 1 9 U 7 > 8 survived for eight years and 1+ are still
alive (Rowland and Durbin, 1 9 7 6 ) . The causes of death of 1 3 of these
individuals have been determined from death certificates and none appear
to be related to the administered plutonium. Rundo et al, ( 1 9 7 6 ) measured
the excretion of plutonium in the faeces and urine in some of the subjects.
For two subjects who had been injected intravenously with tetravalent
plutonium-239 as the citrate compound the urinary excretion rates were 7 . 6
and 1+.7 pCi ( . 2 8 and . 1 7 Bq) per day at approximately 1cA days after
injection. These rates corresponded to 2 . 5 2 x ^0~•tyo and 1 .1+1 x 1 0 " ^ of
the injected doses per day respectively. The faecal excretion rates were
about 1+0% of the urinary rates. These observed urinary excretion rates
were approximately an order of magnitude higher than those predicted by
Langham1s equation, and the estimated total excretion was 2 to 3 times
higher than the predictions obtained by integrating Langham1 s equations
for both urinary and faecal excretion (Langham et al, 1 9 5 0 ; Langham, 1 9 5 7 ) .
These results may therefore go some way to explaining over-estimates of
plutonium burdens from bioassay data.
In summary, body content estimates based on Langham1s equation are
likely to be an over-estimate of the true content at late times but many
more autopsy data correlated with urinary excretion data are required
before Langhamfs equation can be confidently amended or replaced.
5 . Effects
Voelz ( 1 9 7 5 ) has reviewed published information on the biological
effects of plutonium in man and concluded that no significant harmful
effects have been seen that can be definitely attributed to this radio-
nuclide. The only clinical or pathological finding reported has been the
development within a few months to several years of fibrous nodules around
the site of plutonium deposits of between about 1+ and 2 0 0 nCi ( 0 . 1 5 and
7 . 1 + kBq) in wounds. Eight cases have been reported (Lushbaugh et al, 1 9 ^ 7 )
which describe nodules not unlike those formed as a result of a foreign body
reaction. One of these lesions developed in the skin of the palm of the
19
hand of a person who had received a puncture wound contaminated with
plutonium four years previously. At the time of the excision the site
still contained 5 nCi ( 0 . 1 £ kBq) of plutonium-239 (Lushbaugh and Langham,
1 9 6 2 ) . Although the lesion was small the basal cells of the epidermis were
atrophic and dyskeratotic. The changes were similar to known precancerous
epidermal cytological changes but any potential development of the lesion
was prevented by its surgical excision. This is normal practice in the
case of superficial puncture wounds. Schofield ( 1 9 7 6 ) has reported that
at Windscale local deposits of alpha emitting radionuclides are surgically
removed if they are in excess of about 1+ nCi ( 0 . 1 5 kBq). A case of
synovial carcinoma allegedly associated with the handling of a leaking
carboy (Tamplin and Cochran, 1 9 7 U ) was not associated with a confirmed
plutonium intake, which would be a necessary prerequisite for establishing
a casual relationship (Voelz, 1 9 7 5 ) •
The most comprehensive follow-up available on workers exposed to
plutonium is that reported by Hempelman et al, ( 1 9 7 3 ) on 2 6 workers who worked
on the Manhattan Project at Los Alamos between 191+3 and 19^4-5- They were
exposed predominantly to aerosols of plutonium when they were involved in
purification and extraction of the metal. Despite uncertainties in body
content estimates exposures were estimated to be between 5 nCi and 1+20 nCi
( 0 . 1 9 and 1 5 - 5 kBq). The only observed signs of ill-health in the exposed
group were those that might be expected in any similar group of unexposed
United States males of this age. One of the men (aged 3 8 ) died of coronary
heart disease while another has recovered from a coronary. This study has
recently been extended and will include a further 2 3 2 persons with
estimated body contents of plutonium in excess of 1+ nCi ( 0 . 1 5 kBq).
In the United Kingdom the National Radiological Protection Board has
set up a National Registry for Radiation Workers. On the Register workers
that have been exposed to plutonium will be noted.
At the British Nuclear Fuel (BNPL) reprocessing plant at Windscale
(Cumbria, United Kingdom) where large quantities of radioactive materials
including plutonium, are processed each year, 11+ workers have an estimated
body content of plutonium of over a maximum permissible body burden (MPBB
= 1+0 nCi ( 1 . 5 kBq.))> mostly resulting from exposures during the first 1 0
years of operation of the plant. There are also 21+ workers with between
50% and 1 0 0 % of one MPBB. No pathological findings can be related to
exposure to plutonium in any of these cases (Schofield, 1 9 7 6 ) . In a recent
court action in the United Kingdom (November 1 9 7 7 ) it was agreed by BNFL
20
and the plaintiffs that, on the balance of probabilities in view of the
special factors in the case, the death from myeloma of an ex-radiation
worker who had been previously employed at BNEL, Windscale, was induced
by radiation at work. The factors included the dosages of irradiation
received and the amount of plutonium within his body, the latter of which
unusually, exceeded the prescribed international limit ( U O nCi ( 1 . 5 k Bq))
and some evidence of a causal relationship between myeloma and radiation.
In an opinion of the case by Dolphin (1 9 7 7 ) 9 it was noted that the man's
exposure history was both to external radiation and to plutonium. It was
likely that the myeloma had been induced by external radiation, the
plutonium contributing little to the risk.
6. Summary
A limited amount of information on the metabolism and effects of
plutonium and other actinides has been obtained from studies of
plutonium workers. The data is difficult to interpret because
many workers are also exposed to external radiation and possibly
to other internally incorporated radionuclides. Prom the small number
of workers who have incorporated plutonium and other actinides there
is no evidence of life shortening or malignant disease which can be
attributed to these intakes. The total number of persons in the
Nuclear Industry is increasing annually and long term follow-up
studies of those exposed to plutonium and higher actinides could
provide valuable information. A centralised system for the collec-
tion of such data in Europe would facilitate its use for improving
the basis upon which standards of protection are determined.
Chapter 4
METABOLISM IN ANIMALS
1. Introduction
In the last 3° years extensive animal studies on the metabolism of
plutonium have been published by workers in many countries including
France, The Federal Republic of Germany, the UK, USA and USSR. This work
has recently been reviewed in a number of publications: ICRP ( 1972b) , Bair
et al, ( 1 9 7 3 ) , Vaughan et al, (1973)> Bair ana Tnompson (197U), Bair (1971+a),
Bair et al, (197U), Dolphin et al, (197U), Durbin ( 1 9 7 5 ) , Bair ( 1 9 7 6 ) .
Animal studies have also been conducted on the metabolism of the higher
actinides americium and curium although data available are considerably
less extensive than for plutonium. This work has been reviewed by ICRP
(1972b) , Durbin (1973) and Bair ( 1 9 7 6 ) .
The object of this chapter is to review data on the metabolism of
plutonium, americium and curium, in animals that may be used to predict
their behaviour in man. However the levels of activity administered to
animals have frequently been greatly in excess of those likely to be
encountered in cases of human contamination, other than in the most severe
accident situations. The amount of actinide deposited in a tissue can
markedly influence its subsequent behaviour and therefore data from
animals given large amounts of activity must be interpreted with caution.
Where appropriate, some human data have also be included in this review.
2. Entry into the body
2.1 Routes of entry
Radioactive materials may enter the body either by inhalation, by
ingestion, through cuts, abrasions or other wounds, or by absorption
through the intact skin.
In the case of actinides any intake may be considered to consist of
two different fractions. Firstly a soluble (transportable) fraction that
rapidly enters the systemic circulation and is either deposited in tissues
or excreted. Although the size of this fraction depends upon the physico-
chemical form and on the route of entry in general its tissue distribution
and retention does not. Secondly there is a relatively insoluble (poorly
transportable) fraction due either to the formation of colloids after the
hydrolysis of soluble forms of actinides (eg, nitrate) at the site of entry
or resulting from an intake of actinide particles such as the oxide. A
number of physical and chemical factors influence the behaviour of this
21
22
second fraction. Polymers are formed more readily from plutonium compounds
than from the higher actinides (Chapter 2 ) and the extent of colloid
formation is also influenced by the mass of actinide deposited. For equal
activities of plutonium-239- plutonium-238, americium-2Ul and curium-2L|.2
deposited in a tissue the relative masses are 1 : 0 . 0 0 3 6 : 0 . 2 : 0 . 0 0 0 0 2
respectively and plutonium is therefore much more likely to form polymers.
In the case of intakes of particles of plutonium-239> plutonium-238,
americium-2i;1 and curium-22+2 the relative specific activities are approxi-
mately 1 : 3 0 0 : ^ 0 : 5 U » 0 0 0 respectively. The particles with a higher specific
activity would be expected to break up more readily in tissues as a result
of radiolytic activity. Radiolytic activity may also help to mobilise
americium and curium from any polymers formed in tissues.
When large amounts of activity are deposited, giving a high local dose
of radiation, fibrosis may develop preventing its transport to other
tissues. This may occur particularly at wound sites (Lushbaugh and Langham,
1 9 6 2 ) .
2 . 2 Inhalation
Retention in the lungs
Inhalation is the most likely route of accidental intake of signifi-
cant quantities of plutonium in man (Voelz, 1 9 7 5 ) • This would also be
expected to be the case for americium and curium. These actinides may be
deposited in the respiratory system either individually or in combination
with other active or inactive materials. It is important therefore to
understand factors influencing their deposition in and 'learance from the
lung both as individual species and as mixtures.
Animal experiments have shown that the regional deposition of an
aerosol in the respiratory system depends mainly on the particle size
distribution. The chemical form of the compound inhaled influences the
subsequent clearance from the lung (Report of the Task Group on Lung
Dynamics, ICRP, 1 9 6 6 a ) .
Lung retention curves for inhaled actinides in both man and animals
have generally been fitted by either two or three exponentials or a power
function. Within the first few days after exposure a fraction of the
deposited activity is rapidly cleared from the respiratory tract. In the
case of insoluble compounds such as plutonium dioxide the majority (> 99%)
of this fraction is activity deposited in the upper regions of the
respiratory tract which is subsequently cleared by the mucociliary
escalator up the bronchi and trachea swallowed and excreted in the faeces.
23
For soluble actinide compounds some activity is also rapidly translocated
to the blood. The first phase of clearance has a half-time of about one
day (Morrow et al, 1 9 6 7 ) .
Particles deposited in the pulmonary region of the lung and in the
terminal bronchioles below the ciliated epithelium are cleared slowly. In
a survey of published data on in vivo and bioassay measurements after
plutonium dioxide inhalation in large animals and man, Watts ( 1 9 7 5 ) showed
that the slower component of retention could be described by two components
with half times of 30 days and 5 0 0 days. The overall retention R(t) with
time (t) was described by the equation:-
R(t) = A exp ~ ( 2 ^ 2 S ) + B exp ~ ^ > + C exp "
The relative proportions of the three components A, B and C depend
considerably on the particle size distribution and the physico-chemical
form of the inhaled aerosol and therefore cannot be specified.
The retention half-time for the slower component of retention of
plutonium dioxide in the lungs of smaller animals varies from about 1 5 0 to
5 0 0 days in rodents and 2 0 0 to 1 2 5 0 days in dogs (Bair, 1 9 7 6 , Buldakov
et al, 1 9 6 9 ) . In the dog studies lung retention half-times of 1 0 0 0 days or
longer have been found following initial lung deposits of from 0 . 2 uCi
( 7 . 1 ; kBq) to about 5 0 uCi ( 1 . 9 MBq) of plutonium dioxide (Park et al, 1 9 7 2 ) .
These levels of activity may have influenced clearance mechanisms. In the
hamster alveolar clearance of plutonium dioxide is known to be inhibited
with an increase in the initial lung deposit (Sanders, 1 9 7 6 a ) .
The mechanism of clearance of these slower phases from the terminal
and respiratory bronchioles and alveoli is not clear but involves the
rapid phagocytosis of particles by alveolar macrophages which are
eventually cleared up the ciliary escalator or to lymph nodes. Some
material is also solubilised and translocated to the blood. The localisa-
tion of plutonium particles within macrophages has been demonstrated in
autoradiographs prepared from sections of lung tissue (Sanders, 1 9 6 9 ) . It
has been suggested that plutonium particles not phagocytosed by these cells
are found in type I alveolar wall cells (Sanders and Adee, 1 9 7 0 ) . However,
recent studies by Brightwell and Ellender ( 1 9 7 7 ) in hamsters have shown
that 90% of an initial lung deposit of plutonium dioxide can be removed
from the lungs by bronchopulmonary lavage (Chapter 8 ) and that most of this
activity (> 90%) has been accumulated by macrophages. Uptake of plutonium
particles by alveolar wall cells is therefore probably not of great
2k
significance.
The temperature of formation of inhaled plutonium particles affects
the retention of plutonium in the lung. This is illustrated by the
results shown in Table 1 + . 1 . At temperatures of 900°C or 1 1 5 0°C the
retention half-time of plutonium dioxide prepared from the chloride is
similar to values reported by Bair ( 1 9 7 6 ) for beagle dogs exposed to
plutonium dioxide. With lower temperatures of preparation the retention
half-times are more like those found for soluble plutonium compounds
(Mewhinney et al, 1 9 7 6 a ) . These changes are due to differences in solu-
bility of the aerosol caused by differences in the chemical form of
plutonium produced by heat treatment. At 325°C "^ne aerosol particles
would consist of a mixture of plutonium chloride, oxychloride and plutonium
dioxide. At higher temperatures of preparation the production of plutonium
dioxide, would be favoured. Particle size itself also influences retention.
For oxides of various sized particles calcined at similar temperatures
retention half-times are generally less for aerosols with a smaller part-
icle size distribution (Bair et al, 1 9 6 3 ) .
Following the inhalation of more soluble compounds of plutonium there
is a greater transfer of activity to the blood resulting in a faster rate
of clearance from the lung. The retention half-times for plutonium inhaled
as organic complexes, nitrate of fluoride range from about 30 to 3 0 0 days
in rats, hamsters and dogs (Buldakov et al, 1 9 6 9 , Bair, 1 9 7 6 ) .
Americium and curium compounds are generally cleared from the lungs
of rats and dogs more rapidly than plutonium compounds. Figure U . 1 shows
data obtained by Nenot et al, ( 1 9 7 2 ) in rats that had inhaled plutonium-
2 3 8 , plutonium-239> americium-2i+1 or curium-2l|.2 as the nitrates. Clearance
of both americium and curium was more rapid than plutonium. This may result
from the lesser tendency of americium and curium to form polymers in the
lung than plutonium and a greater rate of solubilisation of any polymers
that are formed. Figures U . 2 , 1+.3 and k»k show autoradiographs of sections
of lungs of rats exposed to americium, curium and plutonium nitrates.
These autoradiographs show the formation of plutonium polymers in the lung.
Alpha activity due to the presence of both americium and curium is more
uniformly distributed throughout the lung tissue.
Figure shows data obtained from studies in beagle dogs of the lung
retention of oxides of plutonium, americium and curium and also curium
chloride. Both americium and curium leave the lung more rapidly than
plutonium with little difference apparent in the pulmonary retention of the
Table
U.1
Distribution of plutonium in tissues of Beagle Dogs
56 days after inhalation of plutonium aerosols
Compound
Particle
Size
(MAD)
No. of
dogs
Percent of initial lung deposit
Tj of
Lung
Retention
(days)
Compound
Particle
Size
(MAD)
No. of
dogs
Lung
TBLN
Liver
Skeleton Urine
Faeces
Tj of
Lung
Retention
(days)
Plutonium
-239 dioxide
(3
25°C)
a
1.9
P
3 5k
o.
k 5
.9
7.6
1
.2
30
180
Plutonium
-239 dioxide
(6
00°C)
a
1.9
P
3 67
0.
6 1
.3
2.1
0.7
28
3U
0
Plutonium
-239 dioxide
(9
00°C)
a
1.9
P
3 80
o.
k ND
0.2
0
-3
19
> 5
00
Plutonium
-239 dioxide
(H
50°C)
a
1.9
P
3 87
ND
0.2
o.
h 11
>
50
0
Plutonium
-238 dioxide
(1
150°
C)
1.9
m
3 81
h.
2 0
.9
2.3
o.
k 9
.0
> 5
00
| Plutonium
-238 dioxide
(1
150°
C)
1.3
P 3
88
3.5
1
.0
2.2
0
.1
k.o
250
AMAD
Activity median aerodynamic diameter of the aerosol
TBLN
Tracheo-bronchial lymph nodes
ND
Activity not detected
p
Poly disperse aerosol, geometric standard deviation >
1.2
m
Mono disperse aerosol, geometric standard deviation <
1.2
a
Prepared by heating plutonium chloride at various temperatures
Ref: Mewhinney et al,
(1
97
6a)
25
. 2 6
1 0 0
ue
pjn
q
6u
n|
)D 1
1;u i
jo %
D a y s p o s t i n h a l a t i o n
Figure 1+.1 Retention of actinides in the lung after their inhalation as
nitrates (pH 1 . 5 ) . Redrawn from Nenot et al, ( 1 9 7 2 ) .
"Reproduced from Health Physics Vol. 2 2 , p. 6 5 9 , 1 9 7 2 , by
permission of the Health Physics Society."
27
Figure i+.2 Autoradiograph of a section of rat lung 7 days after inhalation
of americium-2U1 nitrate (Provided by R. Masse, Commissariat a
l'Energie Atomique, France).
28
Figure I 4 . 3 Autoradiograph of a section of rat lung 7 days after inhalation
of curium-2UU nitrate. (Provided by R. Masse, Commissariat a
l'Energie Atomique, France).
29
Figure U - U Autoradiograph of a section of rat lung 7 days after inhalation
of plutonium-239 nitrate. (Provided by R. Masse, Commissariat
a l'Energie Atomique, France).
30
1 0 0
2 3 9 Pu(N0 3 )£
0 1
2 U
C m C l 3 •
C m O 1 ? 3
_L
2 3 9 P u O o - 3 5 0 ° C
JL 4 0 0 8 0 0
T i m e a f t e r e x p o s u r e , d a y s
1 2 0 0
Figure U - 5 Lung retention of inhaled transuranic elements in beagle dogs.
Redrawn from McClellan et al, ( 1 9 7 2 c ) . "Reproduced from Health
Physics Vol. 22, p. 817 , 1972, by permission of the Health
Physics Society."
%
of
Init
ial
lun
g
bu
rd
en
o
o
31
two forms of curium. Similar results for the lung retention in dogs of
oxides of americium and curium have been obtained by Craig et al, ( 1 9 7 6 ) .
These results would be anticipated from the differences in solubility and
specific activity of the various oxides. It has also been shown that in
water particles of americium are unstable and become amorphous on ageing
(James et al, 1 9 7 8 ) .
The majority of experimental studies on the retention of actinides in
the respiratory system have used single actinide preparations in isolation.
In practice humans would normally be exposed to mixtures of actinides
either alone or in combination with fission products or other metals.
There is however little published work on the retention of such mixtures.
Data summarised by Bair ( 1 9 7 6 ) on the retention of americium and
plutonium in dogs after their inhalation in particles consisting of
mixtures of the oxides showed that separation of americium from plutonium
in the lung was barely detectable as long as 6 years after inhalation.
Studies in hamsters have also demonstrated that following the inhalation
of particles containing oxides of both plutonium and americium (americium
1 0 % by activity, 0 . 1 8 % by mass), the lung retention of the two nuclides
does not differ significantly up to a year after inhalation. With mixed
oxide aerosols of plutonium, americium and sodium oxides the amounts of
plutonium and americium translocated to the blood may increase by more
than a factor of a hundred but the lung retention of both nuclides is
similar (Stather et al, 1 9 7 7 b ; Brightwell and Carter, T 9 7 7 ) .
Some work has been reported on the retention of caesium-137 in the
lungs of beagle dogs following inhalation incorporated in fused alumino-
silicate particles (Boecker et al, 1 9 7 7 ) . The particles were relatively
insoluble in biological fluids and there was little leaching of caesium-137
from the particles. Actinides fused into such an insoluble matrix might be
expected to behave similarly.
The limited data available therefore suggest that following the
inhalation of particles consisting of mixtures of actinides either alone or
in combination with other materials the retention of actinides in the lung
will be influenced by the species present in greatest mass and its chemical
form.
Translocation from the lung to other tissues
Following deposition of actinides in the respiratory system the
activity may be removed by a number of processes. A fraction enters the
blood directly from the lungs after dissolving in tissue fluids. This
32
activity is either transported to other tissues, principally liver and
bone, or it is excreted. A second fraction is accumulated by macrophages
which are cleared from the lung by bronchial and tracheal clearance
mechanisms, swallowed and excreted. A third fraction is translocated via
the lymphatics to regional lymph nodes and some of this material may
ultimately reach the systemic circulation.
The amount of the soluble fraction entering the blood from the lung
either in the first few days after inhalation or as a result of a progres-
sive solubilisation of polymers or particles depends considerably upon the
chemical form of the inhaled material and in the case of relatively insolu-
ble aerosols such as plutonium dioxide on the particle size (Bair et al,
1 9 7 3 , Stather et al, 1 9 7 5 , Stradling et al, 1 9 7 7 ) . However, the distribu-
tion of actinides in the body following their entry into the systemic
circulation is in general independent of the physico-chemical form deposited
in the lungs.
Table 1+.2 shows the results from studies in which the distribution of
plutonium in extrapulmonary tissues of the rat was measured following the
pulmonary intubation of solutions or suspensions of various plutonium
compounds that had passed through a filter with a pore size of 1 0 0 nm or
less. In the case of citrate and nitrate forms more than 90% of the
original preparation passed through the filter but for a plutonium dioxide
suspension the comparable value was about 0 . 2 % . Despite these differences
the transportable fraction of each preparation distributed between the liver
and skeleton in a manner similar to that found for intravenous plutonium
citrate. It has been shown that measurements of the ultra-filterable
fraction of plutonium in an aerosol suspension can be used to give an
estimate of the transportable fraction of the aerosol (Kanapilly et al, 1 9 7 3 ,
Stather et al, 1 9 7 5 , Miglio et al, 1 9 7 7 ) .
The distribution of plutonium in the tissues of dogs and rats exposed
to two relatively soluble forms of plutonium (the citrate and the nitrate)
is shown in Table U . 3 « There is little retention in the thoracic lymph
nodes but appreciable amounts of activity are deposited in other extra-
pulmonary tissues. Because the major sites of deposition of plutonium
that has entered the systemic circulation are the skeleton and the liver
only the activity in the liver is given separately. The results in both
dogs and rats show that plutonium is more transportable in the lung when
administered as citrate than as nitrate probably as a result of the more
rapid hydrolysis of plutonium nitrate at physiological pH to form relatively
Table fr.g
d .
Tissue distribution of plutonium
in rats one week after pulmonary intubation in various chemical forms
Compound
No.
of
Animals
Pore size
of
filter (nm)
Percentage of
solution or
suspension
passing filter
(#)
% Administered Activity
Ref
Compound
No.
of
Animals
Pore size
of
filter (nm)
Percentage of
solution or
suspension
passing filter
(#)
Lung
Liver
Skeleton and
other soft
tissues
Total tissue
deposit (T)
x
10
0 (o
/o)
Ref
Plutonium dioxide
3.
h 10
0 0.
3k
59
.2
3.5
1
8.6
22
.1
15
.8
A
Plutonium dioxide
3.
8 10
0 0
.16
U3-
5 U
.2
27
.8
32.0
1
3.1
A
Plutonium nitrate
6 25
96
5
2.2
6
.5
30.8
2
7.3
1
7.
k A
Plutonium citrate
6 25
99
1
5.9
1
1.2
5
8.^
69
.6
16
.1
A
Plutonium dioxide
+ sodium oxide
a> ^
6 25
5k
5^
.9
3.1
15
.5
18
.6
16
.7
A
Plutonium citrate
0
6 25
99
0
.16
12
.9
69
.2
82.1
1
5-7
B
U)
a
Filtered aerosol suspension
b
Atomic ratio of plutonium and sodium in mixed aerosol
1
:19
.2
c
Administered by intravenous injection
d
Plutonium
-239
Re
f: A. Stather et al,
(1
97
5)
B. Stather and Howden
(1
97
5)
Table
U
* 3
Distribution of plutonium after inhalation as nitrate or citrate
Compound
Species
% Plutonium Administered (see footnote)
Reference
Species
Time
(days)
Lung
TBLN
Liver
Skeleton plus
other soft tissues
Faeces Urine
Reference
Dog
1 Ik
0
.05
1.U
6
Ballou and Park,
19
72
Dog
30
37
0.2
0 5
.3
38
10
0 29
o.
l+o
16
38
Rat
1 27
_
9.5
U
5 Stather and Howden,
19
75
28
9 -
U.3
59
1
82
1.8
-
2.5
58
Dog
1 88
0
.06
0.3
2 1
.8
Ballou and Park,
19
72
Dog
30
32
0.1+
9 U
3 1
00
U1
0.6
10
28
Rat
1 78
_
1.8
3
-2
0 0
Morin et al,
19
72
Rat
30
U0
-1
.0
7.7
1+
2 9
.2
90
1$
-0
.3
1+.1+
69
11
Rat
1 9
6 0.6
1.9
0
0.2
Morin et al,
19
72
Rat
30
53
-2
.2
18
.1
2k
2.5
Rat
30
32
-1
.5
11
Ballou,
19
75
10
0 12
-
o.5
9
20
0 k
-o.
l+
12
Rat
30
18
2.2
18
Ballou,
19
75
10
0 9
-1
.8
12
20
0 3
-0.6
21
Plutonium
-239 citrate
Plutonium
-239 citrate
Plutonium
-239 nitrate
Plutonium
-239 nitrate
Plutonium
-238 nitrate
Plutonium
-239 nitrate
Plutonium
-238 nitrate
a
% inhaled activity less faecal activity in first 6 days
b
Administered by pulmonary intubation
c
% inhaled activity less faecal activity in first
3 days
initial lung burden
35
insoluble polymers. In all these studies the proportion of the extra-
pulmonary deposit in the liver is relatively low indicating that plutonium
is entering the blood predominantly in a monomeric form (Lindenbaum et al,
1 9 6 8 ) . These results also show that in the dog there is no reduction in
the liver content of plutonium with time but that it is rapidly cleared
from the rat liver. Because of rapid loss of plutonium and other actinides
from the rat liver long term studies in this species are of little value
for extrapolation to man.
A number of other chemical forms of plutonium have also been studied.
Sodium plutonyltriacetate, ammonium plutonium pentacarbonate, plutonium
chloride (Lyubchanskii, 1 9 ^ 7 ) and plutonium oxalate (filtered through a
2 5 nm filter) (Stather and Howden, 1 9 7 5 ) all behave as relatively soluble
forms of plutonium in rats after their deposition in the lungs. When
administered as the fluoride to dogs plutonium was less readily translocated
to the blood ( 0 . 7 5 % of the initial lung deposit of plutonium was in extra-
pulmonary tissues at 9 0 days), although there was an appreciable deposit in
the tracheobronchial lymph nodes ( U - 5 % at 9 0 days) (Dilley, 1 9 7 0 ) .
Following the administration of a complex of plutonium with the
chelating agent diethylene triamine pentaacetic acid (DTPA) to rats by
pulmonary intubation only 0 . 5 % of the initial lung deposit of plutonium
remained in the lung at 7 days and less than 1 % in the extrapulmonary
tissues (Stather and Howden, 1 9 7 5 ) - This is a consequence of the high
stability of the chelate complex in body fluids and the rapid excretion
of DTPA in the urine.
Extensive information is available in the literature on the distribu-
tion of plutonium in animal tissues following the inhalation of plutonium
dioxide. With few exceptions these studies have shown the low solubility
of plutonium dioxide in the lung (ICRP, 1 9 7 2 b ) . The most comprehensive
data have been obtained in beagle dogs exposed to plutonium dioxide aerosols
with a mass median diameter of about 3 jjm (Park et al, 1 9 7 2 ) . Initial
alveolar deposits varied between less than 1 jiCi and about 5 0 ^iGi ( < 3 7 kBq
to about 1 . 9 MBq).
By 2 years after exposure the liver and skeleton each contained about
1 % of the initial alveolar deposit and the thoracic lymph nodes about 1 0 %
(Figure U « 6 ) . By 1 0 years, about 5% of the activity had translocated to
the skeleton, 1 5 % to the liver and 50% to the thoracic lymph nodes. The
relatively higher level of plutonium in the liver than in the skeleton
after about k years may have resulted from radiation damage to the lungs
36
TIME AFTER EXPOSURE, YEARS
Figure ij.,6 Retention and translocation of alveolar deposited plutonium-239
oxide in beagle dogs. Redrawn from Bair ( 1 9 7 6 ) .
239P
u
CO
NTE
NT
OF
TIS
SU
ES
(% O
F A
LV
EO
LA
R-D
EP
OS
ITE
D 239P
u0
2)
3T
allowing the entry of particles of plutonium directly into the blood or
alternatively some translocation from either bone or lymph nodes to liver
may have occurred. These studies have now been extended to include dogs
exposed to much lower initial lung deposits. It will, however, be more
than 10 years before the study is completed.
The method of preparation of plutonium dioxide can influence the trans-
portability of plutonium in the lung. Mewhinney et al, (1976a) reported
that the amount of plutonium translocated to extrapulmonary tissues was much
greater following the inhalation of low fired plutonium dioxide than of high
fired plutonium dioxide (Table U . 1 ) . Bair (l97Ub) has also reported studies
on beagle dogs that had inhaled plutonium dioxide prepared by heating either
the oxalate or the metal at different temperatures. Although all forms of
plutonium dioxide showed a low transportability in the lung the transport-
able fraction and the activity deposited in the tracheobronchial lymph nodes
varied considerably for different methods of preparation.
Other elements can also influence the behaviour of plutonium dioxide
in the lung. A series of studies have been reported on the lung clearance
of plutonium in rodents following their exposure to mixed aerosols of
plutonium and sodium oxides produced by an exploding wire technique
(Stather et al, 1975; Brightwell and Carter, 1977; Stather et al, 1 9 7 7 ) .
These studies have shown that with an excess of sodium the transportable
fraction of plutonium may be increased to values characteristic of relat-
ively soluble forms of plutonium (Table U.U). Figures !+• 7 and LL.8 show
autoradiographs of sections of lungs from hamsters that had inhaled either
an aerosol of plutonium dioxide particles or a mixed aerosol of plutonium
and sodium oxides (both aerosols had an activity median aerodynamic diameter
(AMAD) of about 1 0 3 Lim and a geometric standard deviation (GSD) of about
1 . 5 ) . In the lungs of animals exposed to plutonium dioxide the majority
of the activity is present as discrete particles but in animals that had
inhaled the mixed oxide aerosol a large proportion of the activity is
diffusely distributed throughout the lung volume indicating breakdown of
the inhaled particles. Filtration studies on aqueous suspensions of mixed
oxide aerosols have shown that the particle size distribution of plutonium
decreases with increasing sodium content of the aerosol. At sodium:
plutonium atomic ratios in excess of about 20:1 up to 50% of the plutonium
is in particles less than 100 nm in diameter whereas in an aqueous suspen-
sion of plutonium dioxide the comparable value is about 0.2% (Stather et
al, 1975 ; Brightwell and Carter, 1 9 7 7 ) . The particles of plutonium passing
the 100 nm filter have been shown to be about 1 nm in diameter and to
Table
k*
k
Distribution of plutonium in tissues of rodents after inhalation
c
or pulmonary intubation of various plutonium compounds
Compound
Species
Time after
exposure
(days)
Method of
administration
% Initial Lung Deposit
Reference
Compound
Species
Time after
exposure
(days)
Method of
administration
Lung
Extra Pulmonary Tissues
Reference
Plutonium dioxide
Rat
8U
Inhalation
11+.
8 0
.15
A
Plutonium citrate
Rat
91
P.I.
h.k
63.8
B
Plutonium nitrate
Rat
91
P.I.
9.6
ho
.Q
B
Plutonium dioxide
+ sodium oxide
3.
Rat
8h
Inhalation
5.7
3.
6 A
Plutonium dioxide
+ sodium oxide
a
Hamster
90
Inhalation
2h
26
C
P.I.
Pulmonary intubation
a
Atomic ratio plutonium:sodium in aerosol suspension
1:
20
c
Plutonium
-239
References: A. Stather et al,
(1
97
5)
B. Stather and Howden
(1
97
5)
C. Stather et al,
(1
97
7)
38
39
Figure 4.7 Autoradiograph of a section of hamster lung 6 months after
inhalation of an aerosol of plutonium dioxide. (Provided by
J. Brightwell, National Radiological Protection Board, U.K.)
ho
Figure 1+.8 Autoradiograph of a section of hamster lung 6 months after
inhalation of an aerosol of plutonium dioxide and sodium oxide
(Plutonium: Sodium atomic ratio 1:10J+)- (Provided by
J. Brightwell, National Radiological Protection Board, U.K.)
1+1
readily cross the lung cell membrane, subsequently dissolving in the blood
and behaving as soluble plutonium (Stradling et al, 1 9 7 7 ) . Particles of
this size can readily dissolve as about 90% of the atoms in the particle
are at the surface (Chapter 2 ) .
These results indicate, therefore, that in mixed oxide aerosols of
plutonium and sodium the high biological transportability of the plutonium
is predominantly due to the decreased particle size distribution of the
plutonium dioxide. Metivier (1976) has also suggested that in aerosols
produced by the combustion of plutonium and sodium in the presence of
oxygen some plutonium may be present as Pu(Vl) or Pu(VIl) and this may
influence the transportability of the plutonium in lung.
A number of studies have compared the tissue distribution of plutonium
following the inhalation of plutonium dioxide prepared from either
plutonium-238 or plutonium-239. In rats exposed to aerosols of plutonium-
238 dioxide or plutonium-239 dioxide with similar particle size character-
istics there was a greater translocation of plutonium from the lung to the
skeleton and other soft tissues with plutonium-238 (Table 1+.$). Similarly,
in dogs that had inhaled plutonium-238 dioxide between 2 and 6 years
previously the retention of plutonium in the liver and skeleton was about
10 times that found in dogs that had inhaled plutonium-239 dioxide (Park
et al, 1975 a and b). Further data showing the greater transportability of
plutonium-238 dioxide than plutonium-239 dioxide in animals have been
reported by Mewhinney et al, (1976a) (Table U .1 ) and Stather et al, ( 1 9 7 7 b ) .
An increased transportability of plutonium-238 compared with plutonium-239
has also been found in rats following inhalation as the nitrate (Table U«3)«
The increased transportability of plutonium-238 in lung compared with
plutonium-239 may be attributed to the higher specific activity of particles
containing plutonium-238 resulting in radiolytic activity causing more
rapid breakdown and solubilisation of the particles. The occurrence of a
fragmention process for plutonium dioxide particles in water has recently
been discussed by Fleisher and Raabe ( 1 9 7 7 ) .
Less information is available on the translocation of americium and
curium to other tissues. From studies in rats reported by Nenot et al,
(1971b),the translocation to tissues of americium-21+1 inhaled as the
nitrate (Table U.6) can be compared with the values found for plutonium-238
and plutonium-239 (Table U«3)« These results show that americium is
translocated more rapidly from the lung to extrapulmonary tissues than
plutonium. However as the liver deposit of actinides in rats is rapidly
Table
1+
.5
Comparative distribution of inhaled plutonium-238 dioxide and plutonium-239 dioxide in rats
% Body Activity
Plutonium
-238 dioxide
Plutonium
-239 dioxide
Days after exposure
20
127
U81
1
3 68
1
13
Tissue
Thoracic I#mph Nodes
O.h
3.
U 3
.3
0.3
1
.8
-Lung
82
78
68
97
97
99
Spleen
0.1
3 0.
2 0
.5
0 0.
0U
0
Kidneys
0.5
1
.1
0.5
0
0 0
Liver
2.h
1.7
3
.6
0.02
0
.3
0.3
Skeleton
11
.0
15
.0
23.O
0.01
0.
1 0
.16
Terminal Body
Burden (iCi)
9.5
0
.8
0.21
1
2.5
1
.5
0.6
Plutonium dioxide produced by calcining the oxalate in air at
3
50
CMD
2 =
0
.1, GSD was
1
.5-1
-9 for plutonium
-238
, 1
.7-2
.0 for plutonium
-239
Ref: Stuart et al,
(1
96
8)
quoted by Bair et al,
(1
97
3)
k2
Table
U.6
Distribution of americium
-2U
l in rat tissues after inhalation as the nitrate
Time
(days)
% Americium administered
3.
Time
(days)
Lung
Liver
Skeleton
Kidney
Muscle
Urine
Faeces
1 9
5 2
2.1
0.2
0
.2
0.5
0
10
8.7
22
. h
19
.9
1.8
1.3
1
1.5
3
2.7
45
k.k
2.1
18.1
--
10.0
61
.9
90
h.k
1.5
2
2.3
1
.9
-10.8
57
.9
a
% inhaled activity less faecal activity in first
3 days
Ref: Nenot et al,
(1
97
1b
)
^3
kk
lost from the body an accurate estimate of the total amounts of plutonium
and americium translocated to extrapulmonary tissues in these studies cannot
be obtained. This is a particularly important consideration in the case of
americium as about $0% of the activity entering the blood is deposited in
this tissue.
Studies by Crawley and Goddard (1976) on the tissue distribution of
americium following pulmonary administration as citrate showed that about
80% of the administered activity had translocated to extrapulmonary tissues
by one week after administration. This is a value similar to that reported
for plutonium administered as citrate by a similar technique (Stather and
Howden, 1 9 7 5 ) .
It could be expected that soluble forms of curium would behave
similarly to americium as it has been shown by Crawley and Goddard (1976)
and Stather and Priest (1977) that the lung clearance of these two nuclides
when administered as nitrates do not differ significantly.
A number of animal experiments with oxides of americium and curium
have shown they behave as relatively soluble materials in the lung. In
studies by Craig et al, (1976) in beagle dogs about h$% of the body burden
of americium-2[|.1 at 30 days after exposure was in extrapulmonary tissues.
For curium the comparable value was about 80%. The greater solubility of
curium-2i|l+ oxide than americium-2i|1 dioxide may partly be due to the
smaller particle size of the inhaled aerosol and greater specific activity
(Table U - 7 ) . Similar results have been reported by McClellan et al, (1972a)
on beagle dogs exposed to curium-2L|lL oxide. These studies also indicated
that americium and curium are translocated to liver and bone in fairly
comparable amounts. It is noteworthy that in the study by Craig et al,
(1976) about 30% of the extrapulmonary deposit of curium-2l4+ was accumu-
lated by muscle tissue (Table 1+.7). This result cannot be readily
explained.
Figure k*9 shows an autoradiograph of a section of rat lung from an
animal exposed to americium dioxide. Activity is more diffusely distri-
buted throughout the lung than is found for plutonium dioxide indicating
the breakdown of particles of americium dioxide. This no doubt contributes
to the increase in transportability as compared with plutonium dioxide.
Summary
A model for the deposition and retention of inhaled aerosols in the
human respiratory tract was described in the Report of the Task Group
on Lung Dynamics (ICRP, 1966a) for Committee 2 of the International
Table 1+.7
Tissue distribution of americium-2U1 and curium-21+1+ in beagle dogs after inhalation of
a
b
americium-21+1 dioxide
and curium-21+1+ oxide
% Final Body Activity
Tissue
10 days
30 days
90 days
270
days
Americium
Curium
Americium
Curium
Americium
Curium
Americium
Curium
Lung
78
.5
32
.9
55
.4
19
-9
29
.4
18
.0
13
.8
8.1
Liver
4.1
2
9.1
1
8.9
37
.1
38
.8
35
.5
32
.4
33
-6
Skeleton
5.1
18
.1+
10
.9
19
.8
18
.2
29
.7
45
.1
26
.6
Muscle
8.0
1
2.5
1
1.3
1
3.0
9
.9
10
.0
4.4
2
6.7
Other
Tissues
4.3
7
.1
3.5
1
0.2
3
-7
6.8
4
.3
5.0
a
AMAB
1
.35 GSD
1.7
1
b
AMAB
0
.52 GSB
2.
11+
Reference: Craig et al,
(1
97
6)
h5
1+6
Figure 1+-9 Autoradiograph of a section of rat lung 7 days after inhalation
of americium-2l+1 dioxide. (Provided by R. Masse, Commissariat
a l'Energie Atomique, France).
hi
REPORT OF TASK GROUP OF COMMITTEE 2
AMENDED CONSTANTS FOR U S E WITH T G L M CLEARANCE MoDEi/f
Region Pathway
Compound class
Region Pathway (D) (W) 00
N-P (a) 0.01 d/0.5 0.01 d/0.1 0.01 d/0.01 (b) 0.01 d/0.5 0.4 d/0.9 0.4 d/0.99
T - B (c) 0.01 d/0.95 0.01 d/0.5 0.01 d/0.01 (d) 0.2 d/0.05 0.2 d/0.5 0.2 d/0.99
P (e) 0.5 d/0.8 50 d/0.15 500 d/0.05 (0 — 1 d/0.4 1 d/0.4 (g) — 50 d/0.4 500 d/0.4 (h) 0.5 d/0.2 50 d/0.05 500 d/0.15
L (0 0.5 d/1.0 50 d/1.0 1000 d/0.9
(a)
(c)
(e)
(h)
Lymph nodes (L)
Nasopharynx Region (N-P)
Tracheo- bronchial Region (T-B) p-
Pulmonary Region (P)
(b)
(d) - ( f ) -
i (g)
t The first value listed is the biological half-life; the second is the regional fraction.
Figure U - 1 0 ICRP Task Group on Lung Dynamics model for describing the
respiratory tract retention of inhaled particles (as modified
in ICRP Publication 1 9 ) .
G. I.
T R A C T
B
L
O ! i
O
D
1+8
Commission on Radiological Protection and modified in ICRP Publication
1 9 > 1 9 7 2 (Figure 1+.10). In the model the respiratory tract has been
divided into three regions: the nasopharynx, the tracheobronchial
region and the pulmonary region. The regional deposition of an inhaled
aerosol is considered to be primarily a function of the particle size
distribution. The chemical form of the compound inhaled influences
the subsequent clearance from the lung. In the model retention in the
lung can be for days (Class'D), weeks (Class W) or years (Class Y).
The Task Group Lung Model predicts that following the inhalation of
an aerosol of a relatively soluble (Class W) compound (particle size
1 [im AMAD), 1 2 % of the activity will eventually be transferred to the
blood, and for a less soluble (Class Y) compound 5%. Retention is
exponential with half-times of retention of the long term component
in the lung of 5 0 and 5 0 0 days for Class W and Class Y compounds
respectively.
Studies in animals have shown that plutonium compounds generally
conform to this classification - the oxide is Class Y, the nitrate
and citrate are Class W and plutonium complexed with the chelating
agent diethylenetriaminepentaacetic acid (DTPA) is Class D.
Experimental studies have also shown that all compounds of americium
and curium, except for Class D category, but including the oxides,
are retained in the lung with half-time of a few weeks or months and
should be considered to be Class W. Following the inhalation of
particles consisting of mixtures of actinides or actinides in
combination with other elements, the retention in the lung of the
individual actinides will be similar to that of the material present
in the inhaled particles in greatest mass.
2 . 3 Ingestion
The majority of measurements on the gastrointestinal absorption of
actinides in animals have been made after their administration by gavage
(a technique by which solutions or suspensions are administered through a
tube passed into the stomach). Animals are normally given the actinide as
a single dose. Although this method would be expected to give an indication
of the level of absorption of actinides from the gut the large amounts of
activity that have to be administered may have resulted in the formation of
relatively insoluble polymers in the animals stomach causing a reduction in
the potential for absorption. This will be the case particularly for
plutonium administered as the nitrate. More realistic values for actinide
absorption are likely to be obtained from the continuous feeding of small
^9
concentrations of actinide incorporated in the diet.
Some studies on the absorption of actinides from the gut have used
the pig and dog as experimental animals. Most of the available data,
however, concerns uptake in rodents.
Values for the absorption of various compounds of plutonium-239
administered to adult hamsters by gavage are given in Table i |.8. The
amount of plutonium absorbed is greatest when given as the citrate
(1 x 1 0 " 2 % ) . A similar result in rats of 3 x 10"^% has been reported by
Weeks et al, (1956) and a higher value of 9 x 1 0 " % by Baxter and Sullivan
( 1 9 7 2 ) . The absorption of plutonium administered as the nitrate may
depend on its valency. For Pu(lV) nitrate values reported in rats have
varied between 1 x 1 0 _ 2 % and 1 x lO'^/o (ICRP, 1972b) . For Pu(Vl) uptake
of 1.9% was reported by Weeks et al, ( 1 9 5 6 ) . This result needs to be
further substantiated as the Pu(Vl) was fed to fasted animals in the presence
of an oxidising agent and these extreme conditions may have influenced
absorption. Plutonium dioxide is much less readily absorbed from the
gastrointestinal tract.' The value for hamsters in Table U . 8 (3.!+ x 10 % )
is similar to that found by Baxter and Sullivan (1971 ) in rats (6 x 10 % ) .
If plutonium dioxide is ingested as very small particles absorption may be
enhanced. Brightwell and Carter (1975) have shown that following admin-
istration to rats of a suspension of a mixed oxide aerosol of plutonium and
sodium (Pu:Na atomic ration about 1 :87) by gavage absorption of plutonium
was about 1 x 10~ 2 %. In these suspensions about 50% of the activity is in
particles about 1 nm in diameter (Stradling et al, 1977)•
A number of studies have been reported on the absorption of plutonium
incorporated into plant or animal tissues. Sullivan and Crosby (1976)
found that in rats that were fed on minced newborn rats previously
injected with plutonium-238 nitrate the proportion of the ingested
activity deposited in liver and bone (3 x 10"^%) was about a factor of
10 greater than the value found following the administration of plutonium-
238 nitrate solution. In similar studies with plutonium-238 oxide the
deposit in the liver and skeleton (9 x 1 0 ~ ^ of the ingested activity) was
about a factor of 2 greater than for plutonium-238 oxide suspension
administered by gavage. Sullivan and Garland (1977) have reported that
in rats fed plutonium-238 biologically incorporated into alfalfa (by
growth of the plants on soil containing plutonium) there appeared to be
about a tenfold increase in plutonium-238 gut absorption by the rat
(8.1; x 10 ^% absorbed) over the value found following its administration
as the inorganic nitrate. However, the number of animals in the study was
Table
1+
.8
Absorption of plutonium
-239 and americium-
21+1 from the gastrointestinal tract of the hamster
Compound
No. of
animals
Activity-
administered (iCi)
% Absorbed
3,
Plutonium citrate
6 0
.32
1.0
E-0
2
Plutonium nitrate
0.2
5 1
.6
E-0
3
Plutonium dioxide
6 2
.02
3.1+ E
-05
Plutonium in liver
0
6 1
.2
9.5
E-0
3
Americium citrate
13
0.9
0 1
.2
E-0
2
Americium nitrate
11
0.9
5 5
.6
E-0
2
Americium dioxide
6.1+
1 5
.9
E-0
3
Americium in liver
0
6 1
.0
3.5
E-0
3
a
Corrected for activity excreted in urine and faeces
b
Aged in water for
1+ months
c
Obtained from hamsters given plutonium or americium nitrate
1+ days
before being killed
d
3 to
1+ months old
Reference: Stather et al,
(1
97
8)
50
51
small. Similar studies with guinea pigs were inconclusive because of the
small numbers of animals used and a wide variation in results obtained.
The absorption of plutonium-239 from the hamster gut after its ingestion
in liver was 1 x 1 0 " ^ % (Table 1+.8) , a value similar to that for plutonium
citrate.
In young rats the absorption of plutonium-239 administered as nitrate
or citrate is one or two orders of magnitude greater than in adult rats
(Ballou, 1 9 5 8 ; Mahlum and Sikov, 1 9 6 7 ) .
Fewer data are available on the absorption of americium and curium but
both radionuclides appear to be more readily absorbed than plutonium. In
the hamster (Table 1+.8) absorption of americium-21+1 is a factor of 3 5
greater than plutonium after administration as the nitrate and after
administration as the oxide (aged in water suspension) a factor of 1 7 3
greater. Similar results have been obtained in rats and absorption is
again enhanced in young animals (Table 1+.9) . In rats fed on newborn rats
previously injected with americium nitrate the proportion of the intake
absorbed and deposited in tissues at 7 days ( 3 x 1 0 " ^ % ) was approximately
twice that obtained for the inorganic nitrate form (Sullivan, 1 9 7 7 ) . For
americium in liver absorption in the hamster was less than after adminis-
tration as the nitrate (Table U - 8 ) .
The gastrointestinal absorption of actinides appears to be related to
the absorption of iron. Iron absorption is high during growth (Bothwell
and Finch, 1 9 6 2 ) and absorption of actinides has been shown to be greater
in young animals than adults. Iron absorption is increased in iron-
deficient animals and Ragan et al, ( 1 9 7 U ) showed that the absorption of
plutonium citrate was increased by a factor of 1+-5 in iron deficient mice.
Summary
Studies in animals on the absorption of plutonium from the gastro-
intestinal tract have shown that this is not a major route of uptake
in the adult. For soluble plutonium compounds that have entered the
gut the amount of plutonium absorbed may be assumed to be about
1 x 1 0 - 2 % and for insoluble plutonium dioxide particles absorption
may be taken as 1 x 10""^%. Plutonium dioxide particles should be
treated as soluble if they are less than about 5 nm in diameter.
In some circumstances ingestion may become a significant route of
entry of actinides into the body. Americium and curium are absorbed
more readily from the gastrointestinal tract than plutonium and for
all compounds the amount absorbed can be taken to be about 5 x 1 0 ~ ^ % .
Table U>9
Chemical form
Adult rats
Young rats
0
Reference
Chemical form
Number
% Absorbed
3,
Number
% Absorbed
13
Reference
Americium-210 nitrate
11
1.5
E-0
2 8
5 A
Curium-2144 nitrate
1U
i+.O E
-02
7 2
A
Americium
-2U
1 oxide
6
1.3
E-0
2 10
1
.1
A
Curium
-2i4
i oxide
3 3
.0
E-0
3 5
1.7
vA
11
(U.O
E-0
2)C
h (1
.8)°
A
Americium
-2i|1 chloride
3.0
E-0
2 B
Curium-
21+2 chloride
5.0
E-0
2 ' C
a
Calculated as total activity deposited in liver and skeleton
b
Calculated as total activity in femur + liver + residual carcass
(excluding gastrointestinal tract)
c
Values obtained using curium oxide suspended in water for
k months
before administration
References: A. Sullivan and Crosby
(1
97
5)
B. Zalikin et al,
(1
96
8)
C
Semenov
(1
97
1)
52
Absorption of americium and curium from the gastrointestinal
tract of rats
7
days after administration by gavage
53
In young animals absorption of plutonium, americium and curium is
enhanced relative to the adult. Some studies on actinides incorpora-
ted into plant and animal tissues have shown that they may be absorbed
more readily than inorganic compounds but the results that have been
obtained so far are fragmentary and variable. Further studies are
urgently needed on the absorption of actinides from the gastro-
intestinal tract.
2 .1+ Wounds
Wound contamination with actinides has been simulated in animal
experiments by either intradermal, subcutaneous or intramuscular injection.
These studies have shown that both soluble material and particles may be
translocated from the site of deposition. Soluble complexes rapidly reach
the circulation while particles are essentially limited to slower movement
along lymphatic ducts, leading initially to accumulation in regional lymph
nodes. The principal forms of plutonium and higher actinides that have
been studied in animal experiments are the citrates, nitrates and oxides.
Injection as the citrate complex results in rapid translocation. The
amounts of americium and curium cleared by 1+ days after intramuscular
injection were: in rats, 97% of americium-2l+1 (Durbin et al, 1 9 ^ 9 ) and
9 7 . 3 % of curium-2l+2 (Williams et al, 1 9 6 1 ) , in mice 98% to 99% of americium-
21+1 (Parker et al, 1 9 ^ 2 ) and in monkeys 98 .1+% of americium-2l+1 (Durbin,
1 9 6 2 ) . Subcutaneous injection of americium-2l+1 citrate into the paw of
dogs resulted in the clearance of over 90% in the first day and approxi-
mately 9 5 % by the fourth day (Lloyd et al, 1 9 7 5 ) . Rapid clearance is
consistent with the presence of citrate ions in body fluids as natural
complexing ligands for actinides (Popplewell and Boocock, 1 9 6 8 ; Popplewell
et al, 1 9 7 5 ; Stradling et al, i 9 7 6 ) . The rate of clearance from the site
of injection can be expected to be directly related to the tissue fluid
flow at the site of deposition of either americium, curium or plutonium,
provided there is no binding to tissue components or hydrolysis. However,
a greater retention of plutonium after intramuscular injection in rats as
citrate - 1 9 % after 7 days (Taylor, 1 9 7 3 c ) and 18% after 9 0 days (Nenot et
al, 1 9 6 7 ) suggests that some polymer formation does take place despite the
presence of citrate.
The mineral salts of plutonium, americium and curium are stable in
acid solution but are hydrolysed at physiological pH. Clearance from a
wound site therefore depends either upon the formation of soluble complexes
with ligands in the tissue fluid such as citrate and transferrin (see later)
54
or the movement of particles. Although the concentration of many inorganic
ions are about the same in interstitial fluid as in the plasma, plasma
protein concentrations, including transferrin are only about one-sixth
those in plasma (Durbin, 1 9 7 5 ) • If therefore large masses of actinide are
deposited in a wound as soluble salts only a fraction can rapidly combine
with transferrin or other ligands and be transported, the remainder forms
polymers. This deposit may be slowly solubilised and translocated to the
systemic circulation while some particles may move to the regional lymph
nodes.
Nenot et al, ( 1 9 7 2 ) have studied the clearance of plutonium-238,
plutonium-239 9 americium-2i+1 and curium-2lj.2 from an intramuscular site of
deposition in the rat leg after injection as the nitrate. Values for the
retention of plutonium-238, curium-2lj.2 and americium-2l+1 were very similar
(Figure 1+.11) showing a fast clearance with a half-time ranging from 1 0 - 2 0
days during the first weeks. Plutonium-239 had a much slower rate of
clearance. Two factors will be contributing to the greater retention of
plutonium-239- Firstly polymer formation can be expected to be greatest
for the plutonium-239 deposit because of the greater mass in the injection
solution. An effect of mass has been demonstrated by Harrison et al,
( 1 9 7 7 ) following the intramuscular deposition of varying amounts of
plutonium-239 as nitrate into the thigh muscle of rats. The rate of trans-
location of plutonium was greatest after deposition of the smallest mass
(Figure 1+.12). Secondly the enhanced clearance of plutonium-238,
americium-2I4.I and curium-2i+2 may also have been partly due to their higher
specific activity (Table 2 . 1 ) .
Americium is also cleared more rapidly than plutonium from the paws of
dogs after subcutaneous deposition as the nitrate. 6 0 - 7 0 $ of americium-2Ul —1 —1
( 0 . 9 |iCi kg"" ( 3 3 kBq kg" ) administered) was cleared after one week and approximately 80% after h weeks (Lloyd et al, 1 9 7 5 ) . In a similar experi-
—1 —1
ment with plutonium-239 nitrate ( 0 . 2 p,Ci kg" ( 7 -U kBq kg" ) administered)
(Bistline et al, 1 9 7 2 ) , about 50% of the activity had been cleared by 2
weeks and approximately 7 0 $ by 1 year.
A limited number of studies have been reported on the movement of
oxides of plutonium from the subcutaneous tissue of the forepaws of beagle
dogs. These studies have shown that the translocation of plutonium dioxide
is generally characterised by its insolubility and slow rate of clearance
to other tissues, principally lymph nodes. Thus following the subcutaneous
deposition of air oxidised plutonium dioxide into the paw of dogs approxi-
mately 80% was retained at the injection site at one year (Watters and
55
D a y s p o s t i n j e c t i o n
Figure U«11 Retention of actinides at the site of administration after
intramuscular injection into rats as nitrates (pH 1 . 5 ) .
Redrawn from Nenot et al ( 1 9 7 2 ) . "Reproduced from Health
Physics Vol. 22, p. 6$8, 1972 , by permission of the Health
Physics Society."
%
of
in
itia
l in
jec
te
d
do
se
5 6
100H
TIME ( m o n t h s )
E r r o r b a r s r e p r e s e n t ± S . E . f o r g r o u p s o f 4
a n i m a l s
Figure U . 1 2 The effect of mass on the retention of plutonium-239 in the
extensor cruris muscle of the rat after injection as the
nitrate (Harrison et al, 1 9 7 7 ) .
% INJECTEC A C T I V I T Y
5 7
Lebel, 1 9 7 2 ) . This slow rate of clearance was, however, not found after
similar administration of high fired plutonium dioxide (Bistline et al,
1 9 7 2 ) . Approximately 7 0 $ of the plutonium was cleared after one year, a
rate of clearance similar to that found after deposition of the nitrate.
The greater rate of clearance of the high fired particles may have been
related to their smaller size (geometric mean diameter - 0 . 7 compared
with 7 for air-oxidised plutonium dioxide).
Surprisingly there appears to be no comprehensive information on the
clearance of plutonium dioxide from intramuscular sites of deposition. It
can be anticipated that clearance will be very slow. Studies of the
retention of plutonium dioxide produced by an exploding wire technique have
shown only a few per cent of the activity deposited translocated to other
tissues after k weeks (Harrison et al, 1 9 7 8 ) .
There are no animal data on the behaviour of pure oxides of either
americium or curium at wound sites. There is a greater rate of transloca-
tion of these actinides from the-lung compared with plutonium following
their inhalation as the oxides (see 2 . 2 ) . Similar results might there-
fore be expected following their deposition at a wound site.
Summary
The behaviour of actinide compounds in contaminated wounds depends
on physico-chemical characteristics such as chemical form, particle
size, mass injected and specific activity as well as biological
factors such as the depth and site of deposition, the type of tissue,
tissue fluid flow past the deposit and the dispersion within the
tissue. In general terms, soluble compounds are cleared more readily
than insoluble compounds, subcutaneous deposits more readily than
intramuscular deposits and americium and curium more readily than
plutonium.
2 . 5 Absorption through the intact skin
The few studies that have been reported on the percutaneous absorption
of actinides indicate that this is not a significant route of entry into
the body.
In experiments in animals Oakley and Thompson ( 1 9 5 6 ) found that 0 . 03>$
of plutonium nitrate in 10M HNO^ was absorbed in one hour and 1 - 2 $ in 5
days. Under these conditions severe skin damage would have been expected.
With plutonium nitrate in 0.1M HNO^ 0 . 1 - 0 . ; $ was absorbed in 5 days. In an
experiment in which 0 . 6 ^Ci ( 2 3 kBq) of plutonium nitrate in O . I4M nitric
58
acid were applied to the palm of the hand for 8 hours the amount absorbed
was no greater than 2 x 1 0 ~ ^ % per hour (Langham, 1 9 5 9 ) •
The amount of activity absorbed will depend upon the area contaminated
and may be increased if the skin is damaged or in the presence of solvents
that can penetrate the skin. In an accident in which a solution
containing about 1 \iOi ( 3 7 kBq) of plutonium in 9% HC1 containing EDTA and
a strong detergent was spilled onto a m a n ^ hand, absorption was estimated
to be about 1 0 ~ ^ % (Lister et al, 1 9 ^ 3 ) • Washing was started within about
5 minutes of the accident.
Summary
The results of both animal experiments and observations on humans
contaminated with plutonium indicate that the skin is an effective
barrier to the entry of plutonium into the body and probably to other
transuranics.
3 . Retention in lymph nodes
A proportion of plutonium or other actinides deposited in the
respiratory tract or a wound site translocate to regional lymph nodes.
The retention half-time of activity in these nodes varies markedly in
different experiments but because of their small mass the concentration of
plutonium or other actinides in them can increase to many times that at the
site of deposition or in other tissues and consequently they may receive
high radiation doses.
In a study reported by Bair (1971+a) in dogs that had inhaled plutonium
dioxide, the retention of plutonium in the thoracic lymph nodes after 1
year was about 1 0 % of the initial alveolar deposit, and 50% after 1 0 years.
The concentration of plutonium in the nodes at 1 0 years was approximately
2 0 0 0 times that in the lung and liver and about 2 0 0 0 0 times that in the
skeleton. This is the most extensive study on the retention of plutonium
in the lymph nodes. The amount of plutonium the dogs inhaled was, however,
high and radiation damage to the lung or lymph nodes could have influenced
the retention pattern.
Brightwell et al, ( 1 9 7 6 ) showed that plutonium was retained in the
thoracic lymph nodes of rats to a greater extent following inhalation of
plutonium dioxide ( 0 . 8 5 % of the initial lung deposit after 1 2 months) than
following inhalation of mixed oxide aerosols of plutonium and sodium
( 0 . 2 7 % ) . The difference was attributed to the smaller particle size
distribution of the plutonium in the mixed oxide aerosol. Whether the
59
difference resulted from a faster rate of removal from the nodes or from a
slower rate of translocation to them from the lung was not determined.
The retention of plutonium in the nodes of these rats was considerably-
less than at a comparable time in the experiment with dogs. This could have
resulted from differences in aerosol characteristics, the amount of activity
initially deposited in the respiratory system, or the rates of* clearance
from the lung or lymph nodes.
Craig et al, ( 1 9 7 6 ) compared the clearance of plutonium, americium and
curium from the lungs of beagles after inhalation as the oxides and showed
that accumulation in the thoracic lymph nodes was in the order plutonium-239
> plutonium-238 > americium-2Ul > curium-2144.. Tissues were analysed 3 5 0
days after inhalation of plutonium-238 dioxide and americium-2i|1 oxide,
lj.00 days after inhalation of plutonium-239 dioxide and J00 days after
inhalation of curium-2l4i oxide. The percentage of the translocated activity
accumulated by the lymph nodes was 9 5 • 2 2 , 1 . 5 and 0 . 1 5 $ for plutonium-239,
plutonium-238, americium-2^1 and curium-2l4j. respectively (values estimated
from graphs given in paper). These observations are consistent with
greater solubility of the americium and curium oxide particles.
A study on the translocation of plutonium from simulated subcutaneous
wounds in the dog forepaw showed that retention in the nodes depends upon
the chemical form deposited (Bistline et al, 1 9 7 2 ) . With air oxidised
plutonium dioxide (geometric mean diameter - 7 tim) deposition in the
cervical lymph node showed a continuous build-up to 1 7 % of the administered
activity at the end of one year. After deposition of plutonium nitrate
there was a rapid build-up in the nodes to a maximum of about 2 2 $ of the
administered activity at 1 0 days followed by a decline to about 7 $ at one
year. With high fired plutonium dioxide (geometric mean diameter - 0 . 7 pm)
a less rapid increase in concentration occurred in the nodes, deposition
reaching a maximum at about 5 0 days ( 1 5 $ of the amount administered)
followed by a decrease to about 1 0 $ over the subsequent 9 months.
Schallberger et al ( 1 9 7 6 ) have investigated the movement of plutonium
in the lymphatic system of dogs by cannulating afferent and efferent lymph-
atics of nodes draining the site of simulated subcutaneous wounds. They
collected lymph for up to k hours after injection and showed that there
were cellular and acellular components in both afferent and efferent lymph.
After deposition of plutonium nitrate the acellular component predominated
up to 1+ hours after administration but following deposition of polydisperse
plutonium dioxide particles acellular and cellular components were fairly
60
similar. Although the concentration of plutonium in efferent lymph was
always less than in afferent lymph the study showed that cellular and
acellular plutonium can pass through lymph nodes. This activity will
eventually deposit in other tissues in the body.
These observations suggest that particles accumulated in thoracic
lymph nodes from the lung may also be released and subsequently be
deposited in other tissues of the body. There are, however, no studies
that demonstrate this unequivocably.
There have been few detailed studies on the distribution of actinides
within lymph nodes. In rats (Brightwell et al, 1 9 7 6 ) and dogs (Bair et al,
1 9 7 3 ) exposed to plutonium dioxide the majority of th« plutonium in thoracic
lymph nodes was present as particles or aggregates. The deposits were
predominantly concentrated within and around the medullary region or
cortico-medullary junction but not generally in the germinal centres. In
the rats only some of the thoracic nodes from any one animal contained
activity, suggesting that only a proportion of the nodes drain
directly from the lung. The plutonium within the nodes was located
predominantly in macrophages within the medullary areas (Brightwell et al,
1 9 7 6 ) but it was not possible to identify whether the plutonium was
concentrated in migrating macrophages or the fixed phagocytic cells lining
the medullary sinuses.
Dagle et al, ( 1 9 7 5 ) have used autoradiographic methods to study the
distribution of plutonium in lymph nodes draining a simulated wound in the
hind paw of beagles. The work showed that after injection of high-fired
plutonium-239 dioxide the distribution of plutonium particles was related
to lymph flow through the popliteal node. In dogs sacrificed after k weeks
the plutonium particles were found in the subcapsular areas and areas
between the cortical nodules. From 8 to 3 2 weeks the plutonium particles
became more concentrated in the medullary areas near the efferent
lymphatics. Alpha activity was more pronounoed over regions where
haemosiderin was present. This observation was also made by Brightwell
et al, ( 1 9 7 6 ) in rats.
Summary
A fraction of the plutonium or other actinides deposited either in
the lungs or at a wound site may be translocated to regional lymphatic
tissue. Because of their small mass the radiation dose to these nodes
may greatly exceed that to the site of intake or to other tissues.
Some activity is subsequently released into efferent lymphatic ducts
6l
and will eventually deposit in other tissues of the body.
1+. Transport in the blood
Following the entry of soluble forms of plutonium into the systemic
circulation about 90% of the plutonium is rapidly bound to transferrin, the
protein that normally transports iron in the plasma (Popplewell and Boocock,
1968; Stevens et al, 1968; Turner and Taylor, 1968a) . The association of
americium and curium with transferrin has not been clearly demonstrated but
it is probable that the trivalent actinides also form complexes with
transferrin which, unlike the complex with plutonium, are not sufficiently
stable to withstand chemical separation procedures. Some plutonium in the
plasma remains associated with a small molecular weight species which is
probably citrate (Popplewell et al, 1975) and this may also be true of
americium and curium (Stradling et al, 1 9 7 6 ) .
Durbin (1972) has recently reviewed data on the clearance of plutonium
from the blood of man and 1+ other mammalian species after intravenous
injection as citrate (Table 1+-10). In man $2% of plutonium is cleared
with a half-time of 20 minutes and a further 27% with a half-time of 7
hours. The remaining 21% is cleared with a half-time in excess of one
day. Similar results are obtained for other species although the blood
clearance tends to be faster.
There is no comparable information on the blood clearance of americium
and curium in man. Results obtained in animals have shown that soluble
complexes of americium and curium reaching the circulation are cleared more
rapidly than plutonium. Thus intravenous injection of americium-21+1 in the
rat as the citrate or nitrate resulted in 97-98% clearance after one hour.
For curium-2l+l+ administered as the nitrate 96% was cleared by one hour but
in the case of plutonium-239 administered as nitrate or citrate clearance
was only about 57% and 31% respectively (Turner and Taylor, 1968b). In
beagles Atherton et al, (1973) showed clearance of 90% of americium-2l+1
and curium-2I4.I+ one hour after intravenous administration as citrate and
99% after 7 hours compared with 30% of plutonium-239 after 7 hours.
Polymeric plutonium is rapidly cleared from the blood and deposited
predominantly in cells of the reticuloendothelial system, primarily in the
liver, and to a lesser extent in the spleen and bone marrow (Rosenthal et
al, 1968) . Although the clearance of colloidal plutonium from the blood
has been studied extensively in animal experiments it seems likely that
this is not a chemical form likely to be of importance in the majority of
cases of human contamination.
Table 1
+.10
Disappearance from circulating blood of intravenously injected Pu(lY) citrate
Component
Species
A
B
C
D
E
Day of
last sample
Species
(min)
%
(hr)
%
(days)
%
(days)
(days)
Day of
last sample
Rat
60.3
58
3
7.3
8
.2
0.8
6
.0
8
Dog
hh
11 - i
+8
19
.5
7.3
30
1
.0
2.1
5
.0
0.08
1 2
20
a 3
,00
0
Sheep
68
2h
25
2 -
5 5
.8
1.6
1
.1
U.9
10
Man
52.U
20
27
.1
7.3
1
7.2
1
.2
3.3
5
.0
o.kh
88
U
2
An additional long term component emerged at
80
0 days
(0
.0U
5%, Tj- =
5
,$0
0 days)
Reference: Durbin (1972)
62
a
6 3
Recently Stradling et al, (1977) have shown that small particles of
plutonium dioxide less than about 1 nm in diameter can readily enter the
blood from the lungs. These particles have been found to associate with
citrate in the blood to form an "intermediate" complex. This complex has
a half-life of about 3 minutes in the blood but can pass through the kidney
glomerulus in the ultra-filtrate and be excreted, resulting in an enhanced
urinary excretion vsee later). Ultimately the plutonium particles not
excreted are solubilised, complexed by transferrin or citrate and deposited
in tissues in a manner similar to other soluble forms of plutonium.
After the entry of soluble forms of plutonium into the blood most of
it is rapidly bound to transferrin, a protein that normally transports
iron in the body. The remainder is bound to a smaller molecule which
is probably citrate. It is probable that americium and curium behave
similarly. Soluble complexes of americium and curium are cleared from
the blood more rapidly than plutonium.
5 . Deposition in tissues from the blood
The results of both animal and human studies have shown that for
radiological protection purposes three sites of deposition of plutonium,
americium and curium that have entered the systemic circulation must be
considered. The majority of activity entering the blood (> 90$) is
accumulated in either the liver or the skeleton. Much less is deposited
in other tissues. The retention and distribution of these actinides in
the gonads must also be known as any activity deposited in this tissue
will result in a genetic dose to exposed individuals or populations. Apart
from these 3 tissues activity will be deposited in all the other tissues of
the body but because of the generally lower radiation doses involved
retention in them is of considerably less importance and will not be
further considered.
5.1 Skeleton
Extensive studies in animals have shown that the skeleton is a major
site of deposition of actinides following their entry into the systemic
circulation. The amounts of plutonium, americium and curium deposited in
this tissue and their subsequent fate depend upon the route of administra-
tion, the physico-chemical form, the age of the animal and the amount
administered.
6k
Studies by Rosenthal et al, ( 1 9 6 8 ) have shown that the physico-
chemical form of plutonium entering the blood influences the pattern of
deposition in tissues. If plutonium particles or polymers enter the blood
most of the activity is deposited in the liver but for ultrafiltered
(monomeric) soluble forms of plutonium the majority of the activity is
deposited in the skeleton. The amount of plutonium accumulated by the
skeleton also depends on age. Thus 3 month old beagle dogs, in which
growth is rapid, accumulated about 70% of plutonium administered intraven-
ously as citrate at one to 2 weeks after injection whereas in dogs more
than 1 8 months old deposition in the skeleton was about 3U% (Stevens et al,
1 9 7 6 ) . In weanling rats 7 8 % of plutonium administered intravenously as
citrate was accumulated by the skeleton (skeletal retention taken to be
2 0 x femur concentration), whereas in adult rats only 5 3 % was accumulated
by the skeleton (Sikov and Mahlum, 1 9 7 2 ) . Similar results have been
obtained by Buldakov et al, ( 1 9 ^ 9 ) in lambs and sheep.
Since the first observation by Hamilton ( 1 9 U 7 ) of the deposition of
both plutonium and americium on bone surfaces, the distribution pattern of
plutonium in bone has been described in detail by a number of authors
(Arnold, 1 9 5 1 ; Arnold and Jee, 1 9 5 7 ; Jee and Arnold, 1 9 6 1 ; Jee, 1 9 7 2 ;
Nenot et al, 1 9 7 2 ; Vaughan et al, • 9 7 3 ; Priest, 1 9 7 7 ; Priest and Jackson,
1 9 7 7 ) - After the en-ury of soluble forms of plutonium into the blood much of
it is rapidly bound by the protein transferrin. Much of this activity is then
deposited on endosteal surfaces of bone and to a lesser extent on perio-
steal surfaces and surfaces of vascular channels in cortical bone. These
bone surface deposits irradiate cells within about 1+0 \w of the bone
surface (Figure k.13)•
Not all the plutonium reaching the skeleton is deposited in bone, some
is retained in the bone marrow. In animals given doses of plutonium less —1 —1
than about 1 |iCi kg"" ( 3 7 kBq kg"" ), the concentration of plutonium in the
marrow is highest at short times after plutonium has entered the blood,
when most of the activity is due to plutonium still circulating in the
blood and bone marrow spaces. As blood levels of plutonium fall so do
the levels in the bone marrow. At later times the level of plutonium in the
marrow may increase slightly due to the resorption of bone containing
plutonium (Jee, 1 9 7 2 ; Priest and Jackson, 1 9 7 7 ) .
The rate of disappearance of plutonium from the bone surface depends
upon the age of the animal and the amount of plutonium administered. In
65
Figure Plutonium-2U1 deposited upon a resorbing endosteal bone surface
of rat 2k hours after injection as the citrate. The plutonium
is present on the bone surface and in an osteoclast (bone
resorbing cell). However, no plutonium is present in other
cells in the marrow. (Provided by N. D. Priest, National
Radiological Protection Board, U.K.)
6 6
young, rapidly growing animals plutonium-239 deposited in the metaphyses
is rapidly displaced by endochondral ossification. Thus James and Taylor
( 1 9 7 1 ) showed that the long bone metaphysis of a 7 week old male rat was
completely replaced in less than 3 weeks. Concurrently with growth in
length of the bones the trabeculae are continually remodelling with the
result that plutonium bound to their surfaces is either buried or removed
by osteoblastic resorption and released within a few days of deposition
(Jee et al, 1 9 ^ 9 ; Priest and Jackson, 1 9 7 7 ) • Ultimately the processes of
apposition and resorption result in plutonium tending to become volume
distributed in the bone matrix. At high doses of plutonium (> 1 iCi kg""
( 3 7 kBq kg""1)) the a-radiation dose to bone surfaces results in an
inhibition of bone resorption (Polig, 1 9 7 6 ) and the accumulation of
plutonium by macrophages in the marrow (Arnold and Jee, 1 9 6 2 ; Jee, 1 9 7 2 ;
Priest and Jackson, 1 9 7 7 ) • In young adults the loss of plutonium from
bone surfaces is less rapid than in growing animals. Despite this surface
trabecular deposits of plu-conium, in 1 . 5 year old beagle& given i.v.injec-
1 —1
tions of plutonium-239 citrate (0.016 ..Ci kg"" (0.6 kBq kg ])
had virtually cleared by 6 months (Jee, 1 9 7 2 ) . In mature animals the rate
of removal of plutonium-239 from bone surfaces is slow (Jee, 1 9 7 2 ) . This
can be correlated with the reduction in bone remodelling rates in mature
animals. Frost ( 1 9 6 9 ) has given some values for normal bone formation
rates for cortical bone in the middle of the sixth human rib. Bone
formation rates were 1 . 8 - 1 + . ! $ per year in adults ( 3 0 - 9 0 years of age)
whereas in 1 - 9 year olds the rate was 38% per year and in the first year
of life 8 5 $ per year.
It might be anticipated therefore that provided the numbers of
sensitive osteoprogenitor cells per unit area remain fairly constant,
plutonium deposited on bone surfaces in mature bone would be potentially
more damaging than plutonium deposited in growing bones as the cells near
the surface will receive a greater radiation aose. In all ages, however,
there is significant burial of plutonium deposits in bone and therefore
calculations of dose to the sensitive osteoprogenitor cells on the bone
surface that are based on the assumption that plutonium remains at the
bone surface will be conservative.
The distribution of plutonium in bone is very different to the
alkaline earths. Radioactive isotopes of the alkaline earths can replace
calcium in the crystal lattice structure of bone and readily form a diffuse
deposit throughout the skeleton (ICRP, 1 9 6 8 ) . There are conflicting views
over the chemical form of the major binding sites for plutonium in bone.
67
Teseveleva ( i960) found that 87.5% of plutonium in bone was associated
with the organic matrix and 6% with bone mineral. The chemical procedures
used were, however, extreme and could have redistributed any plutonium
present. Contrary views were expressed by Foreman (1962) who showed that
bone mineral in vitro accumulated plutonium more readily than bone matrix,
and Jee and Arnold (1962) who concluded from studies on normal and
rachitic rats that plutonium was bound mainly to the mineral phase of
bone. However, Taylor and Chipperfield ( 1 9 7 1) showed that glycoprotein
fractions isolated from bovine bone bind plutonium more strongly than
transferrin, collagen or free chondroitin sulphate, suggesting that glyco-
proteins may play an important role in the binding of plutonium to bone.
Plutonium is retained in the skeleton with a long half-time in all
mammalian species studied. Data summarised by ICRP (1972b) suggest that
the half-time of plutonium in the skeleton of experimental animals is
approximately 1 to 2 times the average life expectancy of the species. On
this basis the half-time of plutonium in the skeleton of man was estimated
to range from 65 to 130 years with a mean of about 100 years.
The amounts of americium and curium which deposit in the skeleton
(ie, bone and bone marrow) after their entry in the blood in a soluble
form are very variable. Typical values for the percentage skeletal uptake
following their injection as a monomeric solution lie between 20 and 1+0%
(Durbin, 1973) - This is generally less than the skeletal deposition of
plutonium.
Few studies have directly compared the skeletal uptake of plutonium,
americium and curium. Seidel and Volf (1972) showed that in 3 groups of
rats given intravenous injections of these radionuclides as citrate, the
skeletal uptake of plutonium was approximately 3 times greater than the
value found for americium and curium (Table I4.ll).
In dogs the accumulation of these 3 actinides is more comparable.
Thus after the intravenous administration of plutonium, americium and
curium as citrate the proportions of the administered activity deposited
in the skeleton in the first 3 weeks after administration were 1+9%
(Stover et al, 1972a ) , 29% (Lloyd et al, 1970) and 1+1% (Lloyd et al, 1971+),
respectively.
In the long bones and vertebrae of mature and growing rats americium
becomes deposited on the endosteal and periosteal bone surfaces and around
cortical vascular canals (Hamilton, 191+7; Taylor et al, 1 9 6 1 ; Durbin et al,
Table
M1
Distribution of plutonium
-239. americium-
21+1 and curium-
21+2
in rat tissues
6
days after intravenous injection as citrate
Tissue
% Injected Activity (X, N =
1 + or
5
) Tissue
Plutonium
-239
Americium-
21+1
Curium
-21+
2
Skeleton
62
.0
18
.66
22
.3
Liver
1U
.6
U3
-33
U2
.7
Spleen
0.2k
0
.06
2 0
.07
Kidneys
1.0k
0
.82
3 0
.80
Lung
0.11
+ 0
.10
7 0
.12
Thyroid
0.0
22
0.02
1 0.
021+
Adrenals
0.0
12
0.0
05
0.0
04
Ovaries
0.0
17
0.0
09
0.0
13
Ref: Seidel and Volf (1972)
68
69
1969; Williamson, 1963; Nenot et al, 1 9 7 2 ) . Similar results have been
found in dogs (Herring et al, 1962; Lloyd et al, 1972), mice (Hammarstrom
and Nilsson, 1970a, 1970b) and cynomolgus monkeys (Durbin, 1 9 7 3 ) .
Herring et al, (19^2) showed that the distribution of americium on
bone surfaces in growing dogs varied with growth activity of the surfaces.
The highest amounts of americium were found on resorbing surfaces with
lower amounts on resting and actively growing bone surfaces. These results
are in apparent contrast to those of Williamson (1963) and most other
investigators who have shown that the greates t uptake of americium occurs
at sites of high growth activity among the trabeculae of the primary and
secondary spongiosae. Some americium deposits onto resorbing bone surfaces
and to a lesser extent onto resting surfaces. Its distribution can be
distinguished from plutonium mainly by a high level of deposition in
vascular channels but it is not concentrated in the bone marrow.
The mechanisms of uptake of americium and curium by the skeleton are
not known.
As with plutonium the skeletal uptake of americium and curium is lower
in older animals (Mahlum and Sikov, 1975; Stevens et al, 1976) and the
growth activity of the bone influences the temporal pattern of distribution.
They will also tend to become more evenly distributed throughout the bone
matrix with time. The limited data available for the retention half-times
of americium in the bones of experimental animals are similar to those for
plutonium (ICRP, 1972b) .
5 .2 Liver
The liver and skeleton together accumulate the majority of the
systemic deposit of plutonium, americium and curium which distribute
between these two tissues according to the relative affinities of hepatic
and skeletal tissue for each element. The liver uptake of monomeric
americium and curium from the systemic circulation in rodents is generally
greater than plutonium (ICRP, 1 9 7 2 b ) . In a study by Seidel and Volf (1972)
in rats the liver deposits of plutonium, americium and curium 6 days after
intravenous administration as the citrate were 1l+.6%, 1+3.3% and 1+2.7%
respectively of the administered activity (Table 1+.11) . In dogs deposition
of these actinides in liver is more comparable. Thus at 30 days after in-
halation of americium dioxide and curium oxide the liver accumulated about
1+1+% of the extrapulmonary tissue deposit (Table l+.7)> whilst for plutonium
dioxide it accumulated about 1+0% at 56 days (Table 1+.1). Similar results
are obtained in beagle dogs after intravenous administration. The liver
TO
accumulated about 30% of plutonium, 50% of americium and 35% of curium one
week after intravenous administration as citrate (Lloyd et al, 1971+)•
The half-time of retention of both plutonium and americium in the
liver was about 3 7 0 0 days when the administered activity was 0 . 1 ^Ci
kg""1 ( 3 - 7 kBq kg""1) or less (Stover et al, 1 9 7 1 ; Lloyd et al, 1 9 7 0 ) . With
increasing amounts of plutonium administered, the half-time of retention
was reduced, probably as a consequence of radiation damage to the liver and
the release of plutonium into the blood resulted in an increase in the
skeletal burden. A long half-time of retention of actinides (about 3 4 0 0
days) has also been found in the hamster liver (McKay et al, 1 9 7 2 ) . In the
mouse and rat the liver retention of plutonium after administration in a
monomeric form has a half-time of only about 2 0 days (Rosenthal et al,
1 9 6 8 ; Stather and Howden, 1 9 7 5 ) . In rats plutonium leaves the liver
predominantly in the bile (Ballou and Hess, 1 9 7 2 ) . A rapid rate of loss
of americium from the liver of mice, rats and monkeys has also been reported
(Durbin, 1 9 7 3 ) - Tne hamster and the dog are therefore the most suitable
animals for studies on the hepatic retention of plutonium that can be
related to man. There are no human data from which to estimate the half-
time of retention of plutonium in the liver in man but measurements of
the plutonium content of human livers obtained at autopsy suggest that it is
longer than a few years (Foreman et al, i 9 6 0 ; Magno et al, 1 9 ^ 9 ; Norwood et
al, 1 9 7 3 ; Schofield and Dolphin, 1 9 7 4 ; Mclnroy, 1 9 7 6 ; Voelz, 1 9 7 5 ) . Based
upon an extrapolation from the half-time of retention of plutonium in the
liver of experimental animals, a half-time of retention in the human liver
of 4 0 years has been estimated (lORP, 1 9 7 2 b ) . A similar half-time would be
expected for the higher actinides.
Autoradiographic studies of the distribution of plutonium in the livers
of beagle dogs after intravenous injection of plutonium-239 citrate showed
that the initial site of deposition was the hepatic cells. The uptake was
uniform and localisation within either the reticuloendothelial (RE) cells,
the biliary epithelium or the interstitial areas was very low within a few
days after injection (Taylor et al, 1 9 7 2 ) . By 2 to 3 months following the
injection 01 2 . 9 pCi/kg ( 1 0 7 kBq kg" ) (cumulative dose 3 4 0 to 4 9 4 rads
( 3 . 4 to 4 - 9 Gy) respectively) an increased activity in the RE cells lining
the sinusoids occurred and ultimately some cells became significant "hot
spots". The accumulation of activity by the RE cells appears to have
resulted from the death of hepatic cells and their subsequent uptake by
the phagocytic Kupffer cells lining the sinusoids (Taylor et al, 1 9 7 2 ) .
This movement was seen in dogs given varying levels of plutonium ( 0 . 0 1 7 - 2 . 9
71
1 1 p.Ci kg ( 0 . 6 - 1 0 7 kBq kg" )) but the latent period before l!hot spots11
developed became progressively longer as the injected dose decreased. The
pattern of distribution of americium-2l|1 in the liver of beagle dogs has
been shown to be similar to plutonium (Taylor et al, 1 9 6 9 ) .
A progressive aggregation of plutonium has also been shown in the
livers of mice given injections of polymeric plutonium (Lindenbaum et al,
1 9 6 8 ) . However, the progressive focalisation of activity was not
accompanied by a gradual shift of activity towards the Kupffer cells.
About 60% of the activity was associated with the hepatic cells and about
kO/o with the Kupffer cells between half an hour and 3 months after
administration. In mice injected with a monomeric plutonium preparation
about 70% of the deposit of plutonium was in the hepatic cells at 5 days.
In rats and hamsters the highest concentrations of plutonium are also
found in the hepatic cells up to one week after intravenous administration
as citrate (Priest, 1 9 7 7 ) •
Little is known of the mechanism by which plutonium, americium and
curium are taken up by liver cells. Differential centrifugation studies
of rat and beagle liver have shown that within the liver cells the
actinides are initially concentrated in the cytoplasm, principally in
association with the iron-storage protein, ferritin, (Boocock et al, 1 9 7 0 ;
Stover et al, 1 9 7 0 ; Stevens et al, 1 9 7 3 ) • They are subsequently transf-
erred from the cytoplasm to sub-cellular organelles, principally the mit-
ochondria and lysosomes. Association with nuclei has also been described
(Boocock et al, 1 9 7 0 ) . Autoradiographic studies have demonstrated the
accumulation of some plutonium-21+1 by the nuclei of rat and hamster liver
cells at one day after intravenous administration as citrate (James and
Rowden, 1 9 ^ 9 ; Priest, 1 9 7 7 ) (Figure h^h) although by one week these
deposits have reduced.
Some of the plifbonium and americium associated with beagle and rat
liver at short times after administration has been shown to be extra-
cellular and associated with connective tissue (Stover et al, 1 9 7 0 , 1 9 7 2 b ;
Grube et al, 1 9 7 5 - 1 9 7 6 ) . Perfusion of rat liver removed 6 - 7 % of the
incorporated Pu(lV) after one day and 1 % after 11+ days (Grube et al, 1 9 7 5 ) .
This fraction of the liver deposit may be removed by the intravenous admin-
istration of chelating agents (Chapter 8 ) .
The intracellular distribution of particles of plutonium taken up
by the liver is very different to that of soluble plutonium. Gurney and
72
Figure k*^k Hamster liver at 2k hours after the injection of plutonium-21+1.
Plutonium is concentrated by the liver celts surrounding a
small blood-vessel. Plutonium (B-tracks may be seen over both
the nuclei and the cytoplasm of cells. (Provided by
N. D. Priest, National Radiological Protection Board, U.K.)
73
Taylor (1975 ) showed that they were maximally concentrated in the lysosomes
of rat liver as soon as one hour after intravenous injection, A similar
uptake of particles of americium and curium can he expected.
5 - 3 Gonads
To estimate the human genetic dose resulting from an intake of
plutonium or other actinides, the uptake, distribution and retention in
the gonads must be known. Very little information is available in man and
use must be made of animal data.
Richmond and Thomas ( 1 9 7 5 ) have reviewed data on the deposition of
actinides in the gonads. Following the intravenous administration of
plutonium citrate or nitrate the percentage of the administered plutonium
accumulated by the testes (average for k species) was about k x 1 0 % with
less than a factor of 1 0 between the highest and lowest values (range 1 , 9 2 2
x 1 0 " % to 9 - 5 x 10~~ %). Only one result obtained in 3 dogs (Baxter et al,
1 9 7 3 ) following the intravenous administration of polymeric plutonium, was
below this range ( 1 . 6 x 10""-^%). This chemical form of plutonium is, how-
ever, mainly accumulated by the liver and is unlikely to be representative
of the transportable fraction of plutonium that has entered the blood in
cases of human contamination. The fractional accumulation of plutonium
by the testes is influenced by the relative weights of the testes and the
whole body. In animals in which the weight of the testes is a relatively
large proportion of the body weight (eg, rat and pig) the uptake of
plutonium is greater than in animals in which it is relatively small (eg,
man and dog). If the values for the uptake of plutonium by the testes are
normalised to take account of the differences in testis weight the values
obtained for 7 different species (mouse, rat, hamster, rabbit, dog, pig,
human) vary by only about a factor of 5 (Stather and Rodwell, 1 9 7 7 ) . The
average value for the accumulation of plutonium in these species would then
correspond to a deposition in the human testes of about 1 . 7 x 1 0 ~ 2 % . Until
more data is available 3 x 1 0 ~ 2 % can be taken as the amount of plutonium
or other actinides accumulated by the testes from the blood. If plutonium
was uniformly distributed throughout the body (weight 7 0 kg) the testes
(weight 3 5 g) would accumulate 5 x 1 0 ~ 2 % of the body activity (based on
organ weights given in ICRP Publication 2 3 , 1 9 7 5 ) .
The proportion of plutonium accumulated by the ovaries following
intravenous administration in soluble form was about 3 x 10"" % (average
of 6 species, range 1 . 3 x 1 0 " % to 9 . 8 x 1 0 ~ 2 % ) (Richmond and Thomas 1 9 7 5 ) .
7^
Data reported by Green et al, ( 1 9 7 7 ) gave an average uptake of 1 . 1 x 1 0 - 2 %
per ovary in the mouse in good agreement with these values. In general,
more activity is accumulated by the ovary in rodents than in larger animals.
This may be attributed to its larger fractional body mass in small animals.
Based on these values the amount of plutonium accumulated by the human
ovaries could be taken to be 1 x 1 0 ~ ^ % . If plutonium was distributed
uniformly throughout the body ( 5 8 kg) the ovaries ( 1 1 g) would accumulate
1 . 9 x ICf^ of the body activity (ICRP Publication 2 3 , 1 9 7 5 ) .
Values obtained for accumulation of americium and curium by the gonads
(Richmond and Thomas, 1 9 7 5 ) are similar to those obtained for plutonium.
Data on the retention of plutonium in the testes suggest that it is
retained with a long half-time. In a study reported by Taylor ( 1 9 7 7 ) no
significant change in the total activity in the testes of rats up to 5 7 5
days after intravenous injection as the nitrate was found. Similar results
have been reported in hamsters up to one year after administration as the
citrate (Stather and Rodwell, 1 9 7 7 ) and by Koshurnikova ( 1 9 6 1 ) in rabbits
up to 5 months after administration as the nitrate. The retention of
plutonium in the mouse ovary has been reported by Green et al, ( 1 9 7 7 ) .
Up to 1 8 0 days after intravenous administration as citrate there was no
significant variation in the retained activity.
There are no satisfactory long term data on the retention of americium
and curium in either the testes or ovaries.
Green et al, ( 1 9 7 5 ) have shown using autoradiographic techniques that
after intravenous injection as the citrate plutonium accumulated by the
rodent testes is associated mostly with cells in the interstitial tissue,
outside the seminiferous tubules. Similar findings have been reported by
Taylor ( 1 9 7 7 ) » Brooks et a l , ( 1 9 7 6 c ) , ana Priest ( 1 9 7 7 ) . As a consequence of
this localised accumulation the calculated average dose to the spermato-
gonial stem cells in the mouse in which genetic damage may accumulate, is
greater than the average dose to the whole testes by a factor of 2 to 2 . 5
(Green et al, 1 9 7 5 ) . This activity appears to be concentrated predominantly
in macrophages (Priest and Jackson, 1 9 7 8 ) . In the human about 50% of the
tissue of the testes is interstitial compared with 1 0 % and 1 6 % in the mouse
and hamster respectively. As a consequence no significant dose enhancement
factor for spermatogonia could be calculated when 90% of the plutonium-239
was assumed to be uniformly distributed in the interstitial tissue (Brooks
et al, 1 9 7 6 c ) .
75
Green et al, ( 1 9 7 7 ) have studied the distribution of plutonium in the
mouse ovary. At early times ( 1 and 2 days) after intravenous administration
of plutonium-239 citrate a-tracks were randomly distributed over all tissues
with concentrations of tracks occurring over some atretic follicles. A
second site of accumulation of plutonium-239 was within thecal rings, which
are the post-atretic remains of small follicles. At later times (up to 1 8 0
days) after injection plutonium accumulated in the macrophages of the
medullary stroma probably as a result of the phagocytic activity of these
cells. A similar deposition pattern of plutonium at early times has been
found in the ovaries of the rabbit and hamster (Priest and Jackson, 1 9 7 8 ) .
It is unlikely that this distribution of activity in the ovary would result
in any dose enhancement to developing ovarian follicles.
Summary
For radiological protection purposes there are three main sites of
deposition of actinides that have entered the blood: the skeleton,
the liver and the gonads. The skeleton and liver together accumulate
about 9 0 $ of the activity entering the blood and the activity can be
assumed to be equally divided between them. The half-time of
retention of actinides in the human skeleton is estimated to be 1 0 0
years and in the liver 1+0 years.
It is estimated that the testes will accumulate 3 x 1 0 " ^ %
and the ovaries 1 x lO""^ of the activity entering the
blood. The results of animal studies indicate that there is no
selective accumulation of actinides by the gonads but that any
activity deposited in them is retained indefinately.
6. Excretion
Following intakes of actinides, some of the activity is excreted in
the faeces and in the urine.
Activity in the faeces originates from two sources: either as
a result of activity deposited in the respiratory system being cleared
from the lung via the mucociliary escalator and swallowed, or by direct
secretion into the gut. In rats the main pathway of secretion is by
way of the bile (Ballou and Hess, 1 9 7 2 ) and accounts for the rapid loss
of plutonium from the liver. Non-biliary secretion into the gastro-
intestinal tract of rats have also been reported to account for the
greater rate of loss of plutonium in the faeces than in the bile following
the intravenous injection of plutonium (Astley and Sanders, 1 9 7 3 ) •
76
Plutonium excreted in the urine is derived from the systemic circula-
tion by ultrafiltration in the kidney glomerulus. The majority of plutonium
circulating in the blood following the administration of relatively soluble
forms of plutonium (citrate or nitrate) is bound either to transferrin or
to citrate and it has been shown that it is probably the citrate complex
that is excreted in the urine (Popplewell et al, 1 9 7 5 ) . This is also true
for americium and curium (Stradling et al, 1976) .
More americium and curium than plutonium is cleared into the urine
reflecting the relatively weak binding of the transplutonium elements to
plasma proteins. Thus the total urinary excretion of americium-2i|1 and
curium-2kh in beagle dogs over 3 weeks after intravenous injection as
citrate accounted for 10% and 8% of the injected dose, respectively (Lloyd
et al, 1970, 1 9 7 3 ) . This compares with a value of Iffi of the injected dose
of plutonium-239 obtained in similar studies (Stover et al, 1969). Faecal
excretion over this period accounted for 1%, y/o and 8% of the injected dose
of americium, curium and plutonium respectively. The fraction of the faecal
excretion in dogs that is due to biliary secretion has not been determined
but the high liver retention of the actinides in these animals indicates
that biliary excretion will be low.
Systemic deposits of actinides are difficult to detect by whole body
counting techniques and they are therefore normally assessed from measure-
ments of their rate of excretion in the urine. The results of these
measurements are interpreted on the basis of the equations developed by
Langham (Chapter 3)- Many studies have been reported on the urinary
excretion of actinides in animals that have been used as a guide for inter-
preting the results of bioassay data. For example the relatively high rate
of urinary excretion of both americium and curium indicates that the
application of equations based on the excretion of plutonium in man to
these higher actinides is likely to overestimate systemic deposits.
As a method for the assessment of plutonium entering the systemic
circulation it has been suggested that following accidental intakes of
plutonium, a constant relationship exists between the total urinary
excretion over a limited period of time following exposure and the amount
translocated to tissues (Lafuma, Nenot and Morin, 1 9 7 2 ) . The assumption
is that relatively constant fractions of the actinides entering the blood
are deposited in tissues and excreted in the urine. It has been shown in
studies with rats that the tissue distribution of plutonium following its
entry into the blood is largely independent of the original chemical form
deposited in the lung (Table U-2). Stradling et al, (1977) have, however,
77
demonstrated in rats that particles of plutonium dioxide about 1 nm in
diameter, can readily pass from the lungs into the blood to form an "inter-
mediate" species thought to be formed from the association of the plutonium
particles with citrate ions. This complex is readily excreted in the urine
and results in relatively high levels of urinary excretion. This "inter-
mediate" species is solubilised in the blood with a half-time of about 3
minutes which would suggest that at times later than a few days after
exposure the pattern of excretion should be similar to that found after
the administration of plutonium citrate.
Although it may be possible to make some estimate of the systemic
deposit of plutonium from urinary excretion data it cannot be used to
estimate activity in the lungs or at a wound site as the rate of movement
of activity from the site of deposition to the blood varies very widely
depending upon the chemical form of plutonium deposited.
Summary
Actinides incorporated into the body are excreted both in the faeces
and in the urine. Faecal excretion results from actinides entering
the gut either in mucous cleared from the respiratory system or in
gut secretions. Urinary excretion is due to ultrafiltration through
the kidney of actinide-citrate complexes formed in the blood.
Animal studies have shown that more americium and curium are excreted
in the urine than plutonium. The application of urinary excretion
data for plutonium in man to these higher actinides is therefore
likely to overestimate systemic deposits.
7. General conclusions
There are three main routes of entry of plutonium, americium and
curium into the body: by inhalation, by ingestion and through wounds.
A model for the deposition and retention of inhaled aerosols in the
human respiratory tract was described in the Report of the Task Group on
Lung Dynamics (1966) for Committee 2 of the International Commission on
Radiological Protection and modified in ICRP Publication 1 9 , 1972 . In the
model the respiratory tract has been divided into three regions: the
nasopharynx, the tracheobronchial region and the pulmonary region. The
regional deposition of an inhaled aerosol is considered to be primarily a
function of the particle size distribution. The chemical form of the
compound inhaled influences the subsequent clearance from the lung. In the
model retention in the lung can be for days (Class D), weeks (Class W) or
78
years (Glass Y). The Task Group Lung Model predicts that following the
inhalation of an aerosol of a relatively soluble (Class W) compound
(particle size distribution 1 un AMAD), 1 2 % of the activity will be trans-
ferred to the blood, and for a less soluble (Class Y) compound 5%. Reten-
tion is exponential with half-times of retention of the long term component
in the lung of $ 0 and 5 0 0 days for Class W and Class Y compounds respect-
ively.
Studies in animals have shown that plutonium compounds generally con-
form to this classification - oxides are Class Y, nitrates are Class W and
plutonium complexed with the chelating agent diethylenetriamine penta
acetic acid (DPTA) is Class D. Experimental studies have also shown that
all compounds of americium and curium, except Class D, but including the
oxides, are retained in the lung with half-times of a few weeks or months
and should be considered to be Class W. Following the inhalation of
particles consisting of mixtures of actinides the retention in the lung of
the individual actinides will be similar to that of the material present in
the inhaled particles in greatest mass.
For soluble plutonium compounds that have entered the gut the amount
of plutonium absorbed by adults is about 1 x 1 0 ~ ^ % and for insoluble
plutonium dioxide particles 1 x 1 0 " ^ % - Plutonium dioxide particles should
be treated as soluble if they are less than about 5 nm in diameter,
Americium and curium are absorbed more readily from the gut than plutonium
and a value of 5 x 1 0 " ^ % for all compounds is recommended. Absorption is
enhanced in the young and actinides incorporated in plant and animal tissue
may be absorbed more readily than inorganic compounds.
The behaviour of actinides compounds in contaminated wounds depends on
physico-chemical characteristics such as chemical form, particle size, mass
injected and specific activity as well as biological factors such as the
depth and site of deposition, the type of tissue, tissue fluid flow past
the deposit and the dispersion within the tissue. In general terms,
soluble compounds are cleared more readily than insoluble compounds,
subcutaneous deposits more readily than intramuscular deposits and americium
and curium more readily than plutonium.
The differences in behaviour between plutonium-239 and the higher
actinides can be attributed mainly to physical and chemical factors,
Plutonium forms polymers more readily than the higher actinides at physio-
logical pH and for equal amounts of activity a greater mass of plutonium-
2 3 9 than americium-2l+1 or curium-2U2 is deposited. Thus plutonium-239 is
7 9
more likely to be retained at sites of deposition than the higher actinides.
Particles of americium and curium have a higher specific activity than
plutonium-239 and this will also tend to mobilise them more readily from
any site of deposition.
The tissue distribution of actinides once they are in the blood is
largely independent of the initial physico-chemical form taken into the
body. For an assessment of the consequences of human exposure to these
actinides there are three important sites of deposition: the liver, the
skeleton and the gonads.
The liver and skeleton together accumulate about 90% of the systemic
deposit although the distribution of activity between these two tissues is
very variable. Overall 1+5% of the systemic activity can be considered to
deposit in each tissue. Retention is exponential with half-times in human
skeleton and liver estimated to be 1 0 0 and 1+0 years respectively.
Because of the potential genetic risk the third important site of
deposition from the blood is the gonads. Based upon both animal and human
data it has been estimated that the human testes will accumulate 3 x 1 0 " ^ %
of activity entering the blood and the ovaries 1 x 1 0 " ^ % . Although data on
the retention of actinides in the gonads is very limited animal studies
suggest that they are retained indefinitely.
Acknowledgement
The authors would like to thank Dr. N. Priest and Dr. J. D. Harrison
for their help in the preparation of this Chapter.
Chapter 5
T I S S U E S A T R I S K
1. The Concept of Critical Tissue in Relation to the Biological Effects
of Plutonium and Transplutonium Elements
It is extremely difficult to correlate the spatial distribution of the
dose in the tissues or organs following the deposition of plutonium or
transplutonium elements with the numerous observed biological effects. One
difficulty is caused by the large number of cell types that may be directly
or indirectly affected; this number can be reduced, however, as certain
determining factors also have to be taken into account, such as radiological
sensitivity, localization of the actinides in tissues and the number of
cells at risk. Factors relating to the radionuclide and its deposition in
the organism are equally important: the manner of deposition, whether the
distribution in the tissue is homogeneous or inhomogeneous, the size of the
particles, if the deposit is in a soluble or insoluble form, the specific
activity and the type of radioactive emission, the mobility of the deposit
including its rate of excretion, possible movements within the organ or
tissue itself, and the relationship with the various cell types of differing
radiosensitivities.
In addition, more fundamental factors play a part, such as the charact-
eristics of cell cycles, the variations in radiosensitivity associated with
growth, and cell differentiation and renewal.
This short list illustrates the difficulty in establishing a clear and
exact relationship between the physical features of contamination and a
biological assessment of the damage. Not only are many parameters still
unknown, but it is also practically impossible to apply a common standard
to the various biological effects that are observed; in fact, every type of
lesion seems to have its own dose-effect relationship. In the light of
present knowledge, this relationship may appear in forms that are appreci-
ably different. According to whether we are considering the effect on the
whole organism, a particular organ, a tissue or a cell type; a linear,
curvilinear or sigmoid relationship, or any other form, with or without an
apparent threshold may be obtained (UNSCEAR, 1972).
The tissues most exposed to contamination by plutonium or trans-
plutonium elements are the lung and skeleton. The former being the organ
through which the radionuclide may enter the body and the latter one of the
main organs for deposition, especially when the element is in a more soluble
form. Other organs exposed to significant amounts of activity include the
81
82
liver and lymphoid tissue. Finally, all the other organs and tissues may be
affected by the wide dispersion of the radionuclide in the organism.
1 . 1 Lung
All these introductory remarks can be applied to the lung. However,
certain other factors have to be taken into account, such as the duration
of alpha irradiation of particular cell types. Here a part is played both
by the kinetics of the radionuclide deposited in the lung and by the
kinetics of the cells that are exposed to risk; the fact that two kinetic
systems are involved produces more complex models. For example, a particle
taken up by a macrophage may move either inside an alveolus or even from
one alveolus to another. Furthermore, ventilatory movements of the
alveoli produce a more uniform dose distribution than might be assumed from
an autoradiograph of the particle which shows a "hot spot" that has every
appearance of being stationary (see Chapter 7 ) . This problem is related to
that concerning the number of cells affected by alpha irradiation (NCKP
Report No. 1+6, 1 9 7 5 ; Mayneord and Clarke, 1 9 7 6 ) . According to the nature
and manner of the deposit in the lung, the number of cells at risk varies.
This point underlines, among other things, the difficulty of extrapolating
from one species to another and, in particular, of making intercomparisons
between animals of very different sizes. However, some concepts are now
generally accepted, such as the fact that there will be a higher frequency
of lung cancer for a given radionuclide in a given form when the radio-
nuclide is distrioited more uniformly in the organ (Sanders, 1 9 7 2 , 1 9 7 6 b ;
Morin et al, 1 9 7 6 , 1 9 7 7 ; Bair et al, 'ISlh; Medical Research Council, 1 9 7 5 ) .
A large proportion of the activity in the lung will be phagocytosed by
macrophages. These mature cells form an isolated group with a highly
differentiated cellular type; they receive intense alpha irradiation at
very high dose rates from phagocytosed radioactive particles but their
precursor cells are only slightly affected. The situation is quite
different for the pulmonary cell types that are renewed in situ, such as
the epithelial cells, the cells of the blood and lymphatic vessels, the
lymphoid cells and the cells of the supportive tissue. The radiation
exposure of these different cell types depends on the manner in which
activity is deposited in the lung. The radioactive contaminant can be
transported through the pulmonary lymphatic vessels to the lymph nodes that
drain them; here the problem arises of the irradiation of the cells of the
lymph nodes. Most of the mature cells that circulate or remain in the
vessels, such as erythrocytes, granulocytes, and thrombocytes, are not
killed by low doses of radiation. The radiosensitivity of lymphocytes is
8 3
however well-established. In addition to the irradiation they receive in the
nodes they are also irradiated while passing throiigh the lung. This radio-
sensitivity can give rise to lymphopenia and to immunological consequences.
This effect may be pronounced due to the division rate of lymphocytes in the
capillaries of the lung, which seems much higher than in circulating blood
(Fritsch et al, 1 9 7 5 ) .
Although, anatomically, the bronchial and tracheo-bronchial lymph nodes
are not part of the lung, they do accumulate some of the inhaled radio-
nuclide. These deposits are cleared with a long half-time whatever the
selected reference model may be (Task Group on Lung Dynamics, ICRP 1 9 6 6 a ) .
The concentration of activity in the lymphoid tissue is sufficient reason
to pay it very close attention, although pathology associated with lymph
node irradiation is small or even non-existent. For this reason lymphatic
tissue will be examined in the same context as the other tissues which make
up the lung. This approach is especially appropriate as in the latest lung
model (ICRP 2 6 , 1 9 7 7 ) lymphoid tissue whether scattered in lung parenchyma
or concentrated in nodes, is grouped together with those tissues that are,
strictly speaking, lung tissues.
1 . 2 Skeleton
Among those organs other than the lung that are liable to develop or be
the origin of a pathological disorder resulting from alpha contamination,
the skeleton is of special significance. In this tissue, a number of cell
types are particularly liable to be sensitive to alpha irradiation because
they have a high rate of proliferation. The main types are:
- osteogenic cells in rapidly growing bone
- bone marrow with blood-forming cells (Loutit and vaughan, 1 9 7 1 )
As deposition of plutonium in the skeleton takes place in the marrow and on
the surface of the osteogenic tissue, the resultant pathology is particul-
arly complex. In a mature bone, in which absorption and apposition are
negligible, the number of osteoblasts and osteoclasts present on the surface
is very small. This is not the case with a young bone subject to extensive
remodelling, whose surface is covered with active osteoblasts and osteo-
clasts, all of which are mature differentiated cells; the precursor cells,
pre-osteoblasts and pre-osteoclasts, are also located on the bone surfaces
(Owen, 1 9 7 0 ) (Figure 5 . 1 ) .
In theory, tumours induced by alpha emitters deposited in bone can be
of various types (Vaughan, 1 9 7 3 ) s including osteo-sarcomas, chondro-
sarcomas, leukaemias and reticuloendothelial tumours. The former are by
8U
Figure 5*1 • Autoradiograph showing Pu deposited upon the trabecular surfaces of developing rat bone. Some plutonium has also been engulfed by a large osteoclast. In contrast very few or no (3-tracks are associated with the differentiating pre-osteoblasts within the intertrabecular spaces (Provided by N.D. Priest, National Radiological Protection Board, UK).
85
far the most frequent.
1 . 3 Liver
In view of the large deposits of plutonium in the liver that occur
after any contamination by plutonium or transplutonium elements, hepatic
tissue, composed primarily of hepatocytes and cells of the reticulo-
endothelial system, must be regarded as potentially at risk. This risk might
be higher in man and monkeys than in rats as the element is eliminated
more slowly. The fact that hepatic cancers induced by alpha emitters
oocur very rarely in experimental animals should not allow the potential
risk in man to be overlooked.
1 . 1 + Other tissues
Apart from the lung, bone and the liver every other tissue and organ
in the body is potentially at risk. Although following plutonium contamin-
ation tumours develop in other organs very infrequently, they may become
more significant in the case of elements that are particularly soluble,
such as americium or curium, as well as in the observed cases of synergy
involving many co-factors (Morin et al, 1 9 7 7 ) .
The potential risk from deposition in the gonads by an alpha emitter
constitutes a special case. Data on the genetic effects of plutonium and
the transplutonium elements are very sparse.
2 . Cells Affected by Alpha Irradiation; Cell Type, Function and Radio-
sensitivity
2 . 1 Criteria for defining tissues and cells exposed to risk
The criteria normally selected for assessing somatic risk are the
factors that have a harmful effect on the individual as a whole (ICRP 1 1 ; ,
1 9 6 9 ) . The most important effects, which have direct consequences for the
health of the contaminated person, are as follows:
( 1 ) shortening of the life-span;
( 2 ) anatomical or functional changes in the tissues directly exposed;
( 3 ) the induction of malignant tumours.
Those effects that are offset by a biological response and thus have
no apparent anatomical or functional repercussions are normally disregarded.
For example, the widespread destruction of macrophages by the inhalation of
plutonium particles is offset by the high reproduction rate of these cells,
with the result that the total population in the lung may be above normal
86
(Masse, 1 9 7 1 , 1 9 7 7 ) .
When an effect is studied in isolation, it must be borne in mind that
the same cause (contamination by alpha emitters) produces several effects,
that these effects are not normally simultaneous but consecutive, and that
the appearance of some may prevent the occurrence of others. For this
reason it is essential that these events are studied in sequence, viz. by
examining the effects of a large range of doses. Moreover, these effects
may not only conceal one another but also interfere with each other. Thus
a given frequency of cancers must influence the life-span, but it is just
as likely that other factors bearing no relation to the cancer may inter-
vene. Experiments have frequently shown that animals with cancers induced
by alpha emitters live longer on average than animals of the same exposure
group which have no cancers; this fact is simply related to the latent
period of cancer induction which is equivalent to a relatively large
fraction of their life-span (Morin et al, 1976; Lafuma et al, 1976 ) .
The interference of various pathological effects is most marked in the
lung. Hence the relative importance of each of the following factors in
causing early death is very difficult to gauge accurately:
( 1) respiratory insufficiency and its cardiovascular repercussions;
(2) a reduced resistance to respiratory infections;
( 3 ) any other pathological change in the pulmonary tissue.
In the light of histopathological knowledge, however, it is possible
to distinguish certain cell types according to their kinetics, function and
sensitivity. As direct exposure of cells to alpha radiation is the prime
consideration, the only cells and tissues discussed will be those whose dis-
tance from the primary site of radioactive deposition or from the particle
does not exceed the path travelled in the relevant tissue by the alpha
emission.
2.2 Cell types in relation to alpha irradiation
2.2 .1 Respiratory system
Retention of inhaled particles in the nasopharyngeal (N-P) region
(ICRP Task Group on Lung ])ynamics, 1966) increases very rapidly with the
size of the particle, for while less than 10% are retained in the case of
particles measuring 1 +un (AMAD) about 70% are retained for $ pm particles
and virtually 100% for particles measuring more than about $0 pm.
Elimination in the faeces is rapid and takes place in a few days but,
despite this brief stay in the nasopharynx, it is possible that a single
87
substantial contamination may deliver an appreciable dose to particular
regions of the nasopharynx, especially in the case of a radionuclide with
a high specific activity. In fact, no effect has ever been observed in
spite of the large number of cells that are liable to suffer damage from
alpha irradiation, such as the cells of the basal layer and of the ciliated
epithelium, chromaffin cells, and the serous and mucous acini cells.
It should be pointed out, however, that experimental data on the
effects of large particles are limited; if there is any risk, it is cert-
ainly much lower than the risk associated with the deposition of an equiva-
lent amount of activity in the lower respiratory tract. Elimination by the
gastrointestinal tract has not produced any pathological effects in cells
of the gut wall.
Tracheo-bronchial and pulmonary regions
In the ICRP lung model ( 1 9 6 6 ) the lower regions of the respiratory
tract are divided into the tracheo-bronchial (T-B) and pulmonary (P)
regions. About 5% of relatively large particles measuring, for example,
about 5 pni (AMAD) may be retained in the T-B compartment. These free,
non-phagocytosed particles may deliver significant doses in the space of a
few days, while retained in the T-B compartment. This is likely to be of
minor importance, however, for the following reasons:
( 1 ) no effect has ever been observed in relation to deposits in this
region which are rapidly eliminated via the upper airways and
swallowed;
(2) the dose is always small in comparison with the dose to the pulmonary
region of the lung.
However, it must be borne in mind that extrapolation of the dose-effect
relationship from animals to man is especially difficult where cancers in
this region are concerned. In fact, the upper bronchial tubes are normally
the most common sites for human cancers although some recent work has
suggested that up to £0% of human lung cancers may arise in the terminal
bronchioles (Wynder and Hecht, 1 9 7 6 ) . The trachea, on the other hand, is
affected only very rarely (Chretien and Masse, 1 9 7 5 ) • The preferential site
in animals is, in the main, the terminal bronchi, whereas the upper airways
are very seldom affected. This observation indicates clearly that cancer-
prone cells are located in different regions, depending on the species in
question (Lafuma et al, 1 9 7 U ; Chretien and Masse, 1 9 7 5 ; Bair et al, 1 9 7 U ;
Bair 197i+b).
Observations on animals (Masse, 1 9 7 6 ; Ducousso et al, 1 9 7 3 ) have shown
88
that there is direct breaching of the walls of the bronchioles and that
particles pass directly through the epithelium; this has not been quantified,
however. Observations have shown (Masse et al, 1 9 7 3 ) (Figure 5 . 2 ) that
there is penetration by the particles, followed by their retention in the
region of the bronchial cells, and that this is not affected by any phago-
cytosis. In view of the direct relationship which exists between the
presence of these particles in the ciliated epithelium and the basal cells
and retention in the bronchi, this phenomenon, if it occurs in man, might
contribute towards the neoplastic changes in this region.
Finally, it is in the deep lung that the deposited material remains
longest, and where the relationship between contaminants and biological
components is closest and has been studied most thoroughly. The pulmonary
epithelium appears to be simple, being composed of pneumocytes I and
pneumocytes II; the latter possibly giving rise to the former. There is no
longer any doubt about the origin of alveolar macrophages; they are derived
from the blood monocytes and therefore originate in marrow (Pinkett et al,
1 9 6 6 ) . They can multiply within the alveoli (Masse et al, 1 9 7 0 ) . In
pathological conditions, a stage of interstitial maturation may be observed
(Bowden et al, 19^9)> whereas, in physiological conditions, cellular
maturation occurs directly in the capillaries and alveoli (Masse et al,
1 9 7 7 ) .
With the possible exception of pneumocytes II, these different cell
types are able to accumulate foreign particles by phagocytosis and are
therefore liable to receive high radiation doses. The most actively
phagocytic of these cells is the alveolar macrophage which can ingest
several particles simulataneously, even when these are large. In general,
small particles aggregate within the cell and thus the dose rate to the
component parts of the cell directly adjacent to them is very high and
leads eventually to the death of the cell (Masse et al, 1 9 7 7 ) . Although
macrophages are radioresistant, it is difficult to compare the doses
delivered by external radiation and those received from an internal alpha
emitter. The epithelial cells situated at the bronchiolo-alveolar junction
seem to be especially sensitive to alpha radiation since many malignant
changes appear to originate in this area in animals (Chapter 6 ) .
Blood and Lymph Vessels of the Lung
The blood vessels of the lung are anatomically and physiologically of
special significance; the capillary endothelial cells represent about half
of all the alveolar cells of whatever origin (Miller, 1 9 5 2 ; Fritsch et al,
Figure 5.2 Formation of retention crypts in the monkey (baboon) with
penetration of the peribronchial alveoli after inhalation of
tantalum particles (information provided by R. Masse, CEA,
Departement de Protection, France).
89
90
1 9 7 7 ) » making them numerically the most important of the exposed cell
populations. They are irradiated directly since the endothelial cells of
the capillaries are within reach of the alpha irradiation coming from
actinides deposited in the deep lung, both when the contaminant is free in
the alveolus or when it is contained in macrophages (Figure 5 > . 3 ) . The
relationship between these vascular cells and the damage to them caused
by alpha radiation merits closer examination since the pathology is constant
and because the distribution of vascular tissue in the lung is uniform.
Pathological changes consist mainly of a chronic interstitial pneumonia with
slow, progressive obliteration (Masse et al, 1 9 7 5 ) * Malignant changes of
the haemangiosarcoma type are rare (Fritsch et al, 1 9 7 7 ) . The endothelial
cells probably have quite a higfr sensitivity to alpha radiation. They are
relatively sensitive to external radiation since 2 0 0 0 rad ( 2 0 Gy) delivered
by X-rays at a high dose-rate produces after a few months, cellular
necrosis of these elements (US NRDL, 1 9 ^ 6 ) ; moreover, they have the property
of accumulating certain soluble radionuclides (Masse et al, 1 9 7 5 ) *
It is probable that these changes to vascular tissue are soon
accompanied by a thrombosis in which the local blood platelets play an
important part (Cottier, 1 9 7 5 ) - These evolutive cell processes are a very
important contributory factor in the establishment of parenchymatous
fibrosis which appears as a final stage. Other contributory factors are
changes to the pneumocytes and the resultant fibrinous exudate.
Other vascular cells can be affected by alpha irradiation. These
include the endothelial cells of the terminal arterioles and the post-
capillary venules, as well as the components of the vascular supportive
tissue, such as fibroblasts and fibrocytes. Irradiation of some of these
components - elastic, collagenous, basilar and reticular fibres - might be
at the root of cardiovascular disorders, of which hypertension of the
pulmonary arteries is a typical case.
The mononuclear cells which circulate in these vessels and which make
up almost 20% of the cells of the alveolar wall (Fritsch et al, 1 9 7 7 ) are
liable, where clearance from the lungs is sufficiently slow and their life
span sufficiently long, to receive doses that produce appreciable effects.
Irradiation of the blood circulating within the lung is one of the elements
in the aetiology of the lymphopenia often observed experimentally in various
species, such as the dog (West and Bair, 1 9 6 I + ; Pa*k et al, 1 9 7 2 ; Buldakov
et al, 1 9 7 0 ) or, less often, in monkeys (Nolibe, 1 9 7 6 ) .
On the other hand, changes to other blood cells, such as polymorpho-
91
Figure 5 *3 Alpha emitters in an endothelial cell (information provided by
R. Masse, CEA, Departement de Protection, France).
92
nuclear leucocytes, are not observed when deposition is confined strictly to
the lung, but only when the actinides have migrated to bone; this distinc-
tion is particularly marked with high specific activity radionuclides, such
as plutonium-238 (Park et al, 1970) .
The presence of cellular infiltrates is sometimes observed after
pulmonary contamination by alpha emitters, especially if these are insoluble
(eg, plutonium dioxide); these infiltrates are composed principally of
granular leucocytes, lymphocytes, macrophages and plasma cells. They form
part of the response to the irradiation and there is still some doubt as
to the possible effect of the alpha radiation on these cells and, subse-
quently, on their defence mechanism function. Nevertheless, the total
number of cells affected is very small (Fritsch et al, 1 9 7 7 ) .
The pulmonary lymph vessels are also exposed as they are one of the
routes along which particles deposited in the lung are normally cleared.
Although dose-rates seldom reach high levels, the doses that are received
can be very high since in certain cases (for example, with non-transportable
compounds and others of low transportability) this particular route is
favoured (ICRP Task Group on Lung Dynamics, 1966) . Moreover, it is
conceivable that the dose-rates are subsequently increased as a result
of the obstruction of lymph vessels associated with local irradiation.
The resultant local oedema might then play a part in the formation of
pulmonary fibrosis.
Since the radiation induced lesions are replaced by scar tissue, the
risk incurred by the latter should also be examined. In fact, this replace-
ment tissue can appear well before most of the irradiating contaminant has
been removed. The component parts of the supportive tissue in the lung -
whether normal or replacement tissue - represent cell populations that are
exposed to risk (fibrocytes and fibroblasts). Information on the sensitivity
of different scar tissues is meagre. It is possible that the final effect
is relatively beneficial since scar tissue encapsulates the alpha emitter
to some extent and thus protects cell populations that are much more
sensitive. Obviously, this hypothesis does not preclude effects related to
the size of this replacement tissue which in extreme cases can be sufficient
to cause death.
Lymph Nodes
The consequences of the deposition of plutonium in the lymph nodes in
an insoluble form and, to a lesser extent, in a soluble form, or the
deposition of trivalent transplutonium elements constitutes one of the most
93
important areas of research into the radiotoxicity of alpha emitters. In
fact, for insoluble transuranium elements, the lymph nodes retain activity
with a long half-time; the slow clearance from the nodes can lead to very
high concentrations of the contaminant, whether contamination occurs
through a wound or by inhalation. In the latter case, the concentration
factor and consequently tissue doses can be very high in view of the
differences in mass of the pulmonary parenchyma and the lymph nodes (Pochin,
1 9 6 6 ) .
Routes followed by the lymphocytes circulating through the lymph nodes
are not straightforward and do not conform to any standard pattern. The
study of lymphocyte behaviour is made even more difficult by the presence
of several cell populations which seem to differ in origin, function,
sensitivity, and preferred localization. After entering the node by its
hilum, the lymphocyte carried in the blood can arrive in the parenchyma by
crossing the walls of the post capillary venules situated below the
capillary system; these vessels are found in the para-cortical region of
the node, on the inner edge of its cortical zone. It is in this zone that
the T lymphocytes, which represent about half of the total lymphocyte
population of the node, tend to concentrate. These T lymphocytes also make
up the majority of the lymphocytes that are released into blood circulation
which they reach after returning to the intranodal lymphatics. B lympho-
cytes, which are found mainly in the lymphoid follicles, make up the second
population of lymphocytes that are involved in radiation effects. The para-
cortical areas of the node contain quite large numbers of T and B lympho-
cytes; the large number of macrophages and granulocytes can be involved in
an anti-inflammatory response. Immune reactions lead to an increase in
the number of lymphocytes, probably by the two processes of migration and
local proliferation.
The presence of an alpha emitter in the node, whether or not in
particulate form, can therefore have an effect on its fixed cellular
components, and on the stock of sensitive cells circulating in the normal
way. It is possible that secondary reactions, due to quantitative and
qualitative changes to these lymphocyte populations; take place some
distance away in other lymphoid tissues such as splenic tissue or Peyer's
patches.
The^influence of radiation from alpha emitters on the immune response
is equivocal. On the one hand, it seems that a diffuse deposit, both in
the pulmonary parenchyma and in the nodes, is accompanied by a lessening
of the resistance to infection (Lafuma et al, 1 9 7 4 ) > and that there is a
9 ^
relationship between the homogeneity of distribution of the radioactive
deposit in the organ and the latterfs susceptibility to infection. On the
other hand, the only effects of localised irradiation, ie, not associated
with other, in general non-radioactive, harmful factors, are confined to
the site of irradiation. Moreover, the size of the local response is
proportional to the radiation dose. Present theories attributing radiation
carcinogenesis to a reduction in the general defence mechanisms have not
been conclusively demonstrated, although the lowering of cell-mediated
immunity leads to a large increase in the sensitivity of the rat to
carcinogenesis induced by alpha radiation (Nolibe et al, 1977a ) . It is
also possible that the replacement of the healthy node tissue by scar
tissue which scarcely functions, if at all, has an influence on the local
immune response.
Many other components of the node can be affected, but to a lesser
degree. This fact may be related to the greater radioresistance of the
macrophages and the reticular cells, of other blood cells, and the cells
of the capsule. This fact may also be related to the concentration of
the radionuclide in the area of the node where these components are
situated, such as in the para-cortical sinuses and in the medullary rays
which contain very few primordial lymphoid cells. This non-homogeneous
distribution is typical, even in the case of pulmonary contamination by
elements that are especially soluble. It is of particular importance
in the case of the formation of "hot spots" in the nodes.
Pulmonary Nervous Tissue
The components of the intra-pulmonary nervous tissue are much less
affected by intra-pulmonary irradiation if only because they are
quantitatively small in number. The very low frequency of tumours
arising in this nervous tissue in rats is not necessarily a sign of high
radioresistance, but may simply be related to the small populations
exposed to risk. This hypothesis could account in particular for the
absence in the rat of "oat cell" carcinomas which originate in the
neurosecretory cells of Kultschitsky as this cell type is found only
rarely in the rat (Pritsch et al, 1 9 7 7 ) .
2.2.2 Skeleton
It is well known that different transuranium elements deposit in
different component parts of adult bone. Distinctions should be made
first of all not on the basis of anatomical but of functional criteria.
95
Thus it is the type of tissue at risk which determines the nature of the
pathology. In this discussion, osteogenic tissue and bone marrow are of
central importance.
Bone
The main area of deposition of the transuranium elements in contrast
to the alkaline-earth elements, is the surface of the bone (Chapter i+).
Measurements made on a mature bone show that the distance separating the
bone cells (osteoblasts and osteoclasts) from the surface is in the region
of 10 pm (Vaughan, 1970; ICRP 1 1 , 1968) . This does not preclude the
presence of osteogenic cells in the marrow (Owen, 1970) . Irradiation of
the osteogenic population can give rise to neoplastic formations of the
osteosarcomatous, chondrosarcomatous or fibrosarcomatous type. The
temporal and spatial distribution of the doses delivered to the bone
depends partly on the form in which the radionuclide has been absorbed.
Different effects may therefore be expected, according to the elements
and compounds that are administered; this has in fact been confirmed in
experiments (Morin et al, 1976; Thomas et al, 1972; Ballou and Morrow,
1973)* Plutonium concentrates in large quantities in the osteolytic
periosteum, initially in the phagocytes and then in the fibrous part of
the tissue.
Trivalent elements, such as americium and curium,concentrate readily
in the walls of the vascular canals (Figure 5 » 4 ) ; they seem to be closely
associated with the cartilaginous matrix.
A crucial factor that has to be taken into account is the number of
the cells affected by alpha irradiation. Thus, whether a theoretical or
experimental approach is adopted, the large number of endosteal cells
assumes particular importance. In man, the periosteal and endosteal
surface areas are in the ratio of 8:100 (Sissons et al, 1967) which means
that the endosteal cells are more likely to be the site of malignant
changes. Experiments confirm this working hypothesis (Taylor et al, 1969;
Rosenthal and Lindenbaum, 19^9)• The observation that a uniform distribu-
tion of the element in this bony tissue is more carcinogenic that a non-
uniform distribution for a given level of activity shows the importance
of the number of cell components that are exposed to the risk of malignant
changes (Morin et al, 1977; Rosenthal and Lindenbaum, 1969) .
Bone Marrow
Bone marrow is a composite tissue, which in man and animals is the
origin of many types of tumour, each possibly deriving from a cell type in
9 6
Figure 5 - 4 Localization of curium-2i+2 in the vascular canals after
inhalation of curium-242 nitrate (Nenot et al, 1 9 7 2 ) .
97
the tissue (Vaughan, 1973)* Bone marrow is of mesenchymatous origin, and
contains precursors of the red blood cells, the granulocytes, the megakaryo-
cytes and of a part of the lymphocyte population (Owen, 1970) . Marrow is
in addition amply endowed with vessels (and hence endothelial cells) and
with supportive tissue.
The way in which transuranium elements are deposited in the skeleton
is certainly responsible for the consistently low frequency, or non-
existence, of tumours developing in tissue of mesenchymatous origin, with
the exception of leukaemias. In all animal experiments tumours such as
hemangiosarcomas or fibrosarcomas are always very rare (Taylor et al, 1969;
Masse, 1976) .
On the other hand, a certain number of leukaemias or, more precisely,
tumours arising from uncontrolled proliferation of the marrow cells, have
been observed in animal experiments, with various organs being secondarily
affected, such as the liver, the spleen and the kidney; these leucoblastic
processes are sometimes associated with severe anaemia (Vaughan, 1970) .
Leukaemias occur more frequently with plutonium than with transplutonium
elements (Nenot et al, 1972 ) .
2 .2 .3 Liver
A close study has been made of hepatic tissue with its two main
components, hepatocytes and reticuloendothelial cells; this is particularly
because the rates of hepatic clearance and the relative distribution between
the two component tissues differ enormously from one animal species to
another. In spite of the long residence time of plutonium in the dog and
monkey liver and the presence of large quantities of alpha emitters in the
organ, tumours are observed in it very infrequently, if at all. However,
despite the low incidence of liver tumours in experimental animals, the
liver in man must be considered potentially at risk from intakes of
actinides.
2*2.h Other tissues or organs
There has been a considerable increase in recent years in the number
of tissues or organs that have been found to be directly affected by alpha
irradiation and therefore at risk (without precluding the indirect effects
discussed above); this is due to the increasing number of studies carried
out and the increasing range of compounds and elements used. Thus in
animals that have inhaled plutonium-239 dioxide calcined at a high tempera-
ture the lung is the main organ at risk. Transportable compounds of the
same isotope also expose the skeleton and the liver to high doses. Much
98
more soluble elements such as americium-21+1, curium-21+2 and curium-21+1+,
califoxnium-2f>2 and einsteinium-253» of whatever physico-chemical form,
or even certain compounds of plutonium-238 (ultra-filterable microspheres,
for example) although depositing mainly in the bone and liver are dispersed
throughout the whole of the organism and therefore irradiate a considerable
number of cell types (Ballou and Morrow, 1 9 7 3 ; Nenot and Lafuma, 1 9 7 6 ;
Taysum and Taylor, 1 9 7 2 ; Morin et al, 1 9 7 1 + ; Nenot et al, 1 9 7 1 a ; Taylor
et al, 1 9 7 1 ) . It is impossible therefore to discuss all the tissues
potentially at risk. The main aim must be to determine the levels of
relative risk and to select the critical tissues.
The deposition of soluble elements in the gonads, which contain the
stem germ cells, theoretically exposes them to the dual risk of cancer and
a genetic effect. In experimental animals exposed to actinides no tumours
have been found in the gonads nor have genetic effects ever been demon-
strated. The risk of genetic effects in man must however still be considered.
Finally, it should be noted that the number or organs or tissues
exposed to risk and therefore, ultimately, the number of cell types, is
particularly important for elements which translocate readily in the body.
As cancerous changes are the most important long term pathological effects
that need to be considered, the important factor is no longer the individ-
ual risk to a cell type but the cumulative risk to all the cell types that
are exposed. In other words, in view of the seriousness of cancer the
important unit to take into account is neither the cell, nor the organ or
tissue, but the individual as a whole.
3 . Inter-relationships between effects of Alpha Emitters and Affected
Cells
3 . 1 Influence of cell kinetics on pathological effects
Consideration has to be given to cell kinetics since it is important
in the phenomena of both carcinogenesis and the repair of damage caused by
irradiation. Most of the models put forward are purely speculative, for we
still do not know enough about the mechanism of carcinogenesis, the main
cell types that are involved and the way in which they are renewed. Inter-
action of the various kinetic systems makes an experimental approach very
difficult. For example, a part of the macrophagic population which is
mobilized after respiratory contamination is of bone marrow origin; differ-
ences in response are to be expected, depending on whether the stem cells
of these macrophages were irradiated in situ, as is the case with trans-
portable transplutonium elements with large bone deposits, or not, as is
99
the case with the oxide of plutonium-239. The substantial accumulation of
alpha emitting elements in the macrophages would certainly account for the
rapid death of the cell rather than for any neoplastic changes. However,
it seems surprising that no tumour of this type has ever been described,
considering the constancy of dose delivered to this particular cell
population and the very large number of experiments carried out in very
many laboratories. It should be pointed out, however, that spontaneous
tumours derived from the mature macrophagic system are open to many
different interpretations with the probable exception of histiocytosis-X
in man.
Although our level of knowledge about lymphocytes and their variation
between species is much greater, it is still difficult to correlate their
kinetics with the observed effects if one takes into account both the
compartments in which they lodge and the residence times.
3 . 2 Influence of alpha emitters on certain cell populations
It is in the lung that the effects of alpha irradiation are most
apparent. The earliest effect observed is the death of a large number of
macrophages, associated with the great phagocytosing capability of these
cells.
Phagocytosis is very rapid and acts on a very large part of the inhaled
contaminant. Histologically, the surviving macrophages appear to be
abnormal, a reflection of the effects of radiation is shown, for example, by
their increased size and by the activity of their lysosomes (Masse, 1 9 7 7 ) .
There are also disruptions in the mechanisms in which they are normally
involved; thus, clearance may be affected (Nenot, 1 9 7 1 ) , there may be a
reduction in the mobilizable population that can be extracted from the lung
by lavage (Masse, 1 9 7 1 ) * The death of the macrophages releases the alpha
emitter into the air spaces; the actinide may then be rephagocytosed by a
healthy macrophage. This phenomenon may recur several times, but experi-
mental data does not at present allow a full understanding of all of the
factors involved in this mechanism, despite its apparent simplicity.
Phagocytosis by the endothelial cells in the pulmonary capillaries is
very limited. Lesions due to the presence of the alpha emitter are of the
exudate type. This exudate, rich in fibrin, is soon accompanied by an
increase in the fibrous supportive tissue with many breaks to the endothe-
lial layer. The thromboses in the arterioles and capillaries are similar
to the lesions observed after external radiation (Sanders et al, 1 9 7 1 ) .
100
Lesions in the lung will be described in Chapter 6 (Biological Effects).
Effects on the pneumocytes and the other main components of the deep lung
are direct and the inter-relationships between the physical behaviour of
the emitter and the biological behaviour of the cell are less clear.
i+. Discussion
It is extremely tempting to see a direct link between the alpha
radiation dose to tissues and the malignant or non-malignant changes which
result. The main direction followed by comprehensive work on the risk to
cell populations exposed to radiation is based on the supposition that the
dose must be received directly by a particular cell or cell population in
order to bring about pathological changes. This concept differs from the
hypothesis of a correlation between the seriousness of the effect and the
size of the cell population that is exposed. Experiments on animals and
observations on humans generally produce evidence in favour of the latter
theory. It is less easy to demonstrate that irradiation of a particular
tissue is needed in order to produce an effect. Substantial evidence in
favour of this concept is provided mainly by the almost total absence of
extra-pulmonary cancers after inhalation of insoluble plutonium, in contrast
to the widespread distribution of cancers found after inhalation of actini-
des that are readily transportable in the body. However, when the distri-
bution of these actinides in the organs that give rise to radiation-induced
cancers is studied, a number of anomalies emerge. For example, in animals
of the same strain elements which are deposited in completely different
ways would be expected to give rise to cancers whose site of initiation and
histological type would relate to the region of deposition. This is not so,
however, since analysis of the different types of pulmonary cancers induced
in the rat by such widely-differing alpha emitters as the transuranic
elements, which are deposited in the deep lung, and radon daughters which
are deposited in the upper airways, show a very similar distribution
pattern (Morin et al, 1 9 7 6 ) . This observation may partly result from the
fact that in the rat the frequency of spontaneous bronchial tumours is
practically nil; but it does not explain why the frequency of bronchiolo-
alveolar cancers due to inhalation of radon and its daughters (Chameaud
et al, 1976) should be practically identical to that due to parenchymatous
irradiation produced by the inhalation of plutonium-239 dioxide.
A second problem that needs further study arises from the lack of
consistency that is often observed between the cells that receive the
greatest dose and the histology of the observed tumours. It is very
difficult to arrive at a complete understanding of the histology of each
1 0 1
species and strain, particularly as the development of a "naturally"
occurring cancer may require a promoting agent. It is clearly very diffi-
cult to link the manner of the irradiation with the type of cancer when it
is observed that after inhalation of actinides giving approximately the
same radiation dose to the lung the frequency of pulmonary sarcomas is
2 .5% in one strain of rat and 17% in another (Morin et al, 1 9 7 6 ) . An
extra-ordinarily high frequency of a rare tumour (angiosarcoma) in the
dog has also been noted in dogs that had inhaled cerium-1I4+ in fused clay
particles (Hahn et al, 1973)* This second difficulty may be less discoura-
ging than it at first seems for just as it is essential that the kinetics
of cells at risk should be studied, it is equally important to carry out a
full study of the development of cancer. Two facts then become apparent:
( 1) Cellular changes follow one another in time, always in the same order,
and there is no break in the sequence. For example, in the rat lung
the stages of metaplasia and of adenomatosis precede that of adenoma
which, in turn, precedes that of carcinoma (Morin et al, 1 9 7 7 ) . For
a given dose the periods between the appearance of each effect are of
the same order, the rate of development of the various stages, however,
is a function of the dose. This phenomenon may be responsible for the
predominance of a certain type of cancer after medium doses and of
another type after high doses. For example, bronchiolo-alveolar
carcinoma predominates in rats at low doses, whereas bronchogenic
carcinoma predominates at high doses.
(2) Not only can the different stages in the development of cancer exist
at the same time in the same organ, but it is not unusual to observe
an inter-relationship between different types of cancer. If this
observation is extrapolated to the temporal development of tumours,
it could be concluded that there is really no standard type of lesion.
Thus, a simple lesion at a given time, as seen by histological
examination, becomes a composite lesion when its development with
time is taken into account.
The relative radiosensitivity of cells plays a large part in radiation-
induced pathology. Two points need to be made here: ( 1) The definition of
radiosensitivity is often vague; in fact the most sensitive cell populations
are not necessarily those which develop most cancers - on this basis the
cells in the pulmonary region that would be most liable to cancer induction
would be the epithelial cells. In practice this is not the case. This
phenomenon cannot be accounted for by sterilization (Fritsch et al, 1 9 7 7 ) .
102
It must therefore be concluded that the target cells are cells with a
higher potential for the development of cancer. This may correspond to a
form of ageing in the cell types involved: ciliated cells in the lower
bronchial tubes, Clara cells and pneumocytes II of the bronchioles and
alveoli (Fritsch et al, 1 9 7 7 ) • ( 2 ) Rather than considering the radio-
sensitivity of individual cells, it may be more appropriate to determine
the sensitivities at higher levels in the scale or organisation, whether
at the level of the organ or of the whole body. This concept, moreover,
is in line with current thinking about carcinogenesis.
Finally there are numerous co-factors that are involved in human
pathology and which may influence the development of radiation induced
cancers. Their influence cannot be quantified until more information is
available.
Acknowl e element
The authors would like to express their gratitude to Dr. Roland Masse
for agreeing to revise this chapter.
Chapter 6
P A T H O L O G I C A L EFFECTS IN ANIMALS
1 . Introduction
A substantial amount of experimental research work has been published
on the toxic effects of plutonium, transplutonium elements and other alpha
emitters in animals. These studies have examined different modes of
contamination using various animal species, and have been concerned both
with short- and medium-term toxicology and long-term toxicology. All the
laboratories involved in these studies have concentrated on long-term
effects; these are of major concern for the health of humans, since short-
and medium-term effects are only possible in accidental situations which by
their nature are exceptional. The scarcity or, indeed, the absence of human
data (Chapter 3 ) makes extrapolation of the results of animal studies to man
very difficult, whether for the estimation of lethal of sub-lethal doses,
or dose response relationships for the induction of cancer.
Due to technical difficulties only a limited number of laboratories
are concerned with research into low dose levels. This research is lengthy,
particularly when it entails examining animals with a long life span, such
as the dog or the monkey, it is expensive, and there are difficult problems
of interpretation of the results obtained. In addition to the studies which
concentrate on mortality there are a few studies on radiation-induced
diseases. These studies are, however, very limited because of the diffi-
culties of evaluation and quantification and of the importance for man of
the mortality studies on which emphasis has been placed.
Plutonium is the toxicological "model" for actinides, although from
the physico-chemical and, hence, metabolic point of view its behaviour is
the most complex (Chapter k)»
It is convenient to separate somatic effects into two distinct types:
( 1 ) early and medium-term effects;
( 2 ) delay effects.
These correspond to non-stochastic and stochastic effects (ICRP 2 6 , 1 9 7 7 ) .
2 . Early and Medium-Term Effects
2 . 1 Acute toxicity
There are few studies of the acute radiotoxicity of plutonium, probably
because they would have little relevance to radioprotection. In fact, the
L D ^ 0 o f intravenously-administered plutonium is in the region of
103
10k
— 1 —1 —1 —1
1 mg kg" or 6 1 . 3 p.Ci kg" ( 2 . 3 MBq kg ) in the rat and 0 . 3 mg kg" in the
dog (Moskalev, 1 9 7 2 ) ; extrapolation to man is too difficult for an exact
figure to be given, because of the great anatomical, physiological and
pathological differences between the three species. The L D ^ Q ^ Q °^ inhaled
plutonium-239 in man, which is easier to estimate by extrapolation from
animal studies, is probably about 5 0 mg, or 3 niCi ( 1 1 1 MBq). In this case,
death occurs as a result of massive pulmonary oedema and pulmonary
haemorrhage.
Clearly, it is very difficult to imagine a man inhaling amounts of
plutonium exceeding about 1 0 milligrams. On the other hand, it would be
more reasonable to envisage inhalation of an alpha emitter with a higher
specific activity; for example, the L D ^ Q ^ Q o f plutonium-238 would be
0 . 2 mg. However, even this amount is unlikely to be inhaled except in
exceptional accidental conditions.
The chemical toxicity of plutonium, americium and curium is sometimes
referred to, although no experimental result has demonstrated such an
effect. It is, however, possible to extrapolate from results obtained from
elements with very long physical half lives; very low specific activities
enable acute or subacute chemical toxicity to develop before any delayed
radiotoxic effects appear. This is the case, for example, with neptunium-
2 3 7 , with its physical half life of 2 . 2 million years and a specific activ-
ity 1 0 0 times smaller than that of plutonium-239 (Casey et al, 1 9 6 3 ) . By
comparing the toxic effects of neptunium-237 on the liver with those of the
stable isotope of cerium (Snyder et al, 1 9 5 9 ) , both of which are analogous
to plutonium in respect of their oxidation states and ionic radii ( 0 . 9 2 X ) ,
it has been shown that the maximum permissible body burden of plutonium-239
(k0 nCi, 1 . 5 kBq) (ICRP Publication 2 , 1 9 5 9 ) is smaller by a factor of about
3 3 0 0 0 0 than that which might produce a detectable chemotoxic effect in the
liver (Dolphin et al, 1 9 7 U ) • Thus it is clear that any chemotoxic effects
of plutonium or of the long-lived alpha emitters of the transplutonium
series will not manifest themselves since to a very large extent they are
masked by the radiotoxic effects.
2 . 2 Medium-term effects
Medium-term pathology results from radiation damage to a number of
organs or tissues. Usually it is found in one particular tissue and depends
upon the metabolism of the radionuclide and hence on the mode of contamina-
tion and the physico-chemical form of the contaminant.
Several tissues or organs may be affected at the same time or in
105
succession, provided that pathological changes in the first tissue or organ
affected do not produce rapid death. Any list of the main effects is there-
fore arbitrary, although some clearly predominate in certain conditions,
such as the development of pulmonary fibrosis after inhalation of actinides
or damage to the bone marrow after their intravenous injection.
2.2 .1 Respiratory insufficiency
The clinical symptoms of respiratory insufficiency are an increase in
respiratory rhythm, a drop in arterial oxygen concentration and an increase in
arterial carbon dioxide concentration; these indicate diffuse fibrosis of the
pulmonary parenchyma. The development of fibrosis has been considered in
Chapter 5 (section 2 . 2 . 1 ) . Radiation-induced changes have particular
characteristics which will be described later.
Pulmonary Function
The pulmonary radiation dose required to induce pathological changes
that can be detected clinically or biologically varies from one animal
species to another; it is unlikely that the only factor involved is the
differences in life spans, although a greater natural longevity allows a
larger radiation dose to be accumulated. Medium-term pathological changes
to the lung result in death from respiratory insufficiency within periods
varying on average from one to several months after exposure. In rats,
initial deposits of activity in the deep lung which exceed 0.1 iCi g
( 3 . 7 kBq g~^) bring about functional changes (Buldakov et al, 1970;
Koshurnikova et al, 1968a; Antonchenko et al, 19^9)- In beagles, pulmonary
—1 —1
deposits of similar amounts (0.1 uCi g (3*7 kBq g" )) bring about
death by fibrosis or oedema in less than one year, whether the plutonium is
in the form of a soluble salt (nitrate) or the dioxide (Park et al, 1968; 1970) . At lower dose levels, corresponding to pulmonary deposits of about
—1 —1
0.05 jiCi g ( 1 . 9 kBq g ) or less, fibrosis is more localised and causes
death after a longer interval of about four years (Yuile et al, 1970) . No
plutonium isotope produces fatal fibrotic lesions at less than 0.02 ^Ci g
(0 .7 kBq g 1 ) (Park et al, 1 9 7 5 a ) . In baboons contaminated with plutonium-
239 dioxide at different dose levels fibrosis appears after about three
years and is always in a localised form; it is variable and non-uniform,
and does not cause death (Metiyier, 1 9 7 6 ) .
Similar observations on respiratory function have been made with
transplutonium elements, in particular with americium-24l in dogs (Buldakov
et al, 1972; Thomas et al, 1 9 7 2 ) .
106
Lesion Survey
It is apparent that medium-term toxicity is related to the manner in
which the radionuclide is distributed in the lung (Figure 6 . 1 ) , The more
uniform the dispersal of the element, the greater and earlier the effect.
Table 6 . 1 compares the minimum dose levels that are required to produce
comparable lesions in the rat after inhalation of plutonium, americium and
curium nitrates (Masse et al, 1 9 7 5 ) . In the first month, the main patho-
logical changes are an alveolar oedema and heavy desquamation, accompanied
by many capillary and arteriolar thromboses.
Table 6 . 1
Comparison of doses causing pulmonary lesions in rats after inhalation
of alpha emitters (Masse et al, 1 9 7 5 )
Date of appearance
of pulmonary lesions
Plutonium-239 nitrate Americium-21+1 nitrate Curium-2U1+ nitrate Date of appearance
of pulmonary lesions
Dose (rad)
1st month 17 ,500 5,500 3,500
between 1st and
3 r d month 9,000 U,500 2,500
after 3 r d month
5,600 3,5oo 1,500
Desquamation of pneumocytes II can even lead to the appearance of
pseudo-pores. Very high doses produce widespread necrosis of the parenchyma
and the animals die by drowning in their own fluids. At lower doses the
lesions become established between the first and the third month after
inhalation, with an appreciable growth of elastic fibres and reticulin, and
with interstitial infiltration. There is an uncontrolled growth of the
vascular bed accompanied by a thickening of the alveolar membrane. These
pathological changes account for the clinical development of acute respira-
tory insufficiency and cardiac failure. After the third month, the lesions
have typical features although they vary slightly from one element to
another. They consist of a chronic interstitial pneumonia, accompanied by
foci of classic pneumonia with hyaline membranes and desquamative pneumonia
and disorganization of the interstitial tissue (Figure 6.2). Islets of
pseudo-adenomatosis begin to form. Lesions which appear at times in excess
of one year after exposure occur at much higher cumulative doses. They are
107
Figure 6 . 1 Rat lung 30 days after inhalation of plutonium-239 nitrate.
Non-uniform distribution of the radionuclide in the organ
(information supplied by R. Masse, Departement de Protection,
GEA, France).
Figure 6 . 2 Rat lung 1 5 0 days after inhalation of americium-2Ul nitrate.
Desquamative interstitial pneumonia, with destruction of the
fibrous interstitial tissue (R. Masse et al, 1 9 7 5 ) .
108
109
difficult to demonstrate; the only clear indication being an increased
amount of reticulin. However, refined anatomical and pathological techni-
ques reveal a decrease in the number of capillaries and a disturbance of
the vascular bed. An abnormal cell growth, responsible for an increase in
the weight of the lung but unrelated to changes in collagen content, is
frequently observed. Plutonium induces the most heterogeneous lesions;
necrotic foci are frequent and the interstitial tissue can exhibit all
forms from the normal state to atrophy, including a hyper vascular
condition, infiltration and emphysema.
Curium, in contrast, with its uniform distribution in pulmonary tissue,
produces lesions of atrophic interstitial pneumonia, causing emphysema and
there are large vascular lesions accompanied by oedema. These changes can
allow the entry of infections. It is probable that uniform high dose rate
irradiation from curium does not allow the mobilization of the cell pool
involved in the interstitial reaction that is observed with plutonium or
americium. All these late lesions are generally preceeded by lesions of
bronchiolar and bronchioloalveolar metaplasia. Epidermoid metaplastic
lesions appear in the rat at an early stage, within the first two months.
Adenomatosis occurs later, appearing on average towards the sixth month
(Figure 6 . 3 ) .
In the case of other rodents, such as hamsters and mice, the doses
needed to induce lesions identical to those observed in the rat are of the
same order. Thus, the L D ^ Q i n "the hamster after inhalation of plutonium-
2 3 9 dioxide is about 6 $ 0 0 rad ( 6 5 Gy) in about 7 5 days, and that of the
mouse about 1 1 0 0 0 rad ( 1 1 0 Gy) in about 6 5 days (Brightwell and Stather,
1 9 7 8 ) .
The lesions appearing in dogs are generally comparable (Thomas et al,
1 9 7 2 ) . Involvement of the pleura or sub-pleural localization of the lesions
seems to occur more frequently than in rats. Doses of 2 0 0 0 to $100 rad
( 2 0 to 9 1 Gy) are fatal when received over periods of between 2 and 11+
months ( 2 6 dogs out of 2 8 ) (Bair and Willard, 1 9 6 2 ) . In monkeys it appears
that lesions of chronic interstitial pneumonia are more uniform and largely
unrelated to the heterogeneous distribution in the lung of plutonium-239
dioxide (Masse et al, 1 9 7 5 ) . They appear at lower doses than those
producing the same lesions in rats. There are numerous explanations for
this, but none has been confirmed:
( 1 ) abundance of fibres and fibroblasts in the alveolar walls of monkeys;
( 2 ) the greater pulmonary clearance through interstitial tissue in monkeys
than in rats.
110
Figure 6 . 3 Rat lung six months after inhalation of plutonium. Adenomatosis
of the ciliated cells appears in an area adjacent to the
bronchi (information supplied by R. Masse, Departement de
Protection, CEA, France).
Ill
( 3 ) the greater lymphatic clearance in dogs as compared with that of
monkeys, since the integrity of this clearance route protects, in
particular, the lung against the appearance of fibrosis (Jennings
and Arden, 1 9 6 1 ) .
A comparison of the acute effects of plutonium-239 * cerium-1 hh and
strontium-90 has led some authors to advocate the use of an REE of 1 0 for
the early effects of the alpha emitters in the lung (Smith and Stather,
1 9 7 6 ) .
2 . 2 . 2 Blood
Observations relating to the biological effects on blood vary according
to the animal species studied. Rats and monkeys only show small blood
changes after inhalation, at all levels that have been studied. The deposi-
tion of 0 . 1 +xCi g" ( 3 . 7 kBq g~ ) of plutonium-239 dioxide in the lung of
the monkey is followed only occasionally by lymphopenia and only seems to
affect the B lymphocytes (Nolibe, 1 9 7 6 ) . On the other hand, observations
on beagles show changes to the normal composition of blood and to the blood
cell count in proportion to the dose.
The symptom that appears most invariably after inhalation of plutonium-
2 3 9 dioxide by beagles is lymphopenia. At doses corresponding to a
—1 —1
pulmonary deposition of 0 . 0 U +iCi g" ( 1 . 5 kBq g~ ), blood lymphocytes are
reduced to 3 0 - 5 0 % of the normal value from about one year after contamina-
tion and remain at this level during the whole life span of the dog (Park
et al, 1 9 7 2 ) . The other white blood cells are not affected so frequently.
At higher doses, (> 0 . 1 ^Ci g"1 ( 3 - 7 kBq g" 1)) the effect on the blood
appears much sooner and lymphopenia persists throughout the animal's life.
At much lower levels of respiratory contamination ( 0 . 0 0 1 jiCi ( 3 7 Bq
g~ 1)), lymphopenia occurs later, appearing on average after two years.
—1 —1
Levels as low as 0 . 0 0 0 3 ^Ci g~ ( 1 1 Bq g" ) are required if there are to be
no appreciable changes after three years (Park et al, 1 9 7 6 ) . As plutonium
deposits in the bone and in particular in haemopoietic tissues are very
small after inhalation of insoluble plutonium-239 dioxide, it is probable
that these changes to the blood are caused by the irradiation of the blood
circulating in the parenchyma of the lung and the nodes (Yuile et al, 1 9 7 0 ) .
This pathogenesis was discussed in Chapter 5 (in particular in section
2 . 2 . 1 ) .
This theory is in line with the effects on blood caused by soluble
forms of plutonium which irradiate in particular the haemopoietic tissues
after their translocation to the skeleton. Thus both the lymphocytes and
112
the neutrophils in the blood are depressed by inhalation of amounts of
plutonium citrate and plutonium nitrate that give doses to bone between
1 0 0 and I4OO rad ( 1 - 1 ; Gy) (Buldakov et al, 1 9 7 0 ; Ballou et al, 1 9 7 2 ) ,
Haematologic changes always appear earlier than with plutonium dioxide;
there is a drop in the total number of white cells towards the end of the
second week after exposure with widespread symptoms of lymphocyte and
neutrophil depression, leukopenia rapidly reaches 2$% of the normal value.
Apart from this, the erythrocytes, the haemoglobin count and the hematocrit
reading remain unchanged.
The effects of plutonium-238 dioxide are closer to those induced by
transportable forms of plutonium-239 than to those induced by its oxidized
forms, thus reflecting its relatively soluble nature (Park et al, 1 9 7 0 ) .
The effects on the blood after inhalation of transplutonium alpha
emitters are similar to those observed after inhalation of a transportable
form of plutonium. Their uniform distribution in the lung probably delivers
a higher dose to the blood cells than in the case of a non-uniform distribu-
tion; a fact which may explain why lymphopenia seems to be the most marked
phenomenon, overshadowing the effects on the other white cells despite the
large deposits of radionuclide in the blood-forming organs (Buldakov et al,
1 9 7 2 ; Thomas et al, 1 9 7 2 ) .
Einsteinium, is rapidly translocated from the lungs to the blood and
produces very large bone deposits giving high dose rates. With this radio-
nuclide the incidence of malignant changes to the primordial blood cells is
very high; these changes consist above all of lymphoid leukaemias and, to a
smaller extent, of myeloid leukaemias (Ballou et al, 1 9 7 2 ) .
Although qualitative changes to the blood have been widely studied,
observations on quantitative changes to the different cell types under
different experimental conditions are not sufficient to establish a dose
effect relationship. Determining such a relationship would pose considerable
problems in selecting the appropriate tissue or organ on which to base the
dose.
2 . 2 . 3 Lymph nodes
After contamination by inhalation or through a wound, some plutonium
is deposited in the regional lymph nodes which form the first drainage sites
from the point of entry into the body. The plutonium concentration in the
nodes may reach relatively high values, and in the case of pulmonary contam-
ination by plutonium dioxide, much higher values than the initial concentra-
tion in the lung. These deposits in the tracheo-bronchial and mediastinal nodes,
113
w i t h t h e i r s l o w c l e a r a n c e t o t h e b l o o d , p r o d u c e s i g n i f i c a n t p a t h o l o g i c a l
c h a n g e s . The p r i m i t i v e l e s i o n s c o n s i s t o f a d e p o p u l a t i o n o f t h e g e r m i n a l
c e n t r e s a n d a p r o g r e s s i v e e v o l u t i o n t o w a r d s f i b r o s i s , a c c o m p a n i e d b y a n
a b n o r m a l g r o w t h o f c e l l s . I t i s r e m a r k a b l e t h a t i n h i g h l y c o n t a m i n a t e d
a n i m a l s t h e l y m p h n o d e s w h i c h do n o t c o n t a i n p l u t o n i u m may a l s o b e t h e
s i t e o f a l y m p h o i d a t r o p h y ( B a i r e t a l , 1973) - B e c a u s e o f t h e t e c h n i c a l
d i f f i c u l t i e s a s s o c i a t e d w i t h s m a l l e r a n i m a l s , q u a n t i t a t i v e m e a s u r e m e n t s
h a v e b e e n made m a i n l y w i t h d o g s . I t s e e m s t h a t t h e b e s t c o r r e l a t i o n w i t h
t h e o b s e r v e d e f f e c t s i s o b t a i n e d w i t h t h e d o s e r a t e r a t h e r t h a n w i t h t h e
d o s e r e c e i v e d . P r e s e n t d a t a i n d i c a t e t h a t i n i t i a l a l v e o l a r d e p o s i t s —1 —1
e x c e e d i n g 0.001 | iCi g " (37 Bq g " ) o f p l u t o n i u m d i o x i d e a r e r e q u i r e d t o
i n d u c e a t r o p h i c l e s i o n s i n t h e i r r a d i a t e d n o d e s . At t h i s l e v e l l e s i o n s
r e q u i r e s e v e r a l y e a r s t o b e c o m e e s t a b l i s h e d ( B a i r e t a l , 1966) . H i g h e r
l e v e l s p r o d u c e l e s i o n s a t a n e a r l i e r s t a g e b u t v i s i b l e c h a n g e s i n l y m p h
n o d e s t r u c t u r e a r e f i r s t s e e n a t a c c u m u l a t e d p u l m o n a r y d o s e s o f a l p h a
r a d i a t i o n s l i g h t l y h i g h e r t h a n t h o s e w h i c h p r o d u c e o b v i o u s l u n g l e s i o n s
( Y u i l e , 1970) . D i f f e r e n c e s o b s e r v e d b e t w e e n p l u t o n i u m 238 a n d p l u t o n i u m -
239 w e r e n o t g r e a t a n d r e l a t e d m o r e t o k i n e t i c s t h a n t o a n a t o m o - p a t h o l o g y .
I n t h e c a s e o f c o n t a m i n a t e d w o u n d s , l y m p h n o d e l e s i o n s h a v e common
f e a t u r e s . A f t e r a n i n j e c t i o n o f p l u t o n i u m - 2 3 9 d i o x i d e i n t o t h e h i n d l e g s
o f d o g s , t h e p o p l i t e a l n o d e s e x h i b i t h y p e r p l a s i a w i t h m a c r o p h a g i c m o b i l i z a -
t i o n , z o n e s o f n e c r o s i s a n d f i b r o s i s , a n d t h e f i n a l t r a p p i n g o f t h e
p a r t i c l e s w i t h i n s c a r t i s s u e ( D a g l e e t a l , 1 9 7 5 ) .
2.2.1+ S k e l e t o n
A l t h o u g h t h e m a i n b o n e p a t h o l o g y f o u n d a f t e r d e p o s i t i o n o f a l p h a
e m i t t e r s i s o s t e o s a r c o m a - f o r m a t i o n , t h e r e i s a m e d i u m - t e r m p a t h o l o g y ,
p r o b a b l y o c c u r r i n g a b o v e a t h r e s h o l d d o s e a n d r e l a t e d t o t h e d o s e d e l i v e r e d .
T h e s e p a t h o l o g i c a l c h a n g e s a r e m o s t m a r k e d i f t h e a c t i n i d e d e p o s i t s r a p i d l y
i n t h e s k e l e t o n . The l e v e l s o f a c t i v i t y r e q u i r e d b e f o r e t h e s e e f f e c t s c a n
b e o b s e r v e d a r e a l w a y s h i g h , i r r e s p e c t i v e o f w h e t h e r t h e y a r e d e t e r m i n e d b y
c l i n i c a l , r a d i o l o g i c a l o r h i s t o l o g i c a l m e t h o d s .
H i g h d o s e s c a n i n d u c e f r a c t u r e s ; t h o s e m o s t f r e q u e n t l y o b s e r v e d
o c c u r r i n g i n t h e r i b s ( J e e e t a l , 1962; T a y l o r e t a l , 1962; Thomas e t a l ,
1 9 7 2 ) . I n b e a g l e s t h e maximum i n c i d e n c e o f f r a c t u r e s i s o b t a i n e d b y t h e 1 1
i n t r a v e n o u s i n j e c t i o n o f 1.0 t o 3.0 jiCi k g " (37 - 111 kBq k g " ) o f
p l u t o n i u m - 2 3 9 a s c i t r a t e . A f t e r t h e i n j e c t i o n o f a m e r i c i u m - 2 4 1 d i o x i d e t h e
d o s e t o t h e s k e l e t o n w h i c h c a u s e s r i b f r a c t u r e s i n d o g s a f t e r a p e r i o d o f
11U
a b o u t t h r e e y e a r s i s e s t i m a t e d t o b e 36OO r a d ( 3 6 G y ) . The f r a c t u r e s i t e s
d o n o t a p p e a r t o h a v e a t e n d e n c y t o c a n c e r - f o r m a t i o n .
S l i g h t r a d i o l o g i c a l c h a n g e s , r e l a t e d t o o s t e o p o r o t i c a n d n e c r o t i c
c h a n g e s a r e n o t e d m o r e f r e q u e n t l y . O s t e o p o r o s i s i s g e n e r a l i z e d b u t
m o d e r a t e , a n d i s a c c o m p a n i e d b y a c o n s o l i d a t i o n o f t h e g r o w t h c e l l s i n t h e
e p i p h y s i s a n d a c o r t i c a l t h i c k e n i n g o f t h e l o n g b o n e s (Langham e t a l , 1 9 5 1 ) -
T h e s e s k e l e t a l c h a n g e s a r e m o s t m a r k e d w h e n t h e c o n t a m i n a t e d a n i m a l i s
y o u n g ( B u s t a d e t a l , 1 9 ^ 2 ; C l a r k e , 1 9 6 2 ; F a b r i k a n t a n d S m i t h , 1 9 6 ! + ) . T h u s
a d m i n i s t r a t i o n o f p l u t o n i u m - 2 3 9 n i t r a t e a t l e v e l s o f 3 - 0 pCi k g " 1 ( 1 1 1 kBq
k g " ) o r a b o v e , g r e a t l y r e d u c e s b o n e g r o w t h ; t h i s o c c u r s a t much l o w e r
d o s e s t h a n w o u l d a p p e a r t o b e r e q u i r e d w i t h a m e r i c i u m . One y e a r a f t e r
i n j e c t i o n , a s h o r t e n i n g o f t h e l o n g b o n e s , a s c o m p a r e d w i t h t h e c o n t r o l s ,
i s o b s e r v e d ; t h i s s h o r t e n i n g c a n b e a s much a t 1 0 $ i n t h e c a s e o f t h e f e m u r .
T h i s d e f e c t i v e g r o w t h i s n o t c a u s e d b y e a r l y o s s i f i c a t i o n b u t p r o b a b l y b y
d i f f u s e s c l e r o s i s o f t h e b o n e . The p r i m i t i v e l e s i o n c a u s i n g t h i s d i s r u p t -
i o n o f o s s i f i c a t i o n a p p e a r s t o b e f i b r o t i c c h a n g e s i n t h e m e d u l l a r y b l o o d
v e s s e l s a n d t h e i n t e r f e r e n c e t o t h e c i r c u l a t i o n o f b l o o d w i t h i n t h e b o n e
t h a t r e s u l t s ( C l a r k e , 1 9 6 2 ) . N e c r o t i c l e s i o n s o f t h e H a v e r s i a n s y s t e m s
may o c c u r a f t e r t h e d e p o s i t i o n o f p l u t o n i u m a n d a r e c o m p a r a b l e t o t h o s e
p r o d u c e d b y r a d i u m . An a p p r e c i a b l e s e c o n d a r y c a l c i f i c a t i o n o c c u r s i n t h e
H a v e r s i a n c a n a l s ( J e e e t a l , 1 9 6 2 ) . F i b r o s i s o f t h e e n d o s t e u m i s c a u s e d
b y a h i g h a l p h a r a d i a t i o n d o s e t o t h e e n d o s t e a l c e l l s ; t h e d e a t h o f t h e s e
c e l l s may a c c o u n t f o r t h e l e s s f r e q u e n t o c c u r r e n c e o f o s t e o s a r c o m a s a t
t h e s e h i g h d o s e l e v e l s .
2 . 3 Summary
S t u d i e s o n t h e a c u t e e f f e c t s o f a c t i n i d e s a r e o f l i t t l e i n t e r e s t i n
t h e f i e l d o f r a d i a t i o n p r o t e c t i o n a s t h e y r e s u l t f r o m l a r g e r a d i a t i o n
d o s e s . The L D g 0 ^ 0 f ° r i n h a l e d p l u t o n i u m - 2 3 9 i s e s t i m a t e d t o b e a b o u t
3 mCi ( 1 1 1 MBq) .
M e d i u m - t e r m p a t h o l o g i c a l c h a n g e s i n t h e l u n g a r e a l s o c a u s e d b y
r e l a t i v e l y h i g h l e v e l s o f d o s e . The f i r s t l e s i o n s a p p e a r i n g a r e
m a i n l y a n a l v e o l a r o e d e m a f o l l o w e d b y a c h r o n i c i n t e r s t i t i a l
p n e u m o n i a ; f i b r o s i s o c c u r s l a t e r a s a r e s u l t o f damage t o t h e
v a s c u l a r b e d . E f f e c t s o n t h e b l o o d d e p e n d u p o n t h e s p e c i e s . I n
d o g s c h a n g e s t o t h e b l o o d c e l l c o u n t a n d i n b l o o d c o m p o s i t i o n o c c u r .
The m a i n c h a n g e o b s e r v e d i s t h e d e v e l o p m e n t o f l y m p h o p e n i a w h i c h i s
d i r e c t l y r e l a t e d t o t h e a m o u n t o f p l u t o n i u m d e p o s i t e d i n t h e l u n g s
o r e n t e r i n g t h e b l o o d . The d e p o s i t i o n o f l a r g e a m o u n t s o f p l u t o n i u m
115
i n t h e l y m p h n o d e s c a u s e s t h e d e p o p u l a t i o n o f g e r m i n a l c e n t r e s a n d
t h e d e v e l o p m e n t o f f i b r o s i s . M e d i u m - t e r m p a t h o l o g y i n t h e b o n e
a p p e a r s a f t e r i n t r a v e n o u s i n j e c t i o n o r i n h a l a t i o n o f t r a n s p o r t a b l e
a c t i n i d e c o m p o u n d s . F r a c t u r e s h a v e b e e n o b s e r v e d i n d o g s i n j e c t e d
w i t h h i g h d o s e s a n d o t h e r c h a n g e s i n t h e b o n e h a v e i n c l u d e d o s t e o -
p o r o s i s a n d n e c r o s i s .
3 . D e l a y e d E f f e c t s
The m e d i u m - t e r m e f f e c t s t h a t h a v e b e e n d e s c r i b e d a r e d u e t o v e r y h i g h
r a d i a t i o n d o s e s w h i c h o c c u r i n man o n l y i n e x c e p t i o n a l , a c c i d e n t a l
s i t u a t i o n s . D e l a y e d e f f e c t s c o m p r i s e m a l i g n a n t c h a n g e s t o v a r i o u s t i s s u e s
o r o r g a n s . T h e y o c c u r p r e d o m i n a n t l y i n t h e m o s t e x p o s e d t i s s u e s ( C h a p t e r
£ : t i s s u e s e x p o s e d t o r i s k ) ; t h e m o s t i m p o r t a n t o f w h i c h i s t h e l u n g ,
s i n c e i t i s b o t h a s i t e o f e n t r y i n t o t h e b o d y a n d a n o r g a n o f d e p o s i t i o n .
The s k e l e t o n , t h e l i v e r a n d a l l t h e o t h e r o r g a n s may a l s o b e a f f e c t e d a t a
f r e q u e n c y t h a t , b r o a d l y s p e a k i n g , v a r i e s a c c o r d i n g t o t h e t r a n s p o r t a b i l i t y
o f t h e p a r t i c u l a r a c t i n i d e a n d t h e a m o u n t d e p o s i t e d i n t h e t i s s u e . I n
a d d i t i o n t o t h e s e m a l i g n a n t c h a n g e s , i n c o r p o r a t i o n o f a c t i n i d e s c a n
i n f l u e n c e t h e l i f e s p a n o f a n i m a l s . As a r e s u l t o f many f a c t o r s o t h e r
t h a n c a n c e r t h e l i f e s p a n may b e l e s s t h a n i n u n e x p o s e d a n i m a l s . A l l t h e
o b s e r v e d e f f e c t s c a n h a v e a d i r e c t o r i n d i r e c t i n f l u e n c e o n t h e l i f e s p a n
( g r e a t e r s e n s i t i v i t y t o i n f e c t i o n r e s u l t i n g f r o m r a d i a t i o n - i n d u c e d i n t e r -
s t i t i a l p n e u m o n i a , s e c o n d a r y c a r d i o p a t h i a , p u l m o n a r y f i b r o s i s l e a d i n g t o
r e s p i r a t o r y d i s o r d e r s , e t c . ) . V e r y o f t e n , n o p a r t i c u l a r p a t h o l o g i c a l
c h a n g e i s o b s e r v e d a n d , a s t h e s h o r t e n i n g o f t h e l i f e s p a n c o u l d b e a n o n -
s t o c h a s t i c ( n o n - r a n d o m ) o c c u r r e n c e , i t i s a p p r o p r i a t e t o s t u d y i t a s a
w h o l e , w i t h o u t m a k i n g a n y d e c i s i o n s r e g a r d i n g i t s c a u s e s . The m a i n f a c t o r s
c a u s i n g t h i s e f f e c t a r e c o n s i d e r e d i n s e c t i o n k o f t h i s c h a p t e r .
3 . 1 Lung
A c o n s i d e r a b l e a m o u n t o f r e s e a r c h i n t o l u n g c a n c e r i n d u c t i o n b y a l p h a
e m i t t e r s h a s b e e n c o n d u c t e d i n e x p e r i m e n t a l a n i m a l s u s i n g s u c h v a r i e d
a n i m a l s p e c i e s a s m i c e , h a m s t e r s , r a t s , r a b b i t s , d o g s a n d m o n k e y s . A l t h o u g h
t h e m a j o r i t y o f t h e s e s t u d i e s h a v e i n v o l v e d r a t s a n d d o g s , i n f o r m a t i o n i s
a v a i l a b l e t h a t a l l o w s d o s e - e f f e c t r e l a t i o n s h i p s t o b e e s t a b l i s h e d i n a
n u m b e r o f s p e c i e s a n d d a t a f r o m s e v e r a l s p e c i e s t o b e c o m p a r e d . R e s e a r c h
c a r r i e d o u t o n m o n k e y s w i l l p r o d u c e u s e f u l r e s u l t s o n l y w h e n t h e a n i m a l s
a r e o l d e r b e c a u s e o f t h e l o n g l a t e n t p e r i o d f o r t h e d e v e l o p m e n t o f l u n g
c a n c e r i n t h i s s p e c i e s .
116
I n r a t s , t a k i n g i n t o c o n s i d e r a t i o n a l l t h e t r a n s u r a n i c e l e m e n t s a s a
w h o l e , t h e f r e q u e n c y o f p u l m o n a r y c a n c e r s r i s e s r a p i d l y w i t h t h e d o s e :
a b o u t 1 0 % f o r 1 $ 0 r a d ( 1 . 5 Gy) ( a v e r a g e l u n g d o s e ) , 26% f o r 3 5 0 r a d ( 3 . 5 Gy)
50% f o r 1 0 0 0 r a d ( 1 0 Gy) a n d 85% f o r 3 2 0 0 r a d ( 3 2 Gy) ( M o r i n e t a l , 1 9 7 7 ) .
At d o s e s a b o v e 5 0 0 0 r a d ( 5 0 Gy) t h e f r e q u e n c y d r o p s d u e t o c e l l s t e r i l i z a -
t i o n a n d b e c a u s e t h e r e i s i n s u f f i c i e n t t i m e f o r t h e c a n c e r t o m a n i f e s t
i t s e l f , d e a t h o f t e n o c c u r r i n g a t a n e a r l y s t a g e f r o m o t h e r c a u s e s . I n f a c t ,
l u n g c a n c e r f r e q u e n c y v a r i e s f r o m o n e r a d i o n u c l i d e t o a n o t h e r . The d o s e
w h i c h c o r r e s p o n d s t o t h e maximum f r e q u e n c y a l s o d e p e n d s o n t h e i n h a l e d
c o m p o u n d . F o r i n s t a n c e , t h e o p t i m a l d o s e i s l o w e r t h a n 5 0 0 r a d ( 5 Gy) f o r
c u r i u m - 2 4 ! | . n i t r a t e a n d a m e r i c i u m - 2 4 1 o x i d e , b e t w e e n 5 0 0 a n d 1 0 0 0 r a d ( 5 a n d
1 0 Gy) f o r p l u t o n i u m - 2 3 8 n i t r a t e o r o x i d e , b e t w e e n 5 0 0 a n d 5 0 0 0 r a d ( 5 a n d
5 0 Gy) f o r a m e r i c i u m - 2 1 + 1 n i t r a t e a n d o v e r 1 0 0 0 r a d ( 1 0 Gy) f o r b o t h
p l u t o n i u m - 2 3 9 o x i d e a n d n i t r a t e ( M o r i n e t a l , 1 9 7 7 ) •
The k i n e t i c s o f p u l m o n a r y c a n c e r d e v e l o p m e n t s e e m s t o b e r e l a t i v e l y
c o n s t a n t b u t t h e s p e e d o f d e v e l o p m e n t i s i n p r o p o r t i o n t o t h e d o s e .
R e g a r d l e s s o f t h e d o s e , t h e r e a r e a s e r i e s o f m o r p h o l o g i c a l c h a n g e s w h i c h
o c c u r o n e a f t e r a n o t h e r . An i d e n t i c a l o r d e r o f e v e n t s o c c u r s i n c o n t r o l
a n i m a l s , b u t i s s l o w e n o u g h f o r t h e c a n c e r t o a p p e a r o n l y i n a v e r y s m a l l
f r a c t i o n o f t h e a n i m a l s s i n c e t h e n o r m a l f r e q u e n c y i s l e s s t h a n 1 % . I f t h e
l i f e s p a n o f r a t s w i t h p u l m o n a r y c a n c e r i s c o n s i d e r e d ( w h i c h i s n o t
n e c e s s a r i l y e q u i v a l e n t t o t h e l a t e n c y o r d e v e l o p m e n t p e r i o d o f t h e c a n c e r ) ,
a c l e a r d i f f e r e n c e b e c o m e s a p p a r e n t b e t w e e n t h e a n i m a l s e x p o s e d t o
r e l a t i v e l y t r a n s p o r t a b l e e l e m e n t s s u c h a s t h e t r a n s p l u t o n i u m e l e m e n t s o r
p l u t o n i u m - 2 3 8 a n d a n i m a l s e x p o s e d t o e l e m e n t s w h i c h a r e s c a r s e l y , i f a t a l l ,
t r a n s p o r t a b l e , s u c h a s p l u t o n i u m - 2 3 9 o x i d e . T h e s e d i f f e r e n c e s a r e m o s t
m a r k e d a t l o w d o s e s . I n t h e c a s e o f t h e o x i d e , f o r e x a m p l e , a 25% m o r t a l i t y
i s r e a c h e d a f t e r a b o u t 3 5 0 d a y s , b u t i n t h e c a s e o f s a l t s g i v i n g a c o m p a r -
a b l e l u n g d o s e a f t e r a b o u t 5 0 0 d a y s . T h i s d i f f e r e n c e b e c o m e s l e s s a f t e r
a b o u t 5 5 0 d a y s , w h e n t h e r e i s a m o r t a l i t y o f a b o u t 50% ( M o r i n e t a l , 1 9 7 6 ) .
I n t e r p r e t a t i o n s a r e o f t e n d i f f i c u l t a s n u m e r o u s d i s t o r t i n g f a c t o r s may b e
i n v o l v e d o w i n g t o t h e e x p e r i m e n t a l d e s i g n . F o r e x a m p l e , t h e f r e q u e n c y o f
p u l m o n a r y c a n c e r s i n d u c e d b y i n h a l a t i o n o f curium-2hh i s n o t a s h i g h a s
m i g h t b e a n t i c i p a t e d ; t h e m o s t p r o b a b l e r e a s o n f o r t h i s i s t h e h i g h r a d i o -
t o x i c i t y o f t h e e l e m e n t , d u e t o i t s h o m o g e n e o u s d i s t r i b u t i o n i n t h e
p u l m o n a r y p a r e n c h y m a . T h i s c a u s e s a h i g h m o r t a l i t y r a t e a t a n e a r l y a g e ,
e i t h e r d i r e c t l y , o r i n d i r e c t l y a s a r e s u l t o f r a d i a t i o n damage p e r m i t t i n g
t h e d e v e l o p m e n t o f i n f e c t i o n . The s a m e i s t r u e o f e i n s t e i n i u m - 2 5 3 » w h o s e
s h o r t h a l f - l i f e r e q u i r e s t h e i n s t i l l a t i o n o f l a r g e q u a n t i t i e s o f a c t i v i t y
117
( B a l l o u a n d M o r r o w , 1 9 7 3 ) ; "the v e r y h i g h i n i t i a l d o s e r a t e s w h i c h r e s u l t
f r o m t h i s may p r o d u c e c e l l s t e r i l i z a t i o n , t h u s r e d u c i n g t h e i n c i d e n c e o f
c a n c e r d e s p i t e t h e w i d e r a n g e o f d o s e s r e c e i v e d b y t h e l u n g . W i t h d o s e s o f
b e t w e e n 38 a n d 1900 r a d (O .38 a n d 19 G y ) , t h e o b s e r v e d f r e q u e n c y o f l u n g
c a n c e r i s o n l y If/o a n d 1 2 . 5 % r e s p e c t i v e l y .
I n r a t s , l u n g c a n c e r s c a n b e d i v i d e d r o u g h l y i n t o t h r e e t y p e s a c c o r d i n g
t o t h e c e l l s i n w h i c h t h e t u m o u r o r i g i n a t e d : ( a ) b r o n c h i o l o - a l v e o l a r
c a r c i n o m a ( p n e u m o c y t e I I ) ; ( b ) b r o n c h o g e n i c c a r c i n o m a ( e p i d e r m o i d ) ; ( c )
s a r c o m a . I n a g i v e n s t r a i n o f r a t , i n s p i t e o f t h e v e r y d i f f e r e n t a r e a s
o f r e t e n t i o n , n o a p p r e c i a b l e d i f f e r e n c e i s o b s e r v e d b e t w e e n t r a n s p o r t a b l e
a n d n o n - t r a n s p o r t a b l e r a d i o n u c l i d e s .
S a r c o m a s r e p r e s e n t o n a v e r a g e 2% o f p u l m o n a r y c a n c e r s , t h e r e m a i n d e r
b e i n g made u p i n a b o u t e q u a l p r o p o r t i o n s o f b r o n c h i o l o - a l v e o l a r a n d b r o n c h o -
g e n i c c a r c i n o m a s ( M o r i n e t a l , 1 9 7 6 ) . At r e l a t i v e l y l o w d o s e s
a p r e d o m i n a n c e o f t h e b r o n c h i o l o - a l v e o l a r f o r m s i s o b s e r v e d a n d , a t h i g h
d o s e s , a p r e d o m i n a n c e o f b r o n c h o g e n i c f o r m s ; n o d o u b t t h i s m e r e l y
r e f l e c t s t h e d i f f e r e n t s p e e d s o f d e v e l o p m e n t o f d i f f e r e n t t u m o u r s . The
same d i s t r i b u t i o n i s a l s o f o u n d a f t e r i n h a l a t i o n o f r a d o n a n d i t s d a u g h t e r s ,
w h o s e mode o f d e p o s i t i o n i s q u i t e d i f f e r e n t (Chameaud e t a l , 1 9 7 6 ) . T h i s
p o i n t i l l u s t r a t e s t h e i m p o r t a n c e o f a s e n s i t i v i t y p e c u l i a r t o a c e l l t y p e
r a t h e r t h a n t o t h e r e g i o n i n w h i c h m o s t damage o c c u r s a n d h a s b e e n d i s c u s s e d
i n C h a p t e r 5 ( s e c t i o n !+)• F i g u r e 6.1+ t o F i g u r e 6.6 i l l u s t r a t e t h e
d i f f e r e n t f o r m s t h a t p u l m o n a r y c a n c e r s o r i g i n a t i n g i n t h e s e t h r e e c e l l t y p e s
c a n a s s u m e i n t h e r a t .
Much h a s b e e n l e a r n e d b y c o m p a r i n g v e r y many e x p e r i m e n t s o n r a d i a t i o n -
c a r c i n o g e n e s i s c a u s e d b y t h e p u l m o n a r y d e p o s i t i o n o f a c t i n i d e s . I n f a c t ,
v a r i o u s e x p e r i m e n t a l m e t h o d s h a v e b e e n u s e d : t r a c h e a l i n s t i l l a t i o n s w h i c h
g i v e a f a i r l y n o n - u n i f o r m d e p o s i t i o n , i n h a l a t i o n b y a c o n s c i o u s a n i m a l ,
p i n - p o i n t t r a n s - t h o r a c i c i n j e c t i o n s , a n d i n t r a v e n o u s i n j e c t i o n s o f p a r t i c l e s
t h a t l o d g e i n t h e p u l m o n a r y c a p i l l a r i e s . A l s o many r a d i o n u c l i d e s , i n
v a r i o u s p h y s i c o - c h e m i c a l f o r m s h a v e b e e n u s e d : t r a n s f e r a b l e c o m p o u n d s o f
t r i v a l e n t e l e m e n t s t h a t a r e r e a d i l y t r a n s p o r t a b l e a n d g i v e a v e r y u n i f o r m
d i s t r i b u t i o n i n t h e l u n g , h i g h l y i n s o l u b l e c o m p o u n d s w i t h a h i g h l y n o n -
u n i f o r m d i s t r i b u t i o n i n t h e l u n g , a n d e v e n i n s o l u b l e c o m p o u n d s t h a t h a v e a
p a r t i c l e s i z e d i s t r i b u t i o n , s u f f i c i e n t l y s m a l l t o p e r m i t t h e m t o b e
c l a s s i f i e d a s t r a n s p o r t a b l e r a d i o n u c l i d e s ( C h a p t e r !+)• A c o m p a r i s o n o f t h e
r e s u l t s o f t h e s e e x p e r i m e n t s s h o w s t h e h i g h t o x i c i t y o f a m o r e u n i f o r m
d i s t r i b u t i o n o f a c t i n i d e s i n t h e l u n g a n d w i t h t h e e x c e p t i o n o f t h e r e s e r v a -
t i o n s made a b o v e , t h e g r e a t e r f r e q u e n c y o f p u l m o n a r y c a n c e r s w h i c h i s
118
F i g u r e 6.I4. B r o n c h i o l o - a l v e o l a r p u l m o n a r y c a r c i n o m a w i t h p a p i l l o m a
c h a r a c t e r i s t i c s i n r a t ( i n f o r m a t i o n s u p p l i e d b y R. M a s s e ,
D e p a r t e m e n t d e P r o t e c t i o n , CEA, F r a n c e ) .
F i g u r e 6 . 5 N o n - k e r a t i n i z e d , d i f f e r e n t i a t e d e p i d e r m o i d p u l m o n a r y c a r c i n o m a
i n r a t ( i n f o r m a t i o n s u p p l i e d b y R . M a s s e , D e p a r t e m e n t d e
P r o t e c t i o n , CEA, F r a n c e ) .
119
120
F i g u r e 6.6 P u l m o n a r y a n g i o s a r c o m a i n r a t ( i n f o r m a t i o n s u p p l i e d b y R. M a s s e ,
D e p a r t e m e n t d e P r o t e c t i o n , CEA, F r a n c e ) .
121
n o r m a l l y a s s o c i a t e d w i t h i t . A d m i n i s t r a t i o n o f t h e o x i d e o f p l u t o n i u m - 2 3 8
i n t h e f o r m o f m i c r o s p h e r e s , ( u l t r a f i l t e r a b i l i t y 7 2 $ , CMD 0 . 0 2 , GSD 2 . 1 )
w h i c h l e a d s t o a m o r e u n i f o r m d i s t r i b u t i o n , i s o f p a r t i c u l a r i n t e r e s t
( S a n d e r s , 1 9 7 3 ) : d o s e s o f 9 r a d ( 0 . 0 9 G y ) g i v e a p u l m o n a r y c a n c e r f r e q u e n c y
o f 6 . 6 $ ; 3 2 r a d ( 0 . 3 2 Gy) g i v e 2 3 $ a n d 3 7 5 r a d ( 3 . 8 G y ) , 2 5 $ . T h e s e
i n c i d e n c e s a r e v e r y m u c h h i g h e r t h a n t h o s e o b t a i n e d w i t h a n i n s o l u b l e
p l u t o n i u m d i o x i d e a e r o s o l w i t h a n AMAD o f a b o u t 1 ^m. T h e s e c o n s i d e r a t i o n s
a r e r e l e v a n t t o t h e " h o t p a r t i c l e p r o b l e m " a n d a r e d i s c u s s e d f u r t h e r i n
C h a p t e r 7 .
O t h e r r o d e n t s p e c i e s h a v e b e e n u s e d f o r s t u d y i n g p u l m o n a r y c a n c e r s
i n d u c e d b y a c t i n i d e s , b u t a l w a y s o n a s m a l l e r s c a l e ; t h e s e e x p e r i m e n t s a r e
o f r e l e v a n c e , h o w e v e r , s i n c e t h e y a l l o w a n i n t e r c o m p a r i s o n o f r e s u l t s .
R e s u l t s o b t a i n e d i n m i c e g e n e r a l l y c o n f i r m t h o s e o b t a i n e d w i t h r a t s ,
a l t h o u g h t h e f a c t t h a t t h e s e s t u d i e s w e r e c o m p l e t e d some t i m e a g o m a k e s
c o m p a r i s o n d i f f i c u l t , m a i n l y b e c a u s e o f t h e d i f f e r e n t t e c h n i q u e s o f
a d m i n i s t e r i n g t h e a c t i n i d e s ( i n t r a t r a c h e a l i n s t a l l a t i o n o r i n h a l a t i o n )
( T e m p l e e t a l , 1 9 5 9 , i 9 6 0 ) . The l i f e s p a n d o s e s d e l i v e r e d t o t h e l u n g i n
a n i m a l s e x p o s e d t o p l u t o n i u m - 2 3 9 d i o x i d e r a n g e d f r o m 23OO t o 1+000 r a d ( 2 3
t o 2+0 G y ) . I n m i c e , l u n g c a n c e r s w e r e n o t o b s e r v e d i n g r o u p s o f m i c e w i t h
l u n g d o s e s o f s e v e r a l t e n s o f r a d s ( B a i r e t a l , 1 9 6 2 ) b u t t h e n u m b e r o f
m i c e s t u d i e d w a s m u c h l o w e r t h a n f o r r a t s e x p o s e d t o t h e same l e v e l o f
i r r a d i a t i o n a n d t h e r e f o r e n o c l e a r c o n c l u s i o n s c a n b e d r a w n .
R e s u l t s o b t a i n e d w i t h r a b b i t s a r e a l s o i n l i n e w i t h t h e c o n c l u s i o n s
d r a w n f r o m t h e v a r i o u s e x p e r i m e n t s c a r r i e d o u t o n r a t s a n d m i c e
( K o s h u m i k o v a e t a l , 1 9 7 1 ) . The d o s e s s t u d i e d r a n g e f r o m 1 0 0 0 t o 3 0 0 0 r a d
( 1 0 t o 3 0 G y ) , d e l i v e r e d t o t h e l u n g b y p l u t o n i u m - 2 3 9 a d m i n i s t e r e d a s
ammonium p l u t o n i u m p e n t a c a r b o n a t e . The i n c i d e n c e o f c a n c e r w a s 1 8 . 7 $ f o r a n
1 1
i n i t i a l d e p o s i t i o n o f 0 . 1 7 nCi g ~ ( 6 . 3 kBq g " ) ( 1 0 1 0 r a d ( 1 0 G y ) ) t o t h e
l u n g ) .
H a m s t e r s a r e e x c e p t i o n a l m e m b e r s o f t h e r o d e n t f a m i l y i n s o f a r a s
p l u t o n i u m - i n d u c e d p u l m o n a r y c a n c e r s a r e c o n c e r n e d . I n s t u d i e s c o n d u c t e d
t o d a t e t h e f r e q u e n c y o f n e o p l a s t i c c h a n g e s i n t h e l u n g i s , i n f a c t , much
l o w e r i n t h i s a n i m a l t h a n t h a t o b s e r v e d i n r a t s o r m i c e ; d o s e s c a u s i n g a
s i g n i f i c a n t r i s e i n t h e f r e q u e n c y o f p u l m o n a r y c a n c e r s i n r a t s h a v e n o
e f f e c t o n h a m s t e r s , w h e t h e r p l u t o n i u m - 2 3 9 o r p l u t o n i u m - 2 3 8 i s u s e d ( S a n d e r s
a n d M e i e r , 1 9 7 5 ; M e w h i n n e y e t a l , 1 9 7 6 b ) . E x p e r i m e n t s c o n d u c t e d o n
h a m s t e r s a r e r e l a t i v e l y r e c e n t a n d , i n many c a s e s , t h e r e s u l t s a r e s t i l l
i n c o m p l e t e a n d f r a g m e n t a r y .
122
R e s u l t s o f e x p e r i m e n t s o n b e a g l e d o g s a r e much m o r e r e l e v a n t f o r t h e y
h a v e i n v o l v e d l a r g e g r o u p s o f a n i m a l s t h a t h a v e b e e n f o l l o w e d f o r t h e i r
l i f e s p a n . H o w e v e r , n o e x p e r i m e n t h a s r e a l l y b e e n b r o u g h t t o a c o n c l u s i o n ,
s i n c e t h e o n l y s i g n i f i c a n t r e s u l t s a t p r e s e n t a v a i l a b l e a r e c o n c e r n e d w i t h
a n i m a l s t h a t h a v e b e e n e x p o s e d t o r e l a t i v e l y l a r g e i n i t i a l l u n g d e p o s i t s
a n d d i e d p r e m a t u r e l y ; d a t a o n d o g s c o n t a m i n a t e d a t v e r y l o w l e v e l s a n d
h a v i n g n o r m a l l o n g e v i t y a r e t o o i n c o m p l e t e t o b e u s e d . R e s u l t s a t p r e s e n t
a v a i l a b l e c o n c e r n r e l a t i v e l y h i g h d o s e l e v e l s , t h e d e p o s i t i o n s o f
p l u t o n i u m - 2 3 9 d i o x i d e a t p r e s e n t e m p l o y e d r a n g i n g f r o m 0.003 ^Ci g ~ —1 —1 —1
(1 kBq g " ) t o 0.04 ^iCi g"~ ( 1 . 5 kBq g~ ) ( c o r r e s p o n d i n g t o d o s e s o f
b e t w e e n 2000 a n d 12000 r a d (20 a n d 120 G y ) c a l c u l a t e d o n b l o o d l e s s l u n g s ) ;
t h e c o r r e s p o n d i n g s u r v i v a l t i m e s l i e b e t w e e n 2 .5 y e a r s a n d 11 y e a r s ( P a r k
e t a l , 1 9 7 2 ) , a n d t h e s e a n i m a l s e x h i b i t e d a h i g h r a t e o f p u l m o n a r y c a n c e r
(82%). A s m a l l g r o u p r e c e i v i n g a d o s e o f 1200 r a d (12 G y ) t o t h e l u n g
(0.007 tiCi g ~ 1 (0.26 kBq g " " 1 ) ) d u r i n g a n a v e r a g e l i f e s p a n o f 8 y e a r s ,
e x h i b i t e d a p a r t i c u l a r l y h i g h f r e q u e n c y o f p u l m o n a r y c a n c e r (87 .5%); h u t
t h e s m a l l n u m b e r o f a n i m a l s i n v o l v e d (7 d o g s w i t h l u n g c a n c e r o u t o f a n
i n i t i a l g r o u p o f 8) m a k e s t h i s r e s u l t l e s s s i g n i f i c a n t t h a n t h o s e o b t a i n e d
w i t h r a t s . A l l t h e p u l m o n a r y c a n c e r s o b s e r v e d i n b e a g l e s a r e o f t h e
a d e n o c a r c i n o m a t y p e . A f e w o t h e r h i s t o l o g i c a l t y p e s w e r e o b s e r v e d , b u t
t h e s e w e r e a l w a y s a s s o c i a t e d w i t h a f o c u s o f a d e n o c a r c i n o m a . Out o f 32
c o n t a m i n a t e d d o g s , 24 e x h i b i t e d p u l m o n a r y c a n c e r o f t h e a d e n o c a r c i n o m a
t y p e , a s s o c i a t e d i n 5 c a s e s w i t h a p e r i p h e r a l e p i d e r m o i d c a r c i n o m a , i n 2
w i t h a p u l m o n a r y l y m p h a n g i o s a r c o m a a n d i n 1 w i t h a h a e m a n g i o m a . M e t a s t a s i s
w a s f r e q u e n t . The r e s u l t s a r e s t i l l t o o f r a g m e n t a r y f o r p l u t o n i u m - 2 3 8
d i o x i d e , b e c a u s e o f t h e s h o r t t i m e s i n c e t h e s t a r t o f t h e e x p e r i m e n t s a n d
t h e s m a l l number o f d o g s u s e d ( P a r k e t a l , 1976) b u t t h e y a r e c o n s i s t e n t
w i t h t h o s e o b t a i n e d w i t h p l u t o n i u m - 2 3 9 . H o w e v e r , t h e s m a l l s i z e o f t h e
s a m p l e s (2 g r o u p s o f 10 d o g s ) , a n d t h e r e l a t i v e l y h i g h i n c i d e n c e o f o s t e o -
s a r c o m a s t h a t c a u s e d e a r l y d e a t h , i n t r o d u c e g r e a t u n c e r t a i n t y i n t o t h e
r e s u l t s .
A f e w e x p e r i m e n t s u s i n g p r i m a t e s h a v e b e e n s t a r t e d i n t h e l a s t f e w
y e a r s , b u t t h e y a r e a l l m u c h t o o r e c e n t t o a l l o w a s t u d y o f r a d i a t i o n -
i n d u c e d p u l m o n a r y c a n c e r t o b e m a d e . I n r h e s u s m o n k e y s , o n l y m e d i u m - t e r m
p a t h o l o g y , a f t e r a p e r i o d o f t h r e e y e a r s , h a s b e e n s t u d i e d ( B r o o k s e t a l ,
1976a) .
A f e w s t u d i e s o f p u l m o n a r y c a n c e r s i n b a b o o n s h a v e b e e n p u b l i s h e d
( M e t i v i e r e t a l , 1 9 7 2 ) , b u t m o s t o f t h e m s h o u l d b e r e g a r d e d w i t h e x t r e m e
c a u t i o n f o r , a l t h o u g h t h e l e s i o n s p r e s e n t e d h i s t o l o g i c a l f e a t u r e s t h a t w e r e
123
i n d i s p u t a b l y m a l i g n a n t t h e t u m o u r s r e p o r t e d w e r e i s o l a t e d a n d a b n o r m a l l y
e a r l y ( M e t i v i e r e t a l , 197U)• The f i r s t n e o p l a s t i c l e s i o n o c c u r r i n g i n
b a b o o n s a n d e x h i b i t i n g i n d i s p u t a b l e c l i n i c a l a n d h i s t o l o g i c a l s y m p t o m s o f
m a l i g n a n c y a p p e a r e d a f t e r a p e r i o d o f m o r e t h a n s i x y e a r s , w i t h a n i n i t i a l
1 1
l u n g d e p o s i t o f 0.01 jiCi g " (0.37 kBq g~ ) ( M a s s e , 1 9 7 7 ) . A v e r y h i g h d o s e
w a s t h e r e f o r e u s e d , b u t t h e f a c t t h a t t h i s c a n c e r w a s o f a b r o n c h i a l t y p e
m a k e s t h i s a n i m a l m o d e l o f g r e a t v a l u e f o r e x t r a p o l a t i o n t o man .
The r e s u l t s o f t h e s e e x p e r i m e n t s c a r r i e d o u t o n s e v e r a l s p e c i e s
c o n c l u s i v e l y d e m o n s t r a t e t h e c a r c i n o g e n i c a c t i o n o f a c t i n i d e s i n t h e l u n g .
To a c e r t a i n e x t e n t , a m a t h e m a t i c a l a n d s t a t i s t i c a l a n a l y s i s p e r m i t s a d o s e -
e f f e c t r e l a t i o n s h i p t o b e e s t a b l i s h e d . U n f o r t u n a t e l y , h o w e v e r , t h e s e d a t a
d o n o t p r o v i d e a n a d e q u a t e b a s i s f o r a p r e c i s e d e s c r i p t i o n o f t h e f o r m o f
t h e d o s e - e f f e c t r e l a t i o n s h i p a t l o w d o s e s . T h e r e a r e many r e a s o n s f o r
t h i s : i n c l u d i n g d i f f e r e n c e s i n e x p e r i m e n t a l d e s i g n , l a c k o f k n o w l e d g e o n
t h e a g e s p e c i f i c i n c i d e n c e o f c a n c e r i n c o n t r o l a n i m a l s , a n d i n a c c u r a c i e s
i n t h e d e t e r m i n a t i o n o f t h e i n i t i a l l u n g d e p o s i t . F u r t h e r m o r e , some
n e c e s s a r y b a s i c d a t a may n o t b e a v a i l a b l e ( f o r e x a m p l e w h e t h e r t h e c a n c e r
f r e q u e n c y w a s c a l c u l a t e d f r o m t h e t o t a l n u m b e r o f c o n t a m i n a t e d a n i m a l s o r
f r o m t h e a n i m a l s t h a t w e r e a t r i s k , o r w h e t h e r i t w a s b a s e d o n t h e n u m b e r
o f a n i m a l s w i t h c a n c e r o r o n t h e t o t a l n u m b e r o f c a n c e r s ) ; l a s t , b u t n o t
l e a s t , t h e r e a r e n o g r o u p s w i t h s u f f i c i e n t l y l a r g e n u m b e r s o f a n i m a l s t o
a l l o w s t a t i s t i c a l v a r i a t i o n s t o b e a p p r e c i a b l y r e d u c e d . I t i s a l s o v e r y
d i f f i c u l t t o u s e t h e e x p e r i m e n t a l r e s u l t s t o o b t a i n e s t i m a t e s o f t h e e f f e c t s
o n human h e a l t h a s a c e r t a i n n u m b e r o f h y p o t h e s e s h a v e t o b e i n t r o d u c e d t o
j u s t i f y t h e e x t r a p o l a t i o n t o man ( R o s e n b l a t t , G o l d m a n e t a l , 1 9 7 6 ) , a n d
c r o s s - c o m p a r i s o n t e c h n i q u e s h a v e t o b e u s e d ( B a i r e t a l , 1 9 7 6 ) .
The p r o b l e m o f t h e a s s o c i a t e d r i s k s o f r a d i a t i o n e x p o s u r e a n d o t h e r
e n v i r o n m e n t a l f a c t o r s h a s b e e n e x a m i n e d f o r many y e a r s , e s p e c i a l l y f o r
o c c u p a t i o n a l g r o u p s a t h i g h r i s k f o r t h e d e v e l o p m e n t o f l u n g c a n c e r s , s u c h
a s u r a n i u m m i n e r s , a s b e s t o s w o r k e r s , e t c . ( A r c h e r e t a l , 1 9 7 6 ) . N u m e r o u s
s t u d i e s a r e b e i n g c a r r i e d o u t t o e x a m i n e t h e a s s o c i a t i o n b e t w e e n t h e
a d m i n i s t r a t i o n o f a l p h a e m i t t e r s v i a t h e r e s p i r a t o r y t r a c t a n d t o b a c c o
smoke o r o t h e r c a r c i n o g e n i c s u b s t a n c e s , s u c h a s t h e a - b e n z p y r e n e ( L i t t l e a n d
o ' T o o l e , 1974; McGandy e t a l , 1974; S a n d e r s , 1975a ,1975b ; M o r i n e t a l , 1 9 7 7 ) .
A l t h o u g h i n t h e c a s e o f r a d o n a n d i t s d a u g h t e r p r o d u c t s t h e e x p e r i m e n t a l
a n i m a l s u s e d , w h e t h e r t h e y a r e r a t s (Chameaud e t a l , 1976) o r d o g s ( S t u a r t
e t a l , 1 9 7 6 ) , do n o t d e c i s i v e l y c o n f i r m t h e o b s e r v a t i o n s made o n m a n , t h e
p o t e n t i a l s y n e r g i s t i c e f f e c t o f c o m b i n a t i o n s o f c h e m i c a l s a n d r a d i o a c t i v e
t o x i c s u b s t a n c e s f o r t h e p r o d u c t i o n o f c a n c e r m u s t b e c o n s i d e r e d .
12k
The t h o r a c i c l y m p h n o d e s a r e a n i m p o r t a n t l i n k i n t h e t r a n s f e r o f
p l u t o n i u m f r o m t h e l u n g t o o t h e r o r g a n s o f d e p o s i t i o n . The m e d i u m - t e r m
e f f e c t s h a v e b e e n d i s c u s s e d p r e v i o u s l y ( s e c t i o n 2 . 2 . 3 ) . I n f o r m a t i o n o n
c a n c e r p a t h o l o g y i s v e r y l i m i t e d ; n o s i g n i f i c a n t i n c r e a s e h a s b e e n o b s e r v e d
i n t h e n u m b e r o f s a r c o m a s o r i g i n a t i n g i n n o d e s a f t e r c o n t a m i n a t i o n b y
a c t i n i d e s ( P a r k e t a l , 1 9 7 2 ; B a i r e t a l , 1 9 7 4 ; D o l p h i n , 1 9 7 1 ) a n d t h i s
r e i n f o r c e s s i m i l a r o b s e r v a t i o n s made i n d o g s a f t e r c o n t a m i n a t i o n b y w o u n d s
( D a g l e e t a l , 1 9 7 5 ) • A n u m b e r o f l y m p h o s a r c o m a s h a v e b e e n o b s e r v e d i n r a t s
( M o r i n e t a l , 1 9 7 6 ) , b u t t h e y h a v e o r i g i n a t e d i n t h e l u n g ; t h e s e t u m o u r s
d e v e l o p e d f r o m t h e l y m p h o i d t i s s u e d i f f u s e l y d i s t r i b u t e d i n t h e p u l m o n a r y
p a r e n c h y m a a n d n o t f r o m t h e n o d e s .
3 . 2 S k e l e t o n
The m o s t i m p o r t a n t e f f e c t o f a l p h a e m i t t e r s o n b o n e i s t h e i n d u c t i o n
o f n e o p l a s t i c c h a n g e s . The m o s t u s e f u l t e c h n i q u e f o r s t u d y i n g t h e i n d u c t i o n
o f b o n e c a n c e r b y a c t i n i d e s i s t h e i n t r a v e n o u s a d m i n i s t r a t i o n o f s o l u b l e
s a l t s o r c o m p l e x e s ; t h i s m e t h o d a l l o w s m e t a b o l i c , t o x i c o l o g i c , d o s i m e t r i c
a n d c l i n i c a l a s p e c t s t o b e i n v e s t i g a t e d . I n a d d i t i o n , t h i s m e t h o d f a c i l i t a -
t e s a n i n t e r c o m p a r i s o n b e t w e e n t h e d i f f e r e n t s p e c i e s , a s i t r e d u c e s t h e
n u m b e r o f v a r i a b l e s t o a min imum. F o r t h i s r e a s o n a g r e a t d e a l o f r e s e a r c h
d u r i n g t h e l a s t t h r e e d e c a d e s h a s b e e n b a s e d o n t h e i n t r a v e n o u s i n j e c t i o n
o f p l u t o n i u m c i t r a t e i n m i c e , r a t s a n d d o g s .
H o w e v e r , t h i s a p p r o a c h d o e s n o t p r o v i d e a r e a l i s t i c m o d e l f o r a l t h o u g h
i t a l l o w s t h e f e a t u r e s a n d m e c h a n i s m s o f r a d i a t i o n - i n d u c e d b o n e c a n c e r t o b e
a n a l y s e d , i t i s b y n o m e a n s r e p r e s e n t a t i v e o f t h e n o r m a l r o u t e s o f a c c i d e n -
t a l c o n t a m i n a t i o n i n man . F o r t h i s r e a s o n g r e a t i m p o r t a n c e m u s t b e a t t a c h e d
t o e x p e r i m e n t s i n w h i c h t h e r a d i o n u c l i d e r e a c h e s t h e s k e l e t o n a f t e r m i g r a t -
i n g f r o m t h e e n t r y p o i n t ( t h e l u n g , d i g e s t i v e t r a c t o r s k i n w o u n d s ) i n t o t h e
o r g a n i s m .
The s k e l e t o n i s made u p o f t w o d i s t i n c t t i s s u e s : t h e b o n e i t s e l f a n d
t h e b o n e m a r r o w . The s i t e s o f d e p o s i t i o n o f p l u t o n i u m a n d t h e t r a n s p l u t o n i u m
e l e m e n t s i n t h e s k e l e t o n r e s u l t i n t h e b o n e b e i n g a t g r e a t e s t r i s k f o r t h e
p r o d u c t i o n o f m a l i g n a n t c h a n g e s ( C h a p t e r 5> s e c t i o n 2 . 2 . 2 ) .
3 . 2 . 1 Bone
Bone c a n c e r s may i n c l u d e o s t e o s a r c o m a s , c h o n d r o s a r c o m a s ( V a u g h a n , 1 9 7 3 ;
V a u g h a n e t a l , 1 9 7 3 ) o r f i b r o s a r c o m a s o f o s t e o g e n i c o r i g i n ( B a r n e s a n d
K h r u s c h o v , 1 9 6 8 ) . Among t h e a c t i n i d e s p l u t o n i u m a p p e a r s t o c a u s e t h e
h i g h e s t i n c i d e n c e o f o s t e o s a r c o m a s , ( L i s c o e t a l , 1 9 4 7 ; F i n k e l , 1 9 5 9 ;
L a n g h a m , 1 9 5 9 ; D o u g h e r t y a n d M a y s , 1 9 6 9 ; M o s k a l e v e t a l , 1 9 ^ 9 ) • F o r
125
e x a m p l e , c o m p a r a b l e d e p o s i t s o f p l u t o n i u m - 2 3 9 a n d americium-21+1 i n r a t s
c a u s e v e r y d i f f e r e n t i n c i d e n c e s o f o s t e o s a r c o m a : 77% f o r p l u t o n i u m - 2 3 9 a n d
21% f o r americ ium -2 l+1 a d m i n i s t e r e d a s c i t r a t e ( T a y l o r a n d B e n s t e a d , 19^9)•
To r e a c h a n i n c i d e n c e o f 1+6% t h e a m o u n t o f americium -2l+1 h a d t o b e t r i p l e d .
The f a c t t h a t b o n e r e t e n t i o n i s l o w e r f o r a m e r i c i u m t h a n f o r p l u t o n i u m (1+0%
o f t h e i n j e c t e d q u a n t i t y f o r americium-21+1 c o m p a r e d w i t h 60% f o r p l u t o n i u m -
239) i s n o t s u f f i c i e n t t o a c c o u n t f o r t h i s d i f f e r e n c e , w h i c h i s p r o b a b l y d u e
t o d i f f e r e n t c o n c e n t r a t i o n s o n t h e b o n e s u r f a c e . The p h y s i c o - c h e m i c a l f o r m
o f t h e e l e m e n t i s a n i m p o r t a n t f a c t o r i n i t s r a d i o t o x i c i t y . T h u s f o r t h e
s a m e a v e r a g e b o n e d o s e t h e m o n o m e r i c f o r m o f p l u t o n i u m p r o d u c e s b o n e c a n c e r s
m o r e r a p i d l y i n m i c e t h a n t h e p o l y m e r i c f o r m a n d t h e t o t a l n u m b e r o f b o n e
c a n c e r s o b s e r v e d d u r i n g t h e w h o l e l i f e - s p a n i s h i g h e r b y a f a c t o r o f
a p p r o x i m a t e l y 2 ( R o s e n t h a l a n d L i n d e n b a u m , 19^9) • T h i s e x p e r i m e n t i l l u s t r -
a t e s o n c e a g a i n t h e d e c i s i v e r o l e p l a y e d b y t h e l o c a l i z a t i o n o f t h e
p l u t o n i u m , s i n c e t h e m o n o m e r i c f o r m i s d e p o s i t e d i n g r e a t e r q u a n t i t i e s o n
t h e s u r f a c e o f t h e e n d o s t e u m t h a n t h e p o l y m e r i c f o r m a n d t h e d o s e i s
d e l i v e r e d i n a m o r e u n i f o r m f a s h i o n .
A c o m p a r i s o n o f r e s u l t s o b t a i n e d i n v a r i o u s s p e c i e s b r i n g s o u t
a p p r e c i a b l e d i f f e r e n c e s . A p a r t f r o m t h e l o c a l i z a t i o n o f a c t i n i d e s i n t h e
v a r i o u s p a r t s o f t h e s k e l e t o n w h i c h a p p e a r s t o v a r y g r e a t l y f r o m o n e s p e c i e s
t o a n o t h e r ( F i n k e l a n d B i s k i s , 1962; C h r i s t e n s e n e t a l , 1 9 7 2 ) , s e n s i t i v i t y
t o a l p h a i r r a d i a t i o n s e e m s t o v a r y b e t w e e n s p e c i e s , t h e d o g a p p e a r i n g t o b e
t h e m o s t s e n s i t i v e o f t h e a n i m a l s c o m m o n l y u s e d i n e x p e r i m e n t s (Mays e t a l ,
1969) . I n m i c e , t h e l o w e s t l i f e s p a n d o s e t o t h e s k e l e t o n r e s u l t i n g i n a
s i g n i f i c a n t i n c i d e n c e o f o s t e o s a r c o m a s w a s 1+0 r a d (0.1+ Gy) ( a v e r a g e b o n e
d o s e ) w h e r e t h e f r e q u e n c y w a s 3-9% ( a f t e r i . v , p l u t o n i u m c i t r a t e ) ; t h e
f r e q u e n c y r e a c h e d a maximum o f 76.9% a t $60 r a d (5.6 Gy) ( F i n k e l a n d B i s k i s ,
1962) . Lower d o s e s h a v e b e e n r e p o r t e d t o c a u s e e x c e s s c a n c e r s i n r a t s
( B u l d a k o v e t a l , 1970) w i t h 1% o f a d d i t i o n a l o s t e o s a r c o m a s a t 3.6 r a d
(.036 Gy) a n d 3.1% a t 25 r a d (0.25 G y ) ; t h e r e a r e u n c e r t a i n t i e s o v e r t h e
t i m e d u r i n g w h i c h t h e d o s e s w e r e c a l c u l a t e d w h i c h may e x p l a i n t h e
d i s c r e p a n c y b e t w e e n t h e r e s u l t s o b t a i n e d i n t h e t w o r o d e n t g e n e r a . R e l a t -
i v e l y l o w d o s e s , a f t e r i n t r a v e n o u s i n j e c t i o n o f p l u t o n i u m c i t r a t e , h a v e
p r o d u c e d h i g h f r e q u e n c i e s o f b o n e c a n c e r i n b e a g l e s : 33% o s t e o s a r c o m a s f o r
78 r a d (O .78 Gy) t o t h e s k e l e t o n ( a v e r a g e b o n e d o s e , c a l c u l a t e d 1 y e a r
b e f o r e d e a t h ) , a n d 100% f o r 600 r a d (6 G y ) ; t h e r a t e o f i n c r e a s e o f o s t e o -
s a r c o m a s h a s b e e n e s t i m a t e d i n d o g s t o b e 0.38% r a d " 1 (0.00l+% G y " 1 ) , i n
m i c e 0.10% r a d " 1 (0.001% G y " 1 ) a n d i n r a t s , 0,06% r a d " 1 (0.0006% G y " 1 ) ,
w h i c h c o r r e s p o n d s t o a f a c t o r o f 6 t o t h e d o g s ' d i s a d v a n t a g e (Mays a n d
126
L l o y d , 1 9 7 2 ) . I n d o g s , o n t h e o t h e r h a n d , u n l i k e r a t s , n o s i g n i f i c a n t
d i f f e r e n c e h a s b e e n f o u n d b e t w e e n t h e e f f e c t s o f p l u t o n i u m a n d a m e r i c i u m
i n c a u s i n g r a d i a t i o n - i n d u c e d o s t e o s a r c o m a s ( L l o y d e t a l , 1 9 7 2 ) . No b o n e
c a n c e r h a s b e e n f o u n d i n m o n k e y s t h a t h a v e r e c e i v e d i n t r a v e n o u s i n j e c t i o n
o f a m e r i c i u m c i t r a t e d e l i v e r i n g d o s e s t o t h e s k e l e t o n r a n g i n g f r o m 2$0 t o
1000 r a d ( 2 . 5 t o 10 Gy) o v e r p e r i o d s o f t i m e v a r y i n g f r o m 2 t o 6 y e a r s
( D u r b i n , 1973) - I n t r a v e n o u s i n j e c t i o n s o f p l u t o n i u m n i t r a t e g i v e
c o r r e s p o n d i n g r e s u l t s ( M o s k a l e v e t a l , 1969; L e m b e r g , I96I4.).
I n f a c t , t o e x p r e s s t h e t r u e r i s k o f o s t e o s a r c o m a , t h e r a t e o f t r a n s -
l o c a t i o n o f t h e r a d i o n u c l i d e t o t h e b o n e f r o m t h e s i t e o f e n t r y i n t o t h e
b o d y m u s t b e t a k e n i n t o a c c o u n t . A c o m p a r i s o n o f v a r i o u s a c t i n i d e s
a d m i n i s t e r e d t o a n u m b e r o f s p e c i e s u s i n g t h e same r o u t e o f a d m i n i s t r a t i o n
w o u l d b e p a r t i c u l a r l y v a l u a b l e .
F o r r a t s , e x p e r i m e n t a l r e s u l t s a r e a v a i l a b l e w h i c h c o v e r a w i d e r a n g e
o f a c t i n i d e s i n h a l e d i n v a r i o u s f o r m s ; a c l e a r r e l a t i o n s h i p c a n u s u a l l y b e
s e e n b e t w e e n t h e t r a n s p o r t a b i l i t y o f t h e e l e m e n t i n t h e o r g a n i s m a n d i t s
t e n d e n c y t o i n d u c e o s t e o s a r c o m a s ( L a f u m a e t a l , 1975 ; M o r i n e t a l , 1976,
1977; B a l l o u e t a l , 1 9 7 5 ) .
T a b l e 6.2 s h o w s t h e p r o p o r t i o n o f b o n e c a n c e r s i n r e l a t i o n t o l u n g
c a n c e r s p r o d u c e d b y p l u t o n i u m , a m e r i c i u m a n d c u r i u m i n h a l e d i n v a r i o u s
c h e m i c a l f o r m s . Cur ium d o e s n o t c o n f o r m t o t h e t r e n d s h o w n b y t h e o t h e r
e l e m e n t s ; t h e p a u c i t y o f b o t h l u n g c a n c e r s a n d o s t e o s a r c o m a s may b e d u e t o
a g r e a t l y s h o r t e n e d l i f e s p a n o f t h e s e a n i m a l s . E i n s t e i n i u m , w i t h i t s
p h y s i c a l h a l f - l i f e o f 20 . 5 d a y s , i s a s p e c i a l c a s e ; c o m p a r i n g i t w i t h a
s o l u b l e f o r m o f p l u t o n i u m o r a m e r i c i u m may p r o v i d e a b a s i s f o r e s t i m a t i n g
t h e i n f l u e n c e o f h i g h d o s e r a t e s o n t h e i n d u c t i o n o f b o n e c a n c e r s . H e n c e ,
t h e i n c i d e n c e o f o s t e o s a r c o m a s i n r a t s a f t e r i n t r a t r a c h e a l i n j e c t i o n o f
e i n s t e i n i u m - 2 5 3 i s f o r d o s e s o f 600 r a d (6 Gy) d e l i v e r e d i n 5 m o n t h s ,
h a l f o f t h e d o s e b e i n g d e l i v e r e d i n 3 w e e k s ( D u r b i n , 1973) -
127
T a b l e 6 . 2
I n i t i a l Lung
D e p o s i t (+iCi g ~ 1 )
B o n e c a n c e r s / r a t s
Lung c a n c e r s / r a t s
B o n e c a n c e r s / L u n g
c a n c e r s
%
P l u t o n i u m - 2 3 9 d i o x i d e
0 . 0 1 - 0 . 7 3 0 / 1 0 8 6 5 / 1 0 8 0
P l u t o n i u m - 2 3 9 n i t r a t e
0 . 0 8 - 0 . 5 0 2 / 4 2 2 3 / 4 2 9
P l u t o n i u m - 2 3 8 d i o x i d e
0 . 0 1 5 - 0 . 0 9 1 / 4 5 8 / 4 5 1 2
P l u t o n i u m - 2 3 8 n i t r a t e
0 . 1 1 - 0 . 4 0 4 / 5 6 6 / 5 6 6 3
A m e r i c i u m - 2 i + 1 d i o x i d e
0 . 0 2 - 0 .1+8 1 0 / 1 1 4 6 1 / 1 1 4 1 7
A m e r i c i u m - 2 4 1 n i t r a t e
0 . 1 7 - 1 . 5 2 1 6 / 2 0 4 6 5 / 2 0 4 2 5
Curium-21+1+ n i t r a t e
0 . 0 3 - 0 . 2 8 1 / 4 8 9 / 4 8 1 0
E i n s t e i n i u m - 2 5 3 c h l o r i d e
0 . 2 5 - 1 2 . 0 * 2 0 / 9 6 8 / 9 6 2 6 2
* e x p r e s s e d a s pCi i n w h o l e l u n g
I n r a t s , o s t e o s a r c o m a s h a v e b e e n p r o d u c e d w i t h r e l a t i v e l y l o w b o n e
d o s e s : 1 5 r a d ( 0 . 1 5 Gy) r e s u l t e d i n a f r e q u e n c y o f 1 $ f o l l o w i n g i n h a l a t i o n
o f ammonium p l u t o n i u m p e n t a c a r b o n a t e ( g r o u p o f 2 5 0 r a t s a n d 5 0 0 c o n t r o l s )
( K o s h u r n i k o v a e t a l , 1 9 6 8 ) , 5 6 r a d ( 0 . 5 6 Gy) g a v e a f r e q u e n c y o f 1 . 1 %
f o l l o w i n g i n t r a t r a c h e a l a d m i n i s t r a t i o n o f p l u t o n i u m n i t r a t e ( g r o u p o f 9 3
r a t s ) ( B u l d a k o v e t a l , 1 9 7 0 ; K o s h u r n i k o v a , 1 9 6 8 b ) , 1 5 0 r a d ( 0 . 1 5 G y ) ( 0 . 0 9 —1 —1
+iCi g~ ( 3 . 3 kBq g~ ) ) g a v e a f r e q u e n c y o f 9*4% f o l l o w i n g a d m i n i s t r a t i o n o f
p l u t o n i u m - 2 3 8 t h a t w a s 70% u l t r a - f i l t e r a b l e ( S a n d e r s , 1 9 7 3 ) . I n t h i s l a s t
e x p e r i m e n t , i t i s i n t e r e s t i n g t o n o t e t h a t a l o w i n i t i a l p u l m o n a r y d e p o s i t
( 0 . 0 0 7 pCi g " 1 ( 0 . 2 6 kBq g " 1 ) ) g i v i n g 2 0 r a d ( 0 . 2 Gy) t o t h e b o n e d i d
n o t i n d u c e b o n e c a n c e r s b u t p r o d u c e d a h i g h f r e q u e n c y o f p u l m o n a r y c a n c e r s ,
v i z . 23% w i t h 3 2 r a d ( O . 3 2 Gy) t o t h e l u n g ; t h e s e r e s u l t s s h o u l d b e c o m p a r e d
w i t h t h o s e i n T a b l e 6 . 2 . The l o w f r e q u e n c i e s o b s e r v e d i n c e r t a i n e x p e r i m e n t s
C o m p a r i s o n o f t h e n u m b e r o f c a n c e r s i n r a t b o n e a n d l u n g a f t e r
i n h a l a t i o n o f v a r i o u s a l p h a e m i t t e r s
( L a f u m a e t a l , 1 9 7 5 ; B a l l o u e t a l , 1 9 7 5 )
128
i n v o l v i n g l o w d o s e s w h i c h a r e o n l y s l i g h t l y a b o v e t h e f r e q u e n c i e s n o r m a l l y
o c c u r r i n g i n u n e x p o s e d a n i m a l s i n d i c a t e t h e d i f f i c u l t y i n i n t e r p r e t i n g t h e
r e s u l t s ( T a b l e 6 . 2 ) .
A f e a t u r e common t o t h e s e b o n e c a n c e r s i s t h a t t h e y a r e o f t h e o s t e o -
g e n i c s a r c o m a t y p e ( F i g u r e 6 . 7 ) , a n d may m e t a s t a s i z e i n t o v a r i o u s o r g a n s ,
o f w h i c h t h e l u n g i s t h e m o s t i m p o r t a n t . I n a n i m a l s t h a t h a d i n h a l e d
a c t i n i d e s i t i s n o t u n u s u a l t o f i n d a p r i m a r y c a r c i n o m a a n d o s t e o s a r c o m a t o u s
m e t a s t a s i s ( L a f u m a e t a l , 1 9 7 5 ) -
R e s u l t s o b t a i n e d f r o m d o g s c o n f i r m t h e s e d a t a i n r a t s . No b o n e c a n c e r
h a s b e e n o b s e r v e d a f t e r i n h a l a t i o n o f i n s o l u b l e c o m p o u n d s , s u c h a s
p l u t o n i u m - 2 3 9 d i o x i d e ( P a r k e t a l , 1 9 7 6 ) . On t h e o t h e r h a n d , t h e
e f f e c t o f t h e s o l u b i l i t y o f p l u t o n i u m - 2 3 8 d i o x i d e i s t o i n d u c e a n a p p r e c i -
a b l e number o f b o n e c a n c e r s . The m i n i m a l i n i t i a l p u l m o n a r y a c t i v i t y i s o f
t h e same o r d e r a s t h a t o b s e r v e d i n r a t s . The r e s u l t s o f e x p e r i m e n t s c a r r i e d
o u t o n r a t s w i t h p l u t o n i u m - 2 3 8 d i o x i d e a r e c o n s i s t e n t : o s t e o s a r c o m a s h a v e
a p p e a r e d a t a v e r a g e b o n e d o s e s f r o m 5 0 t o 1 5 0 r a d ( 0 . 5 0 t o 1 . 5 Gy) ( S a n d e r s ,
1 9 7 3 ) > c o m p a r a b l e t o t h o s e d e l i v e r e d a f t e r i n t r a p e r i t o n e a l i n j e c t i o n s o f
p l u t o n i u m - 2 3 9 d i o x i d e g i v i n g s i m i l a r a v e r a g e b o n e d o s e s ( S a n d e r s e t a l , 1 9 7 2 ) .
The g r o w t h o f t h e b o n e t h a t o c c u r s d u r i n g a r e l a t i v e l y l a r g e p a r t o f
t h e l i f e o f t h e r a t p l a y s a r o l e i n t h e a g e - r e l a t e d v a r i a t i o n s o f b o n e
s e n s i t i v i t y t h a t h a v e b e e n o b s e r v e d i n t h e s e a n i m a l s .
T h u s , f o r t h e same d o s e s d e l i v e r e d t o b o n e b y a m e r i c i u m - 2 1 + 1 , a s s u m i n g
t h a t a l l o t h e r e x p e r i m e n t a l c o n d i t i o n s w e r e c o m p a r a b l e , t h e i n c i d e n c e o f
o s t e o s a r c o m a s w a s 29% i n y o u n g r a t s a n d o n l y 1 3 - 5 % i n a d u l t r a t s ( D u r b i n ,
1 9 7 3 ) « S i m i l a r r e s u l t s w e r e o b t a i n e d f o r p l u t o n i u m : 2 5 % f o r r a t s t h a t h a d
r e c e i v e d p l u t o n i u m - 2 3 9 a t 7 w e e k s a n d 5% a t 7 m o n t h s , a l t h o u g h t h e l e n g t h o f
t h e l a t e n t p e r i o d may h a v e d i s t o r t e d t h e r e s u l t o b t a i n e d i n o l d a n i m a l s
( F a b r i k a n t a n d S m i t h , 1 9 6 ! + ) . O t h e r s t u d i e s i n r a t s h a v e s h o w n t h e same
t r e n d a l t h o u g h d i f f e r e n c e s w e r e l e s s m a r k e d (Mahlum e t a l , 1 9 7 5 ) .
M i x t u r e s o f p l u t o n i u m a n d s o d i u m r e p r e s e n t a p o t e n t i a l c o n t a m i n a t i o n
r i s k i n c e r t a i n n u c l e a r p o w e r i n s t a l l a t i o n s . O n l y m e t a b o l i c d a t a i s a v a i l -
a b l e o n s u c h m i x t u r e s b u t p a r t i c u l a r a t t e n t i o n s h o u l d b e p a i d t o t h e r i s k
t o b o n e t h a t t h e y r e p r e s e n t . P l u t o n i u m i n p l u t o n i u m - s o d i u m m i x t u r e s i s
r e a d i l y t r a n s p o r t a b l e a n d r e s u l t s i n a h i g h b o n e d e p o s i t w h i c h i s n o t
r e a d i l y r e m o v e d b y c h e l a t i n g a g e n t s ( M e t i v i e r e t a l , 1 9 7 6 ) .
3 . 2 . 2 B o n e marrow
L e u k a e m i a ( s ) a r e t h e m o s t i m p o r t a n t g r o u p o f t u m o u r s o r i g i n a t i n g i n
129
F i g u r e 6.7 O s t e o g e n i c o s t e o s a r c o m a i n r a t s a f t e r i n h a l a t i o n o f a m e r i c i u m
( i n f o r m a t i o n s u p p l i e d b y R. M a s s e , D e p a r t e m e n t d e P r o t e c t i o n ,
CEA, F r a n c e ) .
130
t h e m a r r o w , o t h e r m e s e n c h y m a t o u r t u m o u r s o c c u r v e r y i n f r e q u e n t l y ( F i n k e l
a n d B i s k i s , 19&2). L e u k a e m i a s , a l t h o u g h t h e y a r e a p o t e n t i a l r i s k f r o m
a n y p l u t o n i u m d e p o s i t i n t h e h o n e , o c c u r much l e s s f r e q u e n t l y t h a n o s t e o -
s a r c o m a s ( M o s k a l e v e t a l , 1968) . To a g r e a t e r e x t e n t t h a n t h e t r a n s p l u t o n -
i u m e l e m e n t s , p l u t o n i u m may c a u s e l e u k a e m i c d i s e a s e s t h a t a r e m a r k e d b y a n
a b n o r m a l h y p e r p l a s i a o f t h e c e l l s i n t h e marrow w i t h e f f e c t s i n o t h e r
o r g a n s , s u c h a s t h e s p l e e n , t h e l i v e r o r t h e k i d n e y s a n d t h e d e v e l o p m e n t o f
a l e u c o - e r y t h o b l a s t i c a n a e m i a ( C h a p t e r $ , s e c t i o n 2 .2 ,2 ) ( V a u g h a n , 1970) .
A f e w l e u k a e m i a s h a v e b e e n o b s e r v e d i n r a t s a f t e r i n j e c t i o n s o f p l u t o n i u m
( B e n s t e d e t a l , 1 9 ^ 5 ) • The f r e q u e n c y o f l e u k a e m i a s i s a b o u t 2% o f t h a t o f
o s t e o s a r c o m a s o b s e r v e d i n b e a g l e s c o n t a m i n a t e d b y p l u t o n i u m - 2 3 9 c i t r a t e
a d m i n i s t e r e d i n t r a v e n o u s l y ( V a u g h a n e t a l , 1973) - Lymphomas h a v e b e e n
o b s e r v e d i n m i c e g i v e n i n t r a v e n o u s i n j e c t i o n s o f p l u t o n i u m - 2 3 9 c i t r a t e
( L o u t i t e t a l , 1 9 7 ^ ) • L e u k a e m i a s o c c u r v e r y r a r e l y i n a n i m a l s a f t e r
i n j e c t i o n o r i n h a l a t i o n o f a m e r i c i u m o r c u r i u m .
3- 3 L i v e r
E f f e c t s o n t h e l i v e r s h o u l d b e e x a m i n e d c l o s e l y , d e s p i t e t h e l a c k o f
c o n s i s t e n c y b e t w e e n t h e t h e o r e t i c a l e f f e c t s t h a t m i g h t b e e x p e c t e d a n d t h e
o b s e r v e d e f f e c t s . As p l u t o n i u m i s d e p o s i t e d , b r o a d l y s p e a k i n g , i n e q u a l
p r o p o r t i o n s i n t h e s k e l e t o n a n d i n t h e l i v e r , t h e r i s k o f m a l i g n a n t c h a n g e s
t o t h e l i v e r c o u l d e q u a l o r e v e n e x c e e d t h a t o f b o n e c a n c e r s (Mays e t a l ,
1970) . H o w e v e r , t h i s h a s n e v e r b e e n f o u n d e x p e r i m e n t a l l y i n a n i m a l s t u d i e s .
N u m e r o u s e x p e r i m e n t s h a v e d e s c r i b e d d e l a y e d b u t n o n - n e o p l a s t i c e f f e c t s
a r i s i n g f r o m t h e d e p o s i t i o n o f p l u t o n i u m o r o t h e r a c t i n i d e s i n t h e l i v e r .
—1 —1 L a r g e c o n c e n t r a t i o n s ( a b o u t 10 jiCi k g ~ (37O kBq k g ) ) o f p l u t o n i u m a r e r e q u i r e d t o e n a b l e t h e h e p a t i c d i s t u r b a n c e s , r e l a t e d t o a n e f f e c t o n t h e
h e p a t i c c e l l s t o b e d e t e c t e d c l i n i c a l l y . Lower c o n c e n t r a t i o n s ( l e s s t h a n —1 —1
2 jiCi k g (74 kBq k g ) ) may i n d u c e r e c i r c u l a t i o n o f q u a n t i t i e s o f p l u t o n i u m
i n t h e b l o o d s t r e a m ( L i n d e n b a u m a n d R o s e n t h a l , 1 9 7 2 ) . D i s p e r s e d f o r m s o f
p l u t o n i u m h a v e m o r e e f f e c t t h a n t h e p o l y m e r i c f o r m s , e s p e c i a l l y i n c h a n g i n g
p h a g o c y t i c f u n c t i o n ( K a s h i m a e t a l , 1 9 7 2 ) . H i s t o l o g i c a l c h a n g e s , s u c h a s
c o n c e n t r a t i o n s o f p i g m e n t i n t h e c e l l s o f t h e r e t i c u l o e n d o t h e l i a l s y s t e m
(RES) a r e o b s e r v e d w h e n t h e l o w e s t d o s e s a r e a d m i n i s t e r e d ( T a y l o r e t a l ,
1 9 7 2 ) . The r e l a t i v e d e p o s i t i o n o f p l u t o n i u m i n t h e h e p a t i c c e l l s a n d i n
t h e RES, w h o s e p r o p o r t i o n s v a r y a c c o r d i n g t o t h e s p e c i e s a n d t h e p h y s i c o -
c h e m i c a l f o r m o f t h e c o n t a m i n a n t , may p r o v i d e e x p l a n a t i o n s f o r t h e d i v e r s e
c h a n g e s o b s e r v e d i n t h e s e t w o t i s s u e s ( C o c h r a n e t a l , 19&2; T a y l o r e t a l ,
1966) .
131
On t h e o t h e r h a n d , t h e s e n o n - n e o p l a s t i c c h a n g e s t h a t h a v e b e e n
r e p o r t e d i n s e v e r a l a n i m a l s p e c i e s do n o t i n d i c a t e t h a t t h e l i v e r i s
p a r t i c u l a r l y r e s i s t a n t t o t h e d e v e l o p m e n t o f m a l i g n a n t c h a n g e , a l t h o u g h
t h i s h a s o f t e n b e e n o b s e r v e d ( G e r s h b e i m , 1956; R e e d a n d C o x , 1966) . M e t a -
b o l i c d a t a o b t a i n e d i n v a r i o u s a n i m a l s p e c i e s h a v e s h o w n t h a t r a t s a n d m i c e
r e p r e s e n t p o o r m o d e l s f o r m a n , u n l i k e d o g s a n d h a m s t e r s ( C h a p t e r 1+). One
w o u l d l o g i c a l l y e x p e c t t o f i n d a s i g n i f i c a n t n u m b e r o f c a n c e r o u s c h a n g e s ,
i n s p e c i e s i n w h i c h t h e b i o l o g i c a l h a l f - l i f e i n t h e l i v e r i s l o n g a n d
c o m p a r a b l e t o t h a t o f m a n . I n f a c t , l i v e r t u m o u r s c a u s e d b y h e p a t i c
d e p o s i t i o n o f p l u t o n i u m i n d o g s o n l y a f f e c t t h e b i l e d u c t s ( T a y l o r e t a l ,
1969; T a y l o r e t a l , 1 9 7 2 ) . A f t e r i n j e c t i o n o f p l u t o n i u m c i t r a t e i n d o g s ,
t h e i n c i d e n c e o f i n t r a h e p a t i c t u m o u r s w a s a b o u t 10% ( 1 0 / 9 6 ) , c o m p a r e d w i t h
a n i n c i d e n c e i n t h e c o n t r o l s o f !+%• T h e s e t u m o u r s o c c u r r e d a t 11 y e a r s o n
a v e r a g e (9 .2 - 11+) i n t h e c o n t a m i n a t e d d o g s a s c o m p a r e d w i t h 11+ y e a r s (1 3 -
16.1+) i n t h e c o n t r o l s . I n m o s t o f t h e d o g s , t h e s e t u m o u r s w e r e r e v e a l e d a t
a u t o p s y . A l o w p e r c e n t a g e ( a b o u t 20%) w e r e d i r e c t l y i n s t r u m e n t a l i n c a u s i n g
d e a t h ; i n t h e s e c a s e s , t h e l o w e s t l e v e l o f c o n t a m i n a t i o n t h a t c a u s e d a
t u m o u r (0.001+ p.Ci k g " 1 ( 0 .15 kBq k g " 1 ) ) g a v e a l i v e r d o s e o f 60 r a d (0.60
G y ) .
The q u e s t i o n a s t o why t h e r e a r e n o c a n c e r s i n t h e h e p a t i c t i s s u e s a n d
c e l l s r e m a i n s u n a n s w e r e d . The r e l a t i v e l y l o w r a d i o s e n s i t i v i t y o f t h e l i v e r
i s p r o b a b l y i n f l u e n c e d b y t h e s l o w r e n e w a l o f t h e h e p a t i c c e l l ( P a b r i k a n t ,
1967) ; i t c e r t a i n l y s e e m s t h a t s h o r t e n e d l i f e s p a n s o f c e l l s h e l p t o i n d u c e
c a n c e r o u s c h a n g e s ( W e i n b r e n e t a l , i960; C o l e a n d N o w e l l , 1961+; O o o d a l l ,
1966) . A t l o w c o n t a m i n a t i o n l e v e l s , s u c h a s t h o s e t h a t man m i g h t b e e x p e c -
t e d t o e n c o u n t e r , t h e r e w o u l d n o t b e a s u f f i c i e n t n u m b e r o f o s t e o s a r c o m a s
i n d u c e d t o mask t h e l a t e a p p e a r a n c e o f p r i m a r y l i v e r c a n c e r s ( M a y s e t a l , 19^9) •
M o r e o v e r , t h e d e v e l o p m e n t o f h e p a t i c c a n c e r s m i g h t b e h e l p e d b y t h e p r e s e n c e
o f o t h e r a d d i t i o n a l e n v i r o n m e n t a l f a c t o r s ( c h e m i c a l s , p h a r m a c e u t i c a l s , e t c . ) .
I t i s p r o b a b l e t h a t a m e r i c i u m a n d c u r i u m a r e m o r e t o x i c t h a n p l u t o n i u m s i n c e
t h e y a r e r e t a i n e d i n l a r g e r q u a n t i t i e s i n t h e l i v e r ( A t h e r t o n e t a l , 1968;
N e n o t e t a l , 1 9 7 1 a ) . T h u s , d e s p i t e t h e a b s e n c e o f c o n s i s t e n t s u p p o r t i n g
e x p e r i m e n t a l e v i d e n c e , t h e l i v e r s h o u l d b e r e g a r d e d a s a t i s s u e p o t e n t i a l l y
a t r i s k i n m a n .
3.1+ O t h e r o r g a n s
The p a t h o l o g i c a l e f f e c t s o f p l u t o n i u m o r o f a n y o t h e r a l p h a e m i t t e r i n
s o f t t i s s u e s , w h e r e s e c o n d a r y r e t e n t i o n t a k e s p l a c e , s e e m t o r e s u l t f r o m t h e
d e p o s i t i o n o f a c t i n i d e s i n t h e m . As i n t h e c a s e o f t h e b o n e ( s e c t i o n 3.2)
t h e r e s u l t s i n d i c a t e a n i n c i d e n c e o f c a n c e r s i n s o f t t i s s u e s o t h e r t h a n t h e
132
l u n g a n d t h e l i v e r t h a t i s p a r t i c u l a r l y h i g h w h e n t h e a c t i n i d e i s r e a d i l y
t r a n s p o r t a b l e i n t h e b o d y .
T h i s c a n b e i l l u s t r a t e d b y c o m p a r i n g r e s u l t s o b t a i n e d f o r "two
f o r m s o f p l u t o n i u m . A f t e r i n h a l a t i o n o f i n s o l u b l e p l u t o n i u m - 2 3 9 d i o x i d e b y
r a t s t h e i n c i d e n c e o f c a n c e r s i n s o f t t i s s u e s o t h e r t h a n t h e l u n g i s n e v e r
h i g h e r t h a n t h a t i n t h e c o n t r o l s ; i t i s n o r m a l l y l o w e r t h a n t h a t i n t h e
c o n t r o l s , b e c a u s e t h e l a t t e r l i v e l o n g e r a n d t e n d t o d e v e l o p c a n c e r s l a t e r
i n l i f e ( M o r i n e t a l , 1 9 7 7 ) . I n t h e s e c o n d c a s e , a f t e r i n h a l a t i o n b y r a t s
o f s o l u b l e p l u t o n i u m - 2 3 8 i n t h e f o r m o f c r u s h e d m i c r o s p h e r e s , t h e r e i s a
l a r g e i n c r e a s e i n t h e i n c i d e n c e o f p e r i p h e r a l c a n c e r s ( S a n d e r s , 1 9 7 3 ) • I n
a n i m a l s r e c e i v i n g a d o s e o f 9 r a d ( 0 . 0 9 Gy) t o t h e l u n g , c a n c e r s o f t h e s o f t
t i s s u e s a r e t h r e e t i m e s a s h i g h a s t h o s e i n t h e l u n g . T a b l e 6 . 3 s h o w s t h a t
t h e r e l a t i v e n u m b e r s o f p e r i p h e r a l c a n c e r s i n r e l a t i o n t o p u l m o n a r y c a n c e r s
i s i n v e r s e l y p r o p o r t i o n a l t o t h e d o s e a c c u m u l a t e d b y t h e l u n g ; t h e t w o
e f f e c t s o f r a d i a t i o n o f i n c r e a s i n g n u m b e r o f l u n g c a n c e r s a n d s h o r t e n i n g t h e
l i f e s p a n , m a s k s t h e a p p e a r a n c e o f o t h e r c a n c e r s .
T a b l e 6 . 3
F r e q u e n c y o f c a n c e r s a f t e r i n h a l a t i o n b y f e m a l e r a t o f p l u t o n i u m - 2 3 8
i n t h e f o r m o f c r u s h e d m i c r o s p h e r e s
( S a n d e r s , 1 9 7 3 )
D o s e t o l u n g ( r a d )
N o . o f
r a t s
L i f e s p a n
I n c i d e n c e o f t u m o u r s {%) D o s e t o
l u n g ( r a d )
N o . o f
r a t s
L i f e s p a n
Mammary Lung B o n e L i v e r L e u k a e m i a O t h e r s o f t
t i s s u e s
0 9 2 8 2 5 7 1 . 7 1 . 1 _ _ 2 . 2 1 . 1
9 30 6 5 0 7 3 . 3 6 . 6 - - - 1 9 . 8
3 2 30 5 7 5 6 0 . 0 2 3 . 2 - - - 1 3 . 2
3 7 5 3 2 5 5 0 6 2 . 5 2 5 . 0 9.k - - 1 2 . h
M o r e o v e r , p e r i p h e r a l c a n c e r s a p p e a r a t a l a t e s t a g e i n t h e a b s e n c e o f
a n y i r r a d i a t i o n ; f r e q u e n c i e s i n t h e c o n t r o l s o f 1 % b e f o r e t h e a g e o f 1 . 5
y e a r s , o f 5% b e t w e e n t h e a g e s o f 1 . 5 a n d 2 y e a r s , a n d 1 0 % a f t e r t h e a g e o f
2 a r e n o r m a l .
A m e r i c i u m , w h i c h i s r e a d i l y t r a n s p o r t a b l e i n t h e b o d y i n a l l i t s
c h e m i c a l f o r m s , i l l u s t r a t e s t h e r i s k o f c a n c e r i n d u c t i o n i n s o f t t i s s u e s ,
d u e t o t h e m o v e m e n t o f a c t i n i d e s i n t h e o r g a n i s m . T h u s , a f t e r i n h a l a t i o n o f
a m e r i c i u m d i o x i d e , a t h i r d o f t h e r a t s w i t h c a n c e r o f t h e l u n g a l s o h a v e a
c a n c e r o f t h e o t h e r s o f t t i s s u e s ( M o r i n e t a l , 1 9 7 7 ) . As h a s b e e n n o t e d i n
133
c o n n e c t i o n w i t h o s t e o s a r c o m a s , e i n s t e i n i u m h a s h i g h t o x i c i t y d u e t o i t s
r a p i d t r a n s l o c a t i o n i n t h e b o d y . Thus i n a g r o u p o f 1+8 r a t s t h a t r e c e i v e d
1900 r a d (19 G y ) t o t h e l u n g , 6 p u l m o n a r y c a n c e r s d e v e l o p e d t o g e t h e r w i t h
9 t u m o u r s i n t h e s o f t t i s s u e s a n d 2 l y m p h o i d l e u k a e m i a s , a s w e l l a s 20
o s t e o s a r c o m a s a n d 2 m y e l o i d l e u k a e m i a s ( B a l l o u e t a l , 1975) -
T h e r e f o r e t h e r i s k a s s o c i a t e d w i t h t h e i n h a l e d a c t i n i d e s d o e s n o t o n l y
a r i s e i n t h e l u n g a n d t h e b o n e b u t a l s o e x i s t s i n a number o f o t h e r o r g a n s .
As t h e l i v e r h a s a n i m p o r t a n t p a r t i n t r a n s u r a n i c e l e m e n t m e t a b o l i s m i t a l s o
h a s t o b e c o n s i d e r e d a s a n o r g a n p o t e n t i a l l y a t r i s k . The i n c r e a s e d i n c i d -
e n c e o f c a n c e r s i n o t h e r o r g a n s t h a t i s s o m e t i m e s o b s e r v e d d e p e n d s o n
t h e a n i m a l s t r a i n c h o s e n f o r t h e e x p e r i m e n t . O r g a n s o t h e r t h a n
t h e l u n g , b o n e a n d l i v e r r e c e i v e l o w d o s e s b u t a l t h o u g h t h e i r n u m b e r may
i n c r e a s e t h e o v e r a l l r i s k i t i s n o t p o s s i b l e t o i d e n t i f y a n y o f t h e m a s a
c r i t i c a l t i s s u e .
3.5 Summary
The d e l a y e d e f f e c t s t h a t h a v e t o b e c o n s i d e r e d i n a n i m a l s e x p o s e d t o
p l u t o n i u m , a m e r i c i u m a n d c u r i u m a r e m a l i g n a n t c h a n g e s i n t h e o r g a n s i n
w h i c h t h e y d e p o s i t . The t u m o u r f r e q u e n c y i n d i f f e r e n t t i s s u e s d e p e n d s
u p o n t h e t r a n s p o r t a b i l i t y o f t h e s e a c t i n i d e s i n t h e b o d y . The m a i n
o r g a n s o f d e p o s i t i o n a r e t h e l u n g , s k e l e t o n a n d l i v e r b u t a c t i n i d e s may
a l s o d e p o s i t i n a l l t h e o t h e r t i s s u e s o f t h e b o d y . I n r a t s t h e f r e q u -
e n c y o f r a d i a t i o n i n d u c e d l u n g c a n c e r i n c r e a s e s w i t h t h e d o s e u p t o a
maximum a n d t h e n d e c r e a s e s a s a r e s u l t o f c e l l s t e r i l i z a t i o n a n d d e a t h
o c c u r r i n g b e f o r e t h e d e v e l o p m e n t o f c a n c e r . T h i s maximum i n c i d e n c e
o c c u r s a t l u n g d o s e s a r o u n d 500 r a d (5 Gy) f o r americium-21+1 o x i d e a n d
curium-21+1+ n i t r a t e , b e t w e e n £00 a n d 10OO r a d (5 a n d 10 Gy) f o r p l u t o n -
ium-238 ( o x i d e a n d n i t r a t e ) , b e t w e e n £00 J Q O O r a d (5 a n d £0 Gy) f o r
americium-21+1 n i t r a t e a n d o v e r 1000 r a d (10 G y ) f o r p l u t o n i u m - 2 3 9
( o x i d e a n d n i t r a t e ) . E x p e r i m e n t a l r e s u l t s w i t h o t h e r s p e c i e s c o n f i r m
t h e s e r e s u l t s .
M a l i g n a n t t u m o u r s o f v a r i o u s t y p e s may d e v e l o p i n t h e s k e l e t o n a f t e r
t h e e n t r y o f a c t i n i d e s i n t o t h e b l o o d . T h e s e a r e o s t e o s a r c o m a s ,
c h o n d r o s a r c o m a s o r f i b r o s a r c o m a s . S e n s i t i v i t y t o r a d i a t i o n i n d u c e d
b o n e c a n c e r d e v e l o p m e n t v a r i e s w i t h t h e s p e c i e s c o n s i d e r e d . The d o g
a p p e a r s t o b e t h e m o s t s e n s i t i v e a n i m a l w i t h a n e s t i m a t e d i n d u c t i o n
r a t e o f 0.38% p e r r a d c o m p a r e d w i t h a r a t e o f 0.06% p e r r a d i n t h e r a t .
A f t e r i n h a l a t i o n o f a c t i n i d e s t h e d e v e l o p m e n t o f b o n e t u m o u r s c a n b e
c o r r e l a t e d w i t h t h e i r t r a n s p o r t a b i l i t y i n t h e b o d y a n d t h e a m o u n t
13U
d e p o s i t e d i n t h e s k e l e t o n . L e u k a e m i a s r e s u l t i n g f r o m i r r a d i a t i o n o f
t h e b o n e marrow h a v e b e e n s e e n o n l y r a r e l y i n a n i m a l s e x p o s e d t o
a c t i n i d e s .
L i v e r t u m o u r s h a v e b e e n s e e n o n l y i n f r e q u e n t l y i n a n i m a l s e x p o s e d t o
a c t i n i d e s . I n d o g s , l i v e r t u m o u r s d e v e l o p i n t h e b i l e d u c t s . M a l i g -
n a n t c h a n g e s may a l s o o c c u r o c c a s i o n a l l y i n o t h e r s o f t t i s s u e s i n
a n i m a l s e x p o s e d t o r e a d i l y t r a n s p o r t a b l e f o r m s o f a c t i n i d e s .
U. S h o r t e n i n g o f t h e l i f e s p a n
The s e p a r a t i o n o f t h e d e l a y e d e f f e c t s o n t h e o n e h a n d f r o m l i f e s p a n
s h o r t e n i n g o n t h e o t h e r h a n d i s t o some e x t e n t a r b i t r a r y , f o r t h e f o r m e r
c o n s i s t w h o l l y o f c a n c e r s w h i c h h a v e a s i g n i f i c a n t e f f e c t o n t h e l i f e s p a n .
I n p r a c t i c e , h o w e v e r , d e a t h may o c c u r a s a r e s u l t o f m a s s i v e t i s s u e damage
b e f o r e t h e c a n c e r s a p p e a r a n d t h i s e f f e c t i s n o n - s t o c h a s t i c u n l i k e i n t h e c a s e o f
c a n c e r s . As t h e h i g h e s t i n c i d e n c e o f c a n c e r o c c u r s a t t h e e n d o f l i f e , w i t h
o r w i t h o u t i r r a d i a t i o n , i t i s c l e a r t h a t t h e t w o p h e n o m e n a a r e r e l a t e d ,
p e r h a p s l i n k e d , b u t t h a t t h e a v e r a g e l i f e s p a n o f a g r o u p i s n o t d e t e r m i n e d
s o l e l y b y t h e n u m b e r o f c a n c e r s o r o f c a n c e r - b e a r i n g a n i m a l s i n t h a t g r o u p .
I t i s t h e r e f o r e p o s s i b l e t h a t a s t u d y o f l o n g e v i t y a n d i t s r e l a t i o n s h i p w i t h
i n t e r n a l i r r a d i a t i o n may n o t l e n d i t s e l f t o a p r o b a b i l i s t i c a p p r o a c h .
T a b l e 6.1+ s h o w s r e s u l t s o b t a i n e d i n a n u m b e r o f s t u d i e s o f t h e l e v e l s
o f p l u t o n i u m a n d t r a n s p l u t o n i u m e l e m e n t s t h a t i n f l u e n c e t h e l i f e s p a n o f
v a r i o u s s p e c i e s . The v a l u e o f t h e minimum d o s e p r o d u c i n g s i g n i f i c a n t l i f e
s h o r t e n i n g i s t o b e f o u n d b e t w e e n t h e t w o v a l u e s g i v e n i n t h e t a b l e :
( a ) t h e h i g h e s t d o s e a t w h i c h n o s h o r t e n i n g w a s o b s e r v e d , a n d ( b ) t h e l o w e s t
d o s e t h a t p r o d u c e d a s h o r t e n i n g . I t t h u s a p p e a r s t h a t t h e l o w e s t l e v e l o f
i n i t i a l p u l m o n a r y d e p o s i t i o n w h i c h s h o r t e n s t h e a v e r a g e l i f e s p a n o f r a t s i s
i n t h e r e g i o n o f 0 .01+ jiCi g 1 ( 1 . 5 kBq g 1 ) f o r p l u t o n i u m - 2 3 9 d i o x i d e , —1 —1
0 . 1 ^iCi g ~ ( 3 . 7 kBq g ) o r more f o r t h e t r a n s p o r t a b l e f o r m s o f p l u t o n i u m -
2 3 9 a n d p l u t o n i u m - 2 3 8 d i o x i d e , 0 . 0 5 pCi g ~ 1 ( 1 . 9 kBq g " 1 ) f o r t h e t r a n s -
—1 —1
p l u t o n i u m e l e m e n t s , a n d 0 . 0 0 2 jiCi g ~ ( 0 . 0 8 kBq g™ ) f o r u l t r a - f i l t e r a b l e
p l u t o n i u m - 2 3 8 , w h i c h w a s t h e m o s t s o l u b l e f o r m u s e d . A d o g s l i f e s p a n i s
a f f e c t e d l e v e l s a p p r o x i m a t e l y 3 "to 1 0 t i m e s l o w e r . As c l e a r a n c e r a t e s
d e p e n d u p o n p h y s i c o - c h e m i c a l f o r m s a n d s p e c i e s , i t i s v e r y d i f f i c u l t t o
d e t e r m i n e t h e minimum d o s e t h a t p r o d u c e s l i f e s h o r t e n i n g . The s i z e o f t h e
a n i m a l g r o u p s a l s o i n t r o d u c e s a f a i r l y l a r g e f a c t o r o f u n c e r t a i n t y i n t o t h e
d a t a , a n d m a k e s a n y i n t e r c o m p a r i s o n o f t h e s e many e x p e r i m e n t s d i f f i c u l t t o
i n t e r p r e t . I n r a t s t h e r e s u l t s s u g g e s t t h a t , b r o a d l y , t h e d o s e t o p r o d u c e
l i f e s h o r t e n i n g w o u l d a p p e a r t o b e a b o u t 1 5 0 0 t o 2 0 0 0 r a d ( 1 5 t o 2 0 Gy) t o
135
t h e l u n g f r o m p l u t o n i u m - 2 3 9 d i o x i d e , 5 0 0 t o 1 2 0 0 r a d ( 5 t o 1 2 Gy) f r o m
t r a n s p o r t a b l e p l u t o n i u m - 2 3 9 , 2 0 0 r a d ( 2 0 Gy) f r o m a m e r i c i u m - 2 4 1 , a n d o n l y a
f e w t e n s o f r a d f r o m t h e u l t r a - f i l t e r a b l e f o r m s o f p l u t o n i u m - 2 3 8 d i o x i d e .
T a b l e 6 . 4
S h o r t e n i n g o f l i f e s p a n , a f t e r i n h a l a t i o n o f a l p h a e m i t t e r s ,
i n d i f f e r e n t s p e c i e s
R a d i o n S p e c i e s
( a ) H i g h e s t l e v e l
a t w h i c h e f f e c t w a s n o t o b s e r v e d
( b ) L o w e s t l e v e l
a t w h i c h e f f e c t w a s o b s e r v e d
R a d i o n S p e c i e s ( L u n g ) ( L u n g )
R e x . R a d i o n S p e c i e s
N o . o f a n i m a l s
UCi g""1 Rad N o . o f
a n i m a l s UCi g ~ 1 Rad
P u - 2 3 9 Mouse 1 3 8 0 . 0 0 5 2 0 ( 1 ) d i o x i d e
R a t 6 0 0 . 0 1 7 9 3 2 0 . 0 1 9 ? ( 2 )
R a t 1 4 0 . 0 2 5 1 1 0 0 8 0 . 0 4 1 5 0 0 ( 3 )
D o g - ? ? 3 6 0 . 0 0 3 2 0 0 0 (h) Monkey - ? ? 3 2 0 . 0 5 3 3 0 0 ( 5 )
P u - 2 3 9 R a t 1 3 2 0 . 0 4 2 4 0 1 0 0 0 . 1 5 8 8 0 (6) c i t r a t e
(6)
P u - 2 3 9 R a t 6 5 0 . 0 6 ? 65 0 . 3 7 ? ( 7 ) n i t r a t e
R a t 1 2 0 . 0 1 6 2 2 5 1 8 0 . 1 2 2 8 0 0 ( 3 ) D o g - ? ? h 0 . 1 0 ? (h)
P u - 2 3 8 R a t 30 < 0 . 0 9 ? 2 7 O . 3 6 ? ( 2 ) d i o x i d e
H a m s t e r 4 5 0 . 0 1 ? U6 0 . 1 0 ? ( 8 )
D o g - ? ? 9 > 0 . 0 1 ? ( 9 ) P u - 2 3 8 R a t - 9 ? 30 > 0 . 0 0 2 9 ( 1 0 ) u l t r a f .
( 1 0 )
Am-21+1 R a t 5 0 . 0 3 1 5 0 9 0 . 1 3 7 5 0 ( 3 ) d i o x i d e
0 . 1 3 ( 3 )
Am-21+1 R a t 1 2 0 . 0 6 5 3 9 0 1 9 0 . 1 2 6 7 0 ( 3 ) n i t r a t e
( 3 )
C m - 2 4 4 R a t - 1 2 0 . 1 0 6 0 0 ( 3 ) n i t r a t e
( 3 )
E s - 2 5 3 R a t 4 8 0 . 0 5 3 8 U8 2 . 5 1 9 0 0 ( 1 1 ) c h l o r i d e
2 . 5 1 9 0 0 ( 1 1 )
( 1 ) B a i r e t a l , 1 9 6 2 ( 5 ) M e t i v i e r e t a l , 1 9 7 4 ( 9 ) P a r k e t a l , 1 9 7 6
( 2 ) S a n d e r s , 1 9 7 5 b ( 6 ) K o s h u r n i k o v a e t a l , 1 9 7 1 ( 1 0 ) S a n d e r s , 1 9 7 3
( 3 ) Lafuma e t a l , 1 9 7 5 ( 7 ) B a l l o u e t a l , 1 9 7 5 ( 1 1 ) B a l l o u a n d M o r r o w ,
( 4 ) P a r k e t a l , 1 9 7 2 ( 8 ) M e w h i n n e y e t a l , 1 9 7 6 b 1 9 7 3
136
A d i f f e r e n t a p p r o a c h c o n s i s t s o f c o m p a r i n g t h e L D ^ a t 1 y e a r f o r
d i f f e r e n t a c t i n i d e s i n t h e same s p e c i e s . H o w e v e r , t w o f a c t o r s m u s t t h e n b e
t a k e n i n t o a c c o u n t : ( a ) t h e $0% m o r t a l i t y r a t e o n l y t a k e s i n t o a c c o u n t t h e
s h o r t a n d m e d i u m - t e r m e f f e c t s , a n d i n v i e w o f t h e d e l a y e d e f f e c t s i t i s
s p e c u l a t i o n t o r e g a r d t h i s m o r t a l i t y r a t e a s r e p r e s e n t a t i v e o f t h e a v e r a g e
m o r t a l i t y r a t e o v e r a l i f e t i m e ; ( b ) t h i s L D ^ c o r r e s p o n d s t o t h e p l a t e a u o f
t h e s i g m o i d c u r v e l i n k i n g l i f e s p a n t o d o s e , a n d t h i s i n t r o d u c e s a f a c t o r
o f g r e a t u n c e r t a i n t y i n d e t e r m i n i n g t h e L D ^ Q ( L a f u m a e t a l , 1 9 7 4 , 1 9 7 6 ) .
The r e s u l t s i n T a b l e 6 . 5 s h o w t h a t t h e r e a r e l a r g e d i f f e r e n c e s b e t w e e n t h e
e l e m e n t s , t h e t w o e x t r e m e s b e i n g r e p r e s e n t e d b y c u r i u m n i t r a t e a n d
p l u t o n i u m - 2 3 9 d i o x i d e , w i t h a f a c t o r o f 5 * 5 b e t w e e n t h e t w o L D ^ n v a l u e s .
T a b l e 6 . 5
L D ^ Q a t 1 y e a r e s t i m a t e d f o r t h e r a t a f t e r
i n h a l a t i o n o f d i f f e r e n t a c t i n i d e s
Compound A v e r a g e d o s e t o l u n g
a t 1 y e a r ( r a d )
C u r i u m - 2 4 4 n i t r a t e 1 7 0 0
P l u t o n i u m - 2 3 8 d i o x i d e 2 5 0 0
P l u t o n i u m - 2 3 8 n i t r a t e 3 5 0 0
A m e r i c i u m - 2 4 1 d i o x i d e ) 4 0 0 0 - 5 0 0 0
A m e r i c i u m - 2 4 1 n i t r a t e )
P l u t o n i u m - 2 3 9 n i t r a t e 8 5 0 0
P l u t o n i u m - 2 3 9 d i o x i d e 9 5 0 0
Some a u t h o r s h a v e f a i l e d t o p o i n t t o t h e s e d i f f e r e n c e s i n e f f e c t w h i c h
may b e p r o d u c e d e i t h e r b y d i f f e r e n t a c t i n i d e s o r b y d i f f e r e n t i s o t o p e s o f
t h e same e l e m e n t a s f o r e x a m p l e p l u t o n i u m - 2 3 9 d i o x i d e a n d p l u t o n i u m - 2 3 8
d i o x i d e i n r a t s ( S t u a r t e t a l , 1 9 6 8 ) o r i n d o g s ( P a r k e t a l , 1 9 ^ 9 ) • The
r e a s o n s f o r t h i s a r e p r o b a b l y t w o f o l d : f i r s t l y , t h e d i f f e r e n t p u l m o n a r y
c l e a r a n c e r a t e s o f t h e t w o i s o t o p e s w e r e n o t t a k e n i n t o a c c o u n t a n d t h e
d o s e a n d t h e p u l m o n a r y d e p o s i t a t d e a t h w e r e c o n f u s e d i n t r o d u c i n g a l a r g e
f a c t o r o f e r r o r ; s e c o n d l y , t h e s u r v i v a l c u r v e s o n l y t a k e i n t o a c c o u n t e a r l y
e f f e c t s a t v e r y h i g h d o s e s .
An i n t e r s p e c i e s c o m p a r i s o n i s made d i f f i c u l t b y t h e l a c k o f d a t a a t
l o w d o s e s f o r d o g s a n d a b o v e a l l f o r m o n k e y s . F o r d o g s t h a t h a v e i n h a l e d
p l u t o n i u m - 2 3 9 d i o x i d e t h e e x p e r i m e n t a l d a t a c a n b e p l o t t e d o n l o g - l o g
s c a l e t o g i v e a s t r a i g h t l i n e r e l a t i o n s h i p b e t w e e n s u r v i v a l t i m e a n d l u n g
137
d o s e ( P a r k e t a l , 1 9 7 2 ) ( F i g u r e 6 . 8 ) , On t h e o t h e r h a n d , t h e n u m b e r o f
m o n k e y s t h a t h a v e d i e d a f t e r i n h a l a t i o n o f p l u t o n i u m - 2 3 9 i s s m a l l ( 3 5 ) a n d
m o s t o f t h e m d i e d e a r l y w i t h v e r y h i g h p l u t o n i u m b o d y b u r d e n s . M o r e o v e r ,
t h e o b s e r v e d g r e a t n o n - u n i f o r m i t y o f d i s t r i b u t i o n b e t w e e n o n e l u n g a n d
a n o t h e r h a s a n e n o r m o u s d i s t o r t i n g e f f e c t o n t h e r e s u l t s . H o w e v e r , i t d o e s
s e e m t h a t b a b o o n s a r e m o r e s e n s i t i v e t h a n d o g s t o l a r g e l u n g d o s e s , w i t h a
f a c t o r o f r e l a t i v e t o x i c i t y o f a b o u t 2 . 5 ( M e t i v i e r e t a l , 1 9 7 4 ) . The
s u r v i v a l c u r v e o f b a b o o n s a p p r o a c h e s t h a t o f t h e d o g s b y 2 o r 3 y e a r s
a f t e r i n h a l a t i o n a n d i t i s t h e r e f o r e p o s s i b l e t h a t t o x i c d o s e s a d m i n i s t e r e d
o v e r a l o n g p e r i o d p r o d u c e t h e same e f f e c t s o n t h e s u r v i v a l o f d o g s a n d
m o n k e y s ( B r o o k s e t a l , 1 9 7 6 a ) .
A l l t h e a l p h a e m i t t e r s c a n e f f e c t t h e l i f e s p a n , a l t h o u g h t h e r e i s
n o t a n y o b v i o u s c o r r e l a t i o n b e t w e e n t h e s u r v i v a l t i m e a n d t h e f o r m a t i o n o r
n o n - f o r m a t i o n o f c a n c e r s . On t h e o t h e r h a n d , t h e r e s e e m s t o b e a d e f i n i t e
c o r r e l a t i o n , a l b e i t d i f f i c u l t t o q u a n t i f y , b e t w e e n t h e d e g r e e o f l i f e
s h o r t e n i n g a n d t h e t r a n s p o r t a b i l i t y o f t h e e l e m e n t .
Summary
L i f e s p a n s h o r t e n i n g i n a n i m a l s e x p o s e d t o a c t i n i d e s i s a c o m p l e x
p h e n o m e n a i n v o l v i n g many c a u s e s . I t i s r e l a t i v e l y e a s y t o e s t i m a t e
l i f e s p a n s h o r t e n i n g r e s u l t i n g f r o m h i g h d o s e s a n d t o c o m p a r e d o s e s
f r o m v a r i o u s a c t i n i d e s . T h u s i n r a t s e x p o s e d t o c u r i u m - 2 4 4 t h e l u n g
d o s e r e q u i r e d t o p r o d u c e l i f e s p a n s h o r t e n i n g i n o n e y e a r w a s 1 7 0 0 r a d
( 1 7 Gy) b u t 9 5 0 0 r a d ( 9 5 Gy) i n r a t s e x p o s e d t o p l u t o n i u m - 2 3 9 d i o x i d e .
I t i s much m o r e d i f f i c u l t t o e v a l u a t e t h e d o s e s w h i c h r e s u l t i n a
s i g n i f i c a n t l i f e s p a n s h o r t e n i n g w h e n a n u m b e r o f c a u s e s a r e i n v o l v e d .
A c l e a r r e l a t i o n s h i p b e t w e e n l i f e s p a n s h o r t e n i n g a n d t h e i n d u c t i o n o f
c a n c e r s i s n o t a p p a r e n t .
5 . G e n e t i c E f f e c t s
T h e r e h a v e b e e n v e r y f e w e x p e r i m e n t s r e l a t i n g t o t h e p o s s i b l e e f f e c t s
o n h e r e d i t y o r f e r t i l i t y c a u s e d b y p l u t o n i u m o r a n y o t h e r a c t i n i d e s . No
e f f e c t h a s e v e r b e e n d e m o n s t r a t e d a n d t h e r e f o r e n o c o n c l u s i o n s c a n b e d r a w n .
D e s p i t e t h i s t h e p o t e n t i a l c o n s e q u e n c e s o f t h e d e p o s i t i o n o f a c t i n i d e s i n
t h e g o n a d s may b e i n f e r r e d b y c o m b i n i n g i n f o r m a t i o n o n t h e r a d i a t i o n s e n s i -
t i v i t y o f t h e g o n a d s ( C h a p t e r 9 ) w i t h t h e r e s u l t s o f s t u d i e s o n t h e m e t a -
b o l i s m a n d d o s i m e t r y o f a c t i n i d e s i n t h e g o n a d s ( C h a p t e r 4 ) .
6 . Summary a n d C o n c l u s i o n s
E x t e n s i v e a n i m a l s t u d i e d h a v e d e m o n s t r a t e d t h a t b i o l o g i c a l e f f e c t s f r o m
138
1000
100
S 10
1
f= r M I ^ I H J — » i 1 1 1 1 1 1 1 — i i 1 1 i i y
i s , .
O V v
V,' 15 :
YEARS"
^ © PULMONARY FIBROSIS
- • PULMONARY NEOPLASIA • * » ' i i 1 1 1 m l t i i li M i l
10 100 1000 3000
SURVIVAL TIME (DAYS AFTER EXPOSURE) F i g u r e 6.8 R e l a t i o n s h i p b e t w e e n q u a n t i t y o f p l u t o n i u m - 2 3 9 d e p o s i t e d a n d
s u r v i v a l t i m e o f d o g s ( r e d r a w n f r o m P a r k e t a l , 1 9 7 2 ) .
" R e p r o d u c e d f r o m H e a l t h P h y s i c s V o l . 22, p . 805, 1972 , b y
p e r m i s s i o n o f t h e H e a l t h P h y s i c s S o c i e t y . "
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i n t a k e s o f a c t i n i d e s may o c c u r p r e d o m i n a n t l y i n t h e l u n g , b o n e , l i v e r ,
b l o o d a n d l y m p h n o d e s . Many o f t h e a n i m a l s t u d i e s o n w h i c h t h e s e
o b s e r v a t i o n s a r e b a s e d h a v e u s e d l e v e l s o f a c t i v i t y t h a t a r e c o n s i d e r -
a b l y i n e x c e s s o f t h o s e t o w h i c h humans may b e e x p o s e d o t h e r t h a n i n
s e v e r e a c c i d e n t s i t u a t i o n s . I t m u s t b e a s s u m e d t h e r e f o r e t h a t t h e
c r i t i c a l t i s s u e s i d e n t i f i e d i n a n i m a l s e x p o s e d t o r e l a t i v e l y l o w d o s e s
o f a c t i n i d e s w i l l b e t h e same a s a f t e r e x p o s u r e t o h i g h d o s e s .
I n a p o p u l a t i o n e x p o s e d t o r a d i a t i o n o t h e r f a c t o r s may
i n f l u e n c e t h e d e v e l o p m e n t o f c a n c e r , I f , f o r e x a m p l e , t h e immune
r e s p o n s e o f i n d i v i d u a l s i s i m p o r t a n t i n t h e p r o d u c t i o n o f a l p h a
r a d i a t i o n i n d u c e d c a n c e r s t h e n t h e d o s e t o i n d i v i d u a l t i s s u e s may n o t
b e t h e o n l y f a c t o r t h a t n e e d s t o b e c o n s i d e r e d w h e n d e f i n i n g r i s k .
M o r e o v e r , o t h e r e n v i r o n m e n t a l f a c t o r s s u c h a s s m o k i n g o r c h e m i c a l
p o l l u t a n t s may h a v e a s y n e r g i s t i c e f f e c t i n t h e p r o d u c t i o n o f n e o -
p l a s t i c g r o w t h s . The o r g a n s t h a t w o u l d b e m o s t l i k e l y t o b e a f f e c t e d
b y s u c h f a c t o r s w o u l d b e t h e l u n g s a n d t h e l i v e r . A l t h o u g h h u m o r a l a n d
e n v i r o n m e n t a l f a c t o r s may i n f l u e n c e t h e d e v e l o p m e n t o f c a n c e r s i n man
t h e r e i s n o i n f o r m a t i o n f r o m w h i c h t h e i r e f f e c t c a n a t p r e s e n t b e
q u a n t i f i e d .
Lung
E a r l y e f f e c t s o f i n h a l e d a c t i n i d e s r e s u l t i n g i n d e a t h w i t h i n a b o u t a
y e a r h a v e b e e n o b s e r v e d i n d o g s a n d r o d e n t s t h a t h a v e i n h a l e d a m o u n t s
o f p l u t o n i u m e q u i v a l e n t t o m o r e t h a n a b o u t 1 0 0 uCi ( 3 « 7 MBq) i n m a n .
T h e s e c h a n g e s i n c l u d e o e d e m a , p n e u m o n i t i s a n d f i b r o s i s . A t l o w e r i n t a k e s
( e q u i v a l e n t t o a b o v e a b o u t 1 jiCi ( 3 7 k B q ) i n man) l u n g c a n c e r s h a v e
b e e n o b s e r v e d a s t h e m a i n l a t e e f f e c t i n t h e l u n g o f i n h a l e d a c t i n i d e s .
I n g e n e r a l c a n c e r s o b s e r v e d i n e x p e r i m e n t a l a n i m a l s h a v e d e v e l o p e d
p r e d o m i n a n t l y i n t h e p e r i p h e r a l r e g i o n s o f t h e l u n g . D i f f e r e n c e s h a v e
b e e n o b s e r v e d i n t h e d o s e - r e s p o n s e r e l a t i o n s h i p s f o r t h e d i f f e r e n t
a c t i n i d e s . I n g e n e r a l a m e r i c i u m a n d c u r i u m d i s t r i b u t e f a i r l y u n i f o r m l y
t h r o u g h o u t t h e l u n g t i s s u e a n d a r e more e f f e c t i v e a t i n d u c i n g c a n c e r
t h a n p l u t o n i u m - 2 3 9 w h i c h i s r e t a i n e d i n t h e l u n g m a i n l y i n l o c a l i s e d
d e p o s i t s .
B l o o d a n d b o n e marrow
C h a n g e s i n c i r c u l a t i n g b l o o d c e l l s h a v e b e e n s e e n i n d o g s a f t e r t h e
i n h a l a t i o n o f v a r i o u s p l u t o n i u m c o m p o u n d s . The m o s t f r e q u e n t c h a n g e
s e e n h a s b e e n a c h r o n i c r e d u c t i o n i n l y m p h o c y t e c e l l c o u n t t h a t o c c u r s
f o l l o w i n g a n i n i t i a l l u n g d e p o s i t e q u i v a l e n t t o m o r e t h a n a b o u t 1 jiCi
lUO
( 3 7 k B q ) i n man. The s i g n i f i c a n c e o f t h i s i s n o t k n o w n . I t m i g h t b e
a n t i c i p a t e d t h a t b e c a u s e a c t i n i d e s d e p o s i t i n t h e s k e l e t o n a n d i n l y m p h
n o d e s t h a t b l o o d s t e m c e l l n e o p l a s i a w o u l d b e a c o n s e q u e n c e o f a c t i n i d e
c o n t a m i n a t i o n . L e u k a e m i a h a s h o w e v e r b e e n f o u n d r a r e l y i n a n i m a l s a n d
a l m o s t e x c l u s i v e l y i n r o d e n t s g i v e n l a r g e a m o u n t s o f a c t i v i t y . B e c a u s e
o f t h e o b s e r v e d i n c r e a s e d i n c i d e n c e o f l e u k a e m i a i n humans e x p o s e d t o
e x t e r n a l r a d i a t i o n t h e b o n e marrow i n man m u s t b e c o n s i d e r e d p o t e n t i -
a l l y a t r i s k f r o m e x p o s u r e t o a c t i n i d e s d e p o s i t e d i n t h e s k e l e t o n .
B o n e a n d l i v e r
B o n e f r a c t u r e s h a v e b e e n o b s e r v e d i n d o g s g i v e n i n t r a v e n o u s i n j e c t i o n s
o f l a r g e d o s e s o f p l u t o n i u m - 2 3 9 ( > 1 jxCi ( 3 7 k B q ) k g " b o d y w t ) . A t
l o w e r d o s e s s t u d i e s i n a n i m a l s h a v e s h o w n t h a t b o n e c a n c e r i s t h e m o s t
f r e q u e n t f o r m o f m a l i g n a n c y i n d u c e d b y a c t i n i d e s t h a t h a v e e n t e r e d t h e
c i r c u l a t i o n . I n g e n e r a l t h e a p p e a r a n c e t i m e o f b o n e c a n c e r s i s
d e p e n d e n t u p o n t h e a m o u n t d e p o s i t e d i n b o n e . A v a r i a t i o n i n s e n s i t i v -
i t y b e t w e e n d i f f e r e n t a n i m a l s p e c i e s h a s b e e n d e m o n s t r a t e d a n d t h e r e
a r e t h e r e f o r e d i f f i c u l t i e s i n e x t r a p o l a t i n g t h e s e r e s u l t s t o man .
L i v e r c a n c e r s h a v e o c c u r r e d i n d o g s g i v e n i n t r a v e n o u s i n j e c t i o n s o f
p l u t o n i u m - 2 3 9 b u t t h e y h a v e o c c u r r e d much l e s s f r e q u e n t l y t h a n b o n e
c a n c e r s . D e s p i t e t h i s t h e l i v e r m u s t b e c o n s i d e r e d p o t e n t i a l l y a t
r i s k i n man.
Lymph n o d e s
Some o f t h e a c t i n i d e s d e p o s i t e d e i t h e r i n t h e l u n g s o r a t a w o u n d s i t e
may b e t r a n s l o c a t e d t o r e g i o n a l l y m p h a t i c t i s s u e . B e c a u s e o f t h e i r
s m a l l m a s s t h e r a d i a t i o n d o s e t o t h e s e n o d e s may g r e a t l y e x c e e d t h a t
t o t h e s i t e o f i n t a k e o r t o o t h e r t i s s u e s . E v i d e n c e f r o m s t u d i e s i n
e x p e r i m e n t a l a n i m a l s s u g g e s t h o w e v e r t h a t t h e o n l y s i g n i f i c a n t damage
t h a t o c c u r s i n t h i s t i s s u e i s f i b r o s i s o r n e c r o s i s a n d t h a t t h e y a r e
n o t a p r i m a r y s i t e f o r t h e d e v e l o p m e n t o f r a d i a t i o n i n d u c e d m a l i g n a n t
d i s e a s e . F o r t h i s r e a s o n l y m p h a t i c t i s s u e s h o u l d n o t b e c o n s i d e r e d a
c r i t i c a l t i s s u e f o r i n t a k e s o f a c t i n i d e s .
O t h e r t i s s u e s
R a d i a t i o n - i n d u c e d c a n c e r s h a v e b e e n o b s e r v e d i n o t h e r t i s s u e s f o l l o w i n g
i n t a k e s o f t r a n s p o r t a b l e f o r m s o f a c t i n i d e s b u t t h e y h a v e o c c u r r e d
i n f r e q u e n t l y i n e a c h t i s s u e a n d n e e d n o t b e c o n s i d e r e d i n d i v i d u a l l y
a s c r i t i c a l t i s s u e s .
G o n a d s
No e v i d e n c e o f h e r e d i t a r y e f f e c t s r e s u l t i n g f r o m t h e i n c o r p o r a t i o n o f
a c t i n i d e s i n t h e g o n a d s h a s b e e n d e m o n s t r a t e d i n a n y o f t h e a n i m a l
s p e c i e s s t u d i e d . E s t i m a t e s o f r a d i a t i o n - i n d u c e d h e r e d i t a r y d i s e a s e s
r e s u l t i n g f r o m t h e d e p o s i t i o n o f a c t i n i d e s i n t h e g o n a d s m u s t t h e r e -
f o r e b e o b t a i n e d b y e x t r a p o l a t i o n f r o m s t u d i e s o f t h e c o n s e q u e n c e s o f
e x p o s u r e t o e x t e r n a l r a d i a t i o n .
I n e s t i m a t i n g t h e r a d i a t i o n e f f e c t s i n a p o p u l a t i o n e x p o s e d t o
a c t i n i d e s e s t i m a t e s o f r i s k c o e f f i c i e n t s a r e t h e r e f o r e r e q u i r e d f o r
r a d i a t i o n i n d u c e d c a n c e r s o f t h e l u n g , b o n e , b o n e marrow a n d l i v e r a n d
f o r r a d i a t i o n i n d u c e d h e r e d i t a r y d i s e a s e s .
Chapter 7
T H E "HOT PARTICLE" PROBLEM
1 . T h e o r e t i c a l B a s i s
A number o f r i s k s a r e a s s o c i a t e d w i t h t h e i n c o r p o r a t i o n o f p l u t o n i u m
a n d o t h e r a c t i n i d e s b y t i s s u e s , t h e f o r e m o s t o f w h i c h i s t h e i n d u c t i o n o f
c a n c e r s ( C h a p t e r s 5 a n d 6 ) . The r i s k o f c a n c e r i s n o r m a l l y l i n k e d w i t h t h e
d o s e r e c e i v e d b y t h e t i s s u e e x p o s e d a n d d e p e n d s u p o n t h e d o s e - r e s p o n s e
r e l a t i o n s h i p . T h e r e a r e many m e t h o d s t h a t h a v e b e e n u s e d i n a n a t t e m p t t o
d e f i n e t h e f o r m o f t h e r e l a t i o n s h i p i n a s p r e c i s e a w a y a s p o s s i b l e .
The l u n g i s a t h i g h r i s k a f t e r t h e i n h a l a t i o n o f p l u t o n i u m d i o x i d e a s
i t i s b o t h a s i t e o f e n t r y a n d a n o r g a n o f l o n g - t e r m r e t e n t i o n ( s e e
C h a p t e r s k a n d 6 ) ( I A E A , 1 9 7 3 ; D u r b i n , 1 9 7 3 ; B a i r e t a l , 1 9 7 3 ; B a i r , 1 9 7 4 b ;
B a i r e t a l , 1 9 7 4 ) * I n v i e w o f t h e c o m p l e x i t y a n d d i v e r s i t y o f t h e m e c h a n -
i s m s c o n t r o l l i n g t h e b e h a v i o u r o f p l u t o n i u m i n t h e l u n g , i t i s d e s i r a b l e
t h a t t h e e s t i m a t i o n o f t h e d o s e d e l i v e r e d t o t h e o r g a n s h o u l d b e b a s e d o n
s i m p l e h y p o t h e s e s . The s i m p l e s t a p p r o a c h c o n s i s t s i n e s t i m a t i n g t h e a v e r a g e
d o s e d e l i v e r e d t o t h e o r g a n a s a w h o l e . A s e c o n d p o s s i b i l i t y i s t o t a k e
i n t o a c c o u n t o n l y t h e d o s e a b s o r b e d b y c e l l s a t t h e s u r f a c e o f t h e r a d i o -
a c t i v e d e p o s i t s . A t h i r d p o s s i b i l i t y , w h i c h l i e s b e t w e e n t h e s e f i r s t t w o ,
i s t o c a l c u l a t e t h e i n t e g r a t e d d o s e t o t h e f r a c t i o n o f t h e v o l u m e o f t h e
o r g a n a s s o c i a t e d w i t h t h e r a d i o a c t i v e d e p o s i t . The l a t t e r m e t h o d may a l s o
b e u s e d f o r a n y o r g a n o t h e r t h a n t h e l u n g , b u t i t b e c o m e s p a r t i c u l a r l y
r e l e v a n t i n t h e c a s e o f i n h a l a t i o n o f p l u t o n i u m i n p a r t i c u l a t e f o r m , s i n c e
i t p r o d u c e s a v e r y d i f f e r e n t r e s u l t t o t h e a v e r a g e l u n g d o s e . The m o s t
e x t r e m e e x a m p l e i s p r o v i d e d b y t h e o x i d e s o f p l u t o n i u m - 2 3 9 o r p l u t o n i u m - 2 3 8 .
F o l l o w i n g t h e i r i n h a l a t i o n t h e l o c a l d e p o s i t i o n o f l a r g e a m o u n t s o f e n e r g y
i n a v e r y s m a l l m a s s o f t i s s u e c o n s t i t u t e s t h e f i r s t damage c a u s e d b y t h e
p a r t i c l e . /
R a d i a t i o n p r o t e c t i o n s t a n d a r d s a r e g e n e r a l l y b a s e d o n t h e t w o h y p o -
t h e s e s : t h a t f o r t h e d e v e l o p m e n t o f c a n c e r s t h e r e i s n o t h r e s h o l d f o r t h e
a c t i o n o f i o n i z i n g r a d i a t i o n s a n d t h a t t h e r e i s a l i n e a r r e l a t i o n s h i p
b e t w e e n d o s e a n d e f f e c t ( ICRP 2 6 , 1 9 7 7 ; UNSCEAR, 1 9 7 2 ) . The a v e r a g e
a b s o r b e d d o s e i s a s t a t i s t i c a l c o n c e p t , a n d d o e s n o t t a k e i n t o a c c o u n t t h e
e n e r g y d i s s i p a t e d i n c e l l s o r g r o u p s o f c e l l s i s o l a t e d i n a n o r g a n . T h i s
f a c t i s c l e a r l y i n c o m p a t i b l e w i t h t h e v e r y c o n c e p t o f a " h o t p a r t i c l e " , a n d
t h i s i s why s e v e r a l m o d i f i c a t i o n s t o d o s e c a l c u l a t i o n s h a v e b e e n s u g g e s t e d
t o t a k e i n t o a c c o u n t t h e n o n - u n i f o r m d i s t r i b u t i o n o f a c t i v i t y i n a n o r g a n .
The c o n c l u s i o n f r o m t h e s e c o n s i d e r a t i o n s i s t h a t t h e c a l c u l a t i o n o f m e a n
lk3
Ikk
d o s e i s c o n s e r v a t i v e (ICRP 9 , 1 9 6 6 ; ICRP 1 i | , 1 9 6 9 ; BEIR, 1 9 7 2 ) . C l e a r l y a
u n i f o r m d i s t r i b u t i o n p r o d u c e s i r r a d i a t i o n o f a much g r e a t e r n u m b e r o f c e l l s
t h a n t h e same a m o u n t o f p l u t o n i u m d i s t r i b u t e d i n a n o n - u n i f o r m m a n n e r ; t h i s
i s p a r t i c u l a r l y t r u e w h e n t h e p a r t i c l e s a r e l a r g e . I t i s c o n c e i v a b l e ,
h o w e v e r , t h a t t h e r a d i o s e n s i t i v i t y o f t h e c e l l s i r r a d i a t e d b y t h e p a r t i c l e s
c o u l d b e g r e a t e r t h a n t h e a v e r a g e r a d i o s e n s i t i v i t y o f t h e c e l l s i n t h e
o r g a n , a n d t h e f r e q u e n c y o f r a d i a t i o n - i n d u c e d c a n c e r s w o u l d t h e r e f o r e
i n c r e a s e f a s t e r t h a n a l i n e a r r e l a t i o n s h i p w i t h d o s e w o u l d i n d i c a t e . I n
t h e c a s e o f t h e l u n g , t h e s e h y p o t h e s e s a r e u n t e n a b l e o w i n g b o t h t o t h e
n a t u r e o f t h e d i s t r i b u t i o n o f p a r t i c u l a t e p l u t o n i u m i n t h e l u n g a n d t o o u r
k n o w l e d g e a b o u t t h e r e l a t i v e s e n s i t i v i t i e s o f d i f f e r e n t c e l l p o p u l a t i o n s
t h a t a r e i n v o l v e d (NCRP N O . 1+6, 1 9 7 5 ) . T h i s i s n o t t h e c a s e w i t h b o n e ,
h o w e v e r , w h e r e p l u t o n i u m i s d e p o s i t e d n e a r t h e s e n s i t i v e c e l l s ( V a u g h a n ,
1 9 7 3 ; V a u g h a n e t a l , 1 9 7 3 ) .
I t i s i n f o r m a t i v e t o c a l c u l a t e t h e p r o p o r t i o n o f t h e l u n g t i s s u e t h a t
i s a f f e c t e d b y a l p h a i r r a d i a t i o n a s a f u n c t i o n o f p a r t i c l e s i z e ( T a b l e 7 - 1 )
( R i c h m o n d , 1 9 7 5 ; B a i r e t a l , 1 9 7 4 ) . I f t h e d i a m e t e r o f t h e p a r t i c l e s o f
p l u t o n i u m - 2 3 9 d i o x i d e i s d i v i d e d b y a f a c t o r o f 1 0 , t h e v o l u m e o f t h e l u n g
d i r e c t l y a f f e c t e d i s i n c r e a s e d b y a f a c t o r o f 1 0 0 0 . F o r a g i v e n p a r t i c l e
s i z e , t h e n u m b e r o f p l u t o n i u m - 2 3 8 d i o x i d e p a r t i c l e s r e s u l t i n g i n a g i v e n
a v e r a g e l u n g d o s e i s l o w e r b y a f a c t o r o f a b o u t 2 5 0 t h a n t h e n u m b e r o f
p l u t o n i u m - 2 3 9 d i o x i d e p a r t i c l e s n e e d e d t o g i v e t h e same d o s e ( o w i n g t o t h e i r
d i f f e r e n t s p e c i f i c a c t i v i t i e s ) ; t h i s i m p l i e s t h a t p l u t o n i u m - 2 3 8 d i o x i d e
p a r t i c l e s i r r a d i a t e a b o u t 1 / 2 5 0 o f t h e n u m b e r o f c e l l s i r r a d i a t e d b y
p l u t o n i u m - 2 3 9 d i o x i d e p a r t i c l e s , b u t a t a much h i g h e r d o s e r a t e . H o w e v e r ,
a s t h e s e t w o i s o t o p e s h a v e i n f a c t d i s s i m i l a r p u l m o n a r y c l e a r a n c e r a t e s ,
t h e c u m u l a t i v e d o s e s r e c e i v e d w i l l a l s o d i f f e r . The f u n d a m e n t a l p r o b l e m
w h i c h i s r a i s e d i s t h e r e f o r e t o e s t i m a t e t h e r i s k o f p u l m o n a r y c a n c e r i n
t e r m s o f t h e e x p o s u r e o f a r e l a t i v e l y s m a l l number o f c e l l s t o f a i r l y h i g h
d o s e r a t e s , t h e t w o p a r a m e t e r s - n u m b e r o f p a r t i c l e s a n d d o s e r a t e - v a r y i n g
i n i n v e r s e p r o p o r t i o n t o o n e a n o t h e r f o r a g i v e n t o t a l l u n g c o n t e n t . T h i s
p r o b l e m s h o u l d o n l y b e c o n s i d e r e d w i t h i n p h y s i o l o g i c a l l i m i t s s i n c e , i n a n
e x t r e m e c a s e , a b u r d e n o f 0 . 0 1 6 jiCi ( 5 9 2 B q ) c a n b e r e p r e s e n t e d b y a
s i n g l e p a r t i c l e o f p l u t o n i u m - 2 3 9 d i o x i d e w i t h a d i a m e t e r o f 3 6 ^m; c l e a r l y ,
t h i s s i z e o f p a r t i c l e i s n o t o n e t h a t Can b e i n h a l e d . On t h e o t h e r h a n d ,
t h i s e x t r e m e e x a m p l e s h o w s t h a t o t h e i ? e l e m e n t s w i t h v e r y h i g h s p e c i f i c
a c t i v i t i e s c a n b e c o n c e n t r a t e d i n a S m a l l n u m b e r o f p a r t i c l e s c o n t a i n i n g
r e l a t i v e l y h i g h l e v e l s o f a c t i v i t y .
Ih5
T a b l e 7 .1
R e l a t i o n s h i p o f p a r t i c l e s i z e t o n u m b e r
o f c e l l s a t r i s k f o r a s t a t i c l u n g
b u r d e n o f 0,016 uCi p l u t o n i u m - 2 3 9 d i o x i d e 8 ,
( B a i r e t a l , 197U; R i c h m o n d , 1 9 7 5 )
P a r t i c l e d i a m e t e r
(pm)
Number o f p a r t i c l e s
A c t i v i t y p e r p a r t i c l e
( p C i )
N o . o f i r r a d i a t e d
c e l l s
P e r c e n t o f l u n g
0.1 5 - 4 x 1 0 7 3 x 1 0 " ^ 3 x 1 0 1 1 30
0 . 3 2 . 0 x 1 0 6 0 . 0 1 1 . 3 x 1 0 1 0 1
0 . 7 1 . 8 x 1 0 5 0 . 0 8 1 . 2 x 1 0 9 0 . 1
1 . 0 5 - 4 x 10h
0 . 3 3 . 6 x 1 0 8 0 . 0 3
A s s u m i n g s t a t i c p a r t i c l e s i n a s t r u c t u r e l e s s human l u n g o f u n i f o r m
d e n s i t y 0 . 2 g cm J w i t h a n a v e r a g e c e l l v o l u m e o f 1 0 ^ an . C e l l s a t r i s k
a r e t a k e n t o b e t h o s e i n a s p h e r e o f r a d i u s e q u a l t o t h e a l p h a r a n g e
( 2 0 0 pm a t t h e a s s u m e d d e n s i t y )
The f i r s t a u t h o r s who e x a m i n e d t h e s e p r o b l e m s c l o s e l y c o n s i d e r e d t w o
o p p o s i n g r e s p o n s e s : a n i n c r e a s e i n t h e f r e q u e n c y o f c a n c e r s p e r i r r a d i a t e d
c e l l w i t h t h e d o s e a n d a r e d u c e d c a p a c i t y f o r c a n c e r o u s c h a n g e s w i t h t h e
l o s s o f r e p r o d u c t i v e c a p a c i t y i n t h e i r r a d i a t e d c e l l s ; t h e t i s s u e r e s p o n s e
w a s t h e r e f o r e t h e c o m b i n a t i o n o f t h e s e t w o f a c t o r s ( D e a n a n d Langham, 1 9 ^ 9 ) •
T h e i r h y p o t h e s i s w a s b a s e d o n s t u d i e s o n t h e p r o d u c t i o n o f b o t h b e n i g n a n d
m a l i g n a n t c u t a n e o u s t u m o u r s f o l l o w i n g i r r a d i a t i o n o f t h e s k i n o f r a t s w h i c h
s h o w e d a c l e a r c o r r e l a t i o n b e t w e e n t h e i n c i d e n c e o f c a n c e r a n d t h e n u m b e r
o f a t r o p h i e d h a i r f o l l i c u l e s ( A l b e r t e t a l , 1 9 6 7 a , 1 9 6 7 b , 1 9 6 7 c ) a n d
s u g g e s t e d t h a t t h e i r r a d i a t i o n o f a s i n g l e c e l l c o u l d g i v e r i s e t o a n
i r r e v e r s i b l e c a n c e r - f o r m a t i o n p r o c e s s . S e v e r a l m o d e l s t h a t d i s r e g a r d t h e
f a c t o r o f c e l l s t e r i l i z a t i o n a r e b a s e d o n t h i s i d e a ; t h e y c o n c l u d e t h a t
t h e r e i s a n i n c r e a s e i n r i s k i n t h e c a s e o f a n o n - u n i f o r m p a r t i c u l a t e
d i s t r i b u t i o n ( G e e s a m a n , 1 9 6 8 ; T a m p l i n a n d C o c h r a n , 1 9 7 U ) • T h e s e b a s i c
h y p o t h e s e s h a v e b e e n v e r y w i d e l y d i s c u s s e d a n d r e f u t e d i n t h e i r e n t i r e t y :
( B a i r e t a l , 1 9 7 U ; H e a l y , 1 9 7 4 ; D o l p h i n e t a l , 1 9 7 4 ; M e d i c a l R e s e a r c h
C o u n c i l , 1 9 7 5 ; A l b e r t e t a l , 1 9 7 6 ) ; f o r e x a m p l e , i t i s c l a i m e d t h a t t h e
r i s k w o u l d d e c r e a s e b y a f a c t o r o f 1 1 5 0 0 0 i f a p a r t i c l e c o n t a i n e d 0 . 1 ^iCi
( 3 . 7 k B q ) o f p l u t o n i u m w e r e t o b e b r o k e n i n t o t w o h a l v e s ( M e d i c a l R e s e a r c h
C o u n c i l , 1 9 7 5 ) .
1U6
The g e n e r a l t h e o r e t i c a l c o n c l u s i o n s c o m p a r i n g t h e r e l a t i v e r i s k s o f
u n i f o r m a n d n o n - u n i f o r m d i s t r i b u t i o n o f p l u t o n i u m i n t h e l u n g r e l a t e t o
s e v e r a l p o i n t s ( A l b e r t e t a l , 1 9 7 6 ) : ( a ) b a s i c f a c t o r s o t h e r t h a n j u s t t h e
d o s e ( e x p r e s s e d i n r a d o r r e m ) m u s t b e i n t r o d u c e d t o e x p l a i n t h e w a y s i n
w h i c h a l p h a p a r t i c l e s a c t o n c e l l s , e s p e c i a l l y w h e n t h e t a r g e t s i t e s a r e
s m a l l i n n u m b e r ; ( b ) t h e c o n c e n t r a t i o n o f a l p h a e m i t t e r s i n p a r t i c l e s
r e s u l t s i n o n l y a l i m i t e d n u m b e r o f c e l l s b e i n g i r r a d i a t e d , i r r e s p e c t i v e o f
t h e t o t a l a c t i v i t y d e p o s i t e d ; ( c ) t h e e x t r a p o l a t i o n o f r e s u l t s o b t a i n e d
f o l l o w i n g t h e i r r a d i a t i o n o f t h e h a i r f o l l i c l e o f t h e r a t t o t h e a n i m a l o r
human l u n g d o e s n o t h a v e a n y s c i e n t i f i c b a s i s ; ( d ) i t h a s n o t b e e n d e m o n -
s t r a t e d t h a t t h e i n d u c t i o n o f c a n c e r s i s i n d e p e n d e n t o f d o s e o r t h a t t h e
c o n c e n t r a t i o n o f d e a d c e l l s i s a c o n t r i b u t o r y f a c t o r i n t h e f o r m a t i o n o f
c a n c e r s ; ( e ) m o d e l s b a s e d o n r a d i o b i o l o g i c a l k n o w l e d g e s u g g e s t t h a t t h e
r i s k o f c a r c i n o g e n e s i s i s h i g h e r i n t h e c a s e o f u n i f o r m d i s t r i b u t i o n t h a n
i t i s i n t h e c a s e o f n o n - u n i f o r m d i s t r i b u t i o n . E x p e r i m e n t a l r e s u l t s a l s o
l e a d t o t h e same c o n c l u s i o n s ( s e c t i o n 2 ) .
A r e c e n t m a t h e m a t i c a l m o d e l , w h i c h t a k e s a c c o u n t o f v a r i o u s p a r a m e t e r s ,
c o m p a r e s t h e c o n v e n t i o n a l m o d e l , w h i c h a v e r a g e s d o s e o v e r t h e w h o l e o f t h e
o r g a n (ICRP P u b l i c a t i o n 9> 1966) , w i t h a m o d e l i n w h i c h t h e r i s k o f c a n c e r -
i n d u c t i o n i s r e l a t e d t o a f u n c t i o n o f t h e d o s e a n d t o t h e l o s s o f r e p r o d u c -
t i v e c a p a c i t y i n i r r a d i a t e d c e l l s ( M a y n e o r d a n d C l a r k e , 1 9 7 6 ) . T h i s c a n
o n l y b e a n a p p r o x i m a t i o n , s i n c e t h e m o v e m e n t s o f p a r t i c l e s i n s i d e t h e l u n g
a r e v e r y l i t t l e u n d e r s t o o d a n d t h e s l i g h t e s t m o v e m e n t o f a p a r t i c l e m a k e s
t h e d o s e c o n s i d e r a b l y m o r e u n i f o r m t h a n f o r a s t a t i o n a r y p a r t i c l e . I n t h e
m o d e l t h e e f f e c t s o f h i g h - r e n e r g y p a r t i c l e s m o v i n g r a p i d l y a r e a s s u m e d t o b e
i d e n t i c a l t o t h o s e o f l o w - e n e r g y p a r t i c l e s m o v i n g s l o w l y . No a c c o u n t i s
t a k e n o f t h e r e s p i r a t o r y m o v e m e n t s o f t h e a l v e o l i t h a t make t h e
d i s t r i b u t i o n o f d o s e m o r e u n i f o r m . A p a r t f r o m t h e s e r e s e r v a t i o n s ,
t h i s m o d e l g e n e r a l l y a r r i v e s a t c o n c l u s i o n s i d e n t i c a l t o t h o s e o f t h e
c l a s s i c a l m o d e l s : e s t i m a t i n g r i s k w i t h t h e h e l p o f t h e m e a n d o s e g i v e s t h e
b e s t e s t i m a t e o f t h e u p p e r r i s k l i m i t . I n e x c e p t i o n a l d i s t r i b u t i o n c a s e s
w h e n a l a r g e p r o p o r t i o n o f t h e c e l l s a r e e x p o s e d t o d o s e s i n t h e r e g i o n o f
t h e p e a k o f t h e d o s e - r e s p o n s e c u r v e t h e r i s k may b e u n d e r e s t i m a t e d b y u p t o
a f a c t o r o f $ .
2. E x p e r i m e n t a l A s p e c t s
T h e r e a r e a n u m b e r o f e x p e r i m e n t s w h i c h a l l o w t h e l o c a l e f f e c t s o f a
n o n - u n i f o r m d i s t r i b u t i o n o f a n a l p h a e m i t t e r i n t i s s u e t o b e c o m p a r e d w i t h
t h o s e o f a u n i f o r m d i s t r i b u t i o n o f a n e q u i v a l e n t a m o u n t o f a c t i v i t y .
M o s t a u t h o r s a r e a g r e e d t h a t r e s u l t s o b t a i n e d f r o m i r r a d i a t i o n o f t h e
s k i n c a n n o t b e e x t r a p o l a t e d t o t h e l u n g o r a n y o t h e r o r g a n b e c a u s e o f
d i f f e r e n c e s i n t h e s e n s i t i v i t y o f o r g a n s t o i r r a d i a t i o n ( A l b e r t , 1 9 6 7 a ,
1 9 6 7 b , 1 9 6 7 c ; B a i r e t a l , 1 9 7 4 ; NCRP, 1 9 7 5 ) .
The o n l y e x p e r i m e n t s t o b e c o n s i d e r e d a r e t h o s e t h a t d e a l w i t h a h i g h -
r i s k o r g a n c o n t a m i n a t e d b y a n a l p h a e m i t t e r , a l t h o u g h c e r t a i n e x p e r i m e n t s
c o n d u c t e d w i t h b e t a e m i t t e r s a r e r e l e v a n t t o t h e p r o b l e m ( C e m b e r a n d W a t s o n ,
1 9 5 8 a , 1 9 5 8 b ; Cember e t a l , 1 9 5 9 ; C e m b e r , 1 9 6 4 a , 1 9 6 4 b ) .
P o l o n i u m - 2 1 0 i s a g o o d e x p e r i m e n t a l t o o l , f o r i t c a n e x i s t i n a n
e x t r e m e l y s o l u b l e f o r m o r , o n t h e o t h e r h a n d , b e made i n s o l u b l e b y , f o r
e x a m p l e , f i x a t i o n o n i n e r t p a r t i c l e s o f h a e m a t i t e , ( P e g 0 ^ ) ( L i t t l e e t a l ,
1 9 7 0 a , 1 9 7 0 b ; G r o s s m a n e t a l , 1 9 7 1 ; L i t t l e e t a l , 1 9 7 3 ) . The e x p e r i m e n t s
a r e n o t s t r i c t l y c o m p a r a b l e a s t h e v e r y d i f f e r e n t c l e a r a n c e r a t e s f r o m t h e
l u n g o f t h e t w o f o r m s t h a t a r e b e i n g c o m p a r e d , r e s u l t i n q u i t e d i f f e r e n t
d o s e r a t e s f o r a g i v e n a m o u n t a d m i n i s t e r e d . H o w e v e r , c l e a r c o n c l u s i o n s c a n
b e d r a w n f r o m t h e s e s t u d i e s ; a l p h a i r r a d i a t i o n o f t h e l u n g i s m o r e c a r c i n o -
g e n i c w h e n t h e d o s e i s d e l i v e r e d i n a r e l a t i v e l y u n i f o r m f a s h i o n t o a l a r g e
p a r t o f t h e o r g a n t h a n w h e n t h e same a c t i v i t y i s d e p o s i t e d i n a n o n - u n i f o r m
f a s h i o n w i t h h i g h d o s e r a t e s d e l i v e r e d t o s m a l l v o l u m e s . T h i s d i f f e r e n c e
h o w e v e r d i s a p p e a r s a t q u i t e l o w d o s e s o f t h e o r d e r o f a f e w t e n s o f r a d
( L i t t l e a n d O ' T o o l e , 1 9 7 4 ) .
T r a n s t h o r a c i c i n j e c t i o n s o f p l u t o n i u m - 2 3 9 d i o x i d e i n r a t s d e l i v e r e d
l i f e s p a n d o s e s o f 2 0 0 0 0 0 r a d ( 2 0 0 0 Gy) t o 1 0 % o f t h e l u n g w h e n t h e i n j e c t e d
a c t i v i t y ( 0 . 7 ^Ci ( 2 6 k B q ) ) w a s d i s t r i b u t e d i n 1 0 0 mg o f p u l m o n a r y p a r e n -
chyma ( S a n d e r s a n d P a r k , 1 9 7 1 ) . The i n c i d e n c e o f p u l m o n a r y c a n c e r s w a s
h i g h : 5 o u t o f 1 6 i n s o m e t h i n g o v e r a y e a r . T h i s r e s u l t c a n n o t b e c o m p a r e d
w i t h t h e r e s p o n s e t o t h e same d o s e d i s t r i b u t e d t h r o u g h o u t t h e l u n g f o r
2 0 0 0 0 r a d ( 2 0 0 Gy) ( a l p h a ) w o u l d r e s u l t i n d e a t h f r o m f i b r o s i s i n l e s s t h a n
t h r e e m o n t h s . T h i s e x p e r i m e n t i s t h e o n l y o n e d e m o n s t r a t i n g t h e i n d u c t i o n
o f c a n c e r s w i t h l o c a l i s e d s o u r c e s d e l i v e r i n g v e r y h i g h d o s e r a t e s .
I n o r d e r t o c o m p a r e t h e e f f e c t s o f v a r y i n g a m o u n t s o f a c t i v i t y
d i s t r i b u t e d i n a v a r y i n g n u m b e r o f e m i t t i n g s o u r c e s , r e p r o d u c i n g e x p e r i m e n t -
a l l y t h e c o n d i t i o n s i n T a b l e 7 . 1 > i n t r a v e n o u s i n j e c t i o n s o f c a l i b r a t e d
s p h e r e s ( 1 0 i n d i a m e t e r ) w e r e made i n s u c h a w a y t h a t t h e y b e c a m e f i x e d
i n t h e p u l m o n a r y c a p i l l a r i e s ; t h e v a r i a b l e p a r a m e t e r s a r e t h e a c t i v i t y p e r
u n i t o f t h e m i c r o s p h e r e s , t h e i r n u m b e r , t h e i s o t o p e o f p l u t o n i u m u s e d a n d ,
c o n s e q u e n t l y , t h e a c t i v i t y d e p o s i t e d i n t h e l u n g a n d t h e p r o p o r t i o n o f t h e
l u n g a f f e c t e d ( R i c h m o n d , 1 9 7 5 ; S m i t h e t a l , 1 9 7 5 ? A n d e r s o n e t a l , 1 9 7 4 a ,
1 U 8
1 9 7 U h ) . A l l t h e e x p e r i m e n t s made w i t h t h e s e m i c r o s p h e r e s i r r a d i a t e b e t w e e n
1 a n d 3% o f t h e l u n g a n d c o r r e s p o n d t o d e p o s i t i o n s o f b e t w e e n 0 . 1 1 ; a n d
3 5 6 n C i ( 5 . 2 a n d 1 3 - 2 x 1 0 ^ B q ) ; t h e d o s e d e l i v e r e d t o t h e p o r t i o n o f t h e
l u n g t h a t i s i r r a d i a t e d i s 1 . 3 x 1 0 - 5 t o 1 0 r a d ( 1 . 3 x 1 0 t o 1 0 4 Gy) p e r
y e a r o r , i f i t i s e x p r e s s e d i n r e l a t i o n t o t h e w h o l e o f t h e l u n g , 1 3 t o
3 3 0 0 0 r a d ( 0 . 1 3 t o 3 3 0 G y ) . I n n o n e o f t h e s e e x p e r i m e n t s w a s t h e i n c i d e n c e
o f c a n c e r s i g n i f i c a n t l y h i g h e r t h a n t h a t o b s e r v e d i n t h e v a r i o u s c o n t r o l s ,
o f w h i c h some h a d n e v e r b e e n i n j e c t e d a n d o t h e r s h a d b e e n i n j e c t e d w i t h
i n e r t m i c r o s p h e r e s i n a m o u n t s e q u i v a l e n t t o t h o s e o f t h e e x p e r i m e n t a l
a n i m a l s . M o r e o v e r , t h e l i f e o f t h e a n i m a l s i s a p p a r e n t l y n o r m a l . When a
much l a r g e r p r o p o r t i o n o f t h e l u n g i s i r r a d i a t e d (36%) w i t h t h e same m i c r o -
1 1
s p h e r e s , a t a d o s e o f 1 3 0 0 0 r a d y " ( 1 3 0 Gy y " ) ( 7 0 0 0 0 s p h e r e s ) , t h e r e i s
a n a p p r e c i a b l e i n c r e a s e i n t h e i n c i d e n c e o f p u l m o n a r y c a n c e r ( 1 0 % ) ( T h o m a s ,
1 9 7 7 ) . I n c o n t r a s t t o t h i s , n o p a t h o l o g i c a l e f f e c t h a s b e e n o b s e r v e d i n
r a t s a f t e r t h e i n t r a v e n o u s i n j e c t i o n o f p a r t i c l e s o f p l u t o n i u m - 2 3 8 d i o x i d e
o f v e r y l a r g e d i a m e t e r ( 1 8 0 pm) w h i c h h a v e b e c o m e l o d g e d i n t h e p u l m o n a r y
—1 —1 c a p i l l a r i e s a n d d e l i v e r a d o s e r a t e c a l c u l a t e d a t 3 * 5 rem h ( 3 5 mSv h " , a s s u m i n g RBE f o r a l p h a r a d i a t i o n = 1 0 ) ( R i c h m o n d e t a l , 1 9 7 0 ) . The d o s e
8 —1 6 1 r a t e a t t h e s u r f a c e o f t h e p a r t i c l e , w h i c h i s a b o u t 1 0 r a d h~" ( 1 0 Gy h " )
w o u l d c o r r e s p o n d , i f a v e r a g e d o v e r t h e w h o l e o f t h e l u n g , t o a b o u t 2 x 1 0 ^
r a d ( 2 x 1 0 ^ G y ) i n t w o y e a r s . I t i s d i f f i c u l t t o u n d e r s t a n d why n o e f f e c t
h a s b e e n o b s e r v e d , a p a r t f r o m m i c r o l e s i o n s w i t h t o t a l c e l l u l a r d e g e n e r a t i o n
i n t h e i m m e d i a t e v i c i n i t y o f t h e p a r t i c l e ; h o w e v e r , t h e s e m i c r o l e s i o n s do
n o t c o r r e s p o n d t o n e c r o t i c s t a t e s , f o r t h e c o l l a g e n i n t h e m i s c o n s t a n t l y
b e i n g r e n e w e d . The same r e s u l t s h a v e b e e n o b s e r v e d i n d o g s ( R i c h m o n d e t a l ,
1 9 7 4 ) . A l l t h e s e e x p e r i m e n t s t h a t a r e b a s e d o n t h e i n t r a v e n o u s i n j e c t i o n
o f c a l i b r a t e d s p h e r e s t e n d t o i n d i c a t e t h a t t h e f r e q u e n c y o f l o c a l l y -
i n d u c e d c a n c e r s v a r i e s i n i n v e r s e p r o p o r t i o n t o t h e d e g r e e o f n o n - u n i f o r m i t y ,
a s s u m i n g t h a t t h e r e i s a d i r e c t r e l a t i o n s h i p b e t w e e n t h e i n d u c t i o n o f
c a n c e r s a n d t h e m a s s o f t i s s u e d i r e c t l y e x p o s e d t o r i s k . The m a i n c r i t i c i s m
t h a t c a n b e made o f t h i s s e r i e s o f e x p e r i m e n t s i s t h a t t h e y a r e u n r e a l i s t i c ,
f o r t h e y f a i l c o m p l e t e l y t o r e p r o d u c e t h e b a s i c c o n d i t i o n s o f c o n t a m i n a t i o n
a s t h e i r r a d i a t i n g p a r t i c l e s a r e t r a p p e d i n t h e p u l m o n a r y c a p i l l a r i e s .
H o w e v e r , a s r e g a r d s t h e r e s u l t i n g e f f e c t , i t w o u l d a p p e a r t o b e i r r e l e v a n t
w h e t h e r t h e c e l l i s i r r a d i a t e d f r o m t h e a i r s p a c e s ( a s i n c o n t a m i n a t i o n b y
i n h a l a t i o n ) , o r f r o m t h e b l o o d ( a s w i t h m i c r o s p h e r e s i n j e c t e d i n t r a v e n o u s l y ) .
The g r e a t e s t d i f f e r e n c e t h a t may b e n o t e d b e t w e e n t h e t w o e x p e r i m e n t a l
m e t h o d s c o n c e r n s t h e m o b i l i t y o f t h e p a r t i c l e i n t h e c a s e o f i n h a l a t i o n a n d
i t s l a c k o f m o v e m e n t i n t h e c a s e o f i n t r a v e n o u s i n j e c t i o n . I f t h i s i s t h e
b a s i c r e a s o n f o r t h e p a u c i t y o f p a t h o l o g y o b s e r v e d a f t e r t h e i n j e c t i o n o f
Ik9
m i c r o s p h e r e s , t h e n t h e n u m b e r o f i r r a d i a t e d c e l l s b e c o m e s a v e r y i m p o r t a n t
f a c t o r . I t i s a l s o p o s s i b l e t h a t t h e c e l l s w h i c h g i v e r i s e t o l u n g c a n c e r s
a r e n o t b e i n g i r r a d i a t e d .
F o r t h e s e r e a s o n s some o f t h e m o s t r e l e v a n t e x p e r i m e n t s a r e t h o s e w h i c h
d e a l w i t h v e r y u n i f o r m p u l m o n a r y d e p o s i t i o n s , a n d n o t w i t h n o n - u n i f o r m
p a r t i c u l a t e d e p o s i t i o n s , w h a t e v e r s i d e o f t h e a l v e o l a r w a l l t h e y may b e .
One o f t h e m o s t r e p r e s e n t a t i v e e x p e r i m e n t s d e a l s w i t h the . i n h a l a t i o n b y
r a t s o f f i n e l y c r u s h e d m i c r o s p h e r e s o f p l u t o n i u m - 2 3 8 d i o x i d e ( 7 2 % u l t r a -
f i l t e r a b l e , CMD 0 . 0 2 ) ( S a n d e r s , 1 9 7 2 ; 1 9 7 3 ) ; "the r e s u l t i n g d i s t r i b u t i o n i n
t h e p u l m o n a r y t i s s u e i s o n e o f t h e m o s t u n i f o r m t h a t c a n a t p r e s e n t b e
p r o d u c e d e x p e r i m e n t a l l y w i t h a n o x i d i z e d f o r m o f p l u t o n i u m .
T h e r e i s n o d o u b t t h a t t h e h i g h e s t n u m b e r o f p u l m o n a r y c a n c e r s i s
o b t a i n e d w i t h t h i s f i n e l y d i s p e r s e d f o r m a n d a t v e r y l o w l e v e l s o f a c t i v i t y :
6.6% a t 9 r a d ( 0 . 0 9 Gy) ( d e p o s i t i o n o f 5 n C i ( 1 8 5 B q ) ) , 2 3 . 2 % a t 3 2 r a d
( 0 . 3 2 G y ) ( 1 8 n C i (666 B q ) ) . The f l n o r m a l M f r e q u e n c i e s o b t a i n e d w i t h
p l u t o n i u m - 2 3 8 d i o x i d e a r e o f t h e o r d e r o f a f e w p e r c e n t u p t o a b o u t 1 0 0 r a d
( 1 G y ) a n d i n o r d e r t o o b t a i n f r e q u e n c i e s a l o t h i g h e r t h a n 1 0 o r 20%
l e v e l s o f 1 0 0 0 r a d ( 1 0 Gy) o r more h a v e t o b e r e a c h e d ( C h a p t e r 6 ) . The
c o m b i n a t i o n o f t h e t w o e f f e c t s , t h e i n d u c t i o n o f p u l m o n a r y c a n c e r s a n d t h e
s h o r t e n i n g o f t h e l i f e s p a n , i n s o f a r a s t h e y a r e n o t a s s o c i a t e d w i t h o n e
a n o t h e r , c a n o b v i o u s l y m i n i m i z e t h e e f f e c t i n t h e c a s e o f p a r t i c l e i n h a l a -
t i o n . T h i s p o i n t w a s d i s c u s s e d i n C h a p t e r 6, p a r a g r a p h s 3 - 1 a n d 3 * 4 . T h i s
e x p e r i m e n t u s i n g m i c r o s p h e r e s o f p l u t o n i u m - 2 3 8 d i o x i d e i s e s p e c i a l l y
i m p o r t a n t a l t h o u g h i t i s n o t t y p i c a l o f p l u t o n i u m c o n t a m i n a t i o n , e v e n w h e n
i t i s i n h a l e d i n t h e f o r m o f c i t r a t e o r n i t r a t e s o l u t i o n s . I n f a c t , e v e n
u n d e r t h e n o r m a l c o n d i t i o n s o f r e s p i r a t o r y c o n t a m i n a t i o n b y t h e f o r m s t h a t
a r e c o n s i d e r e d s o l u b l e , p l u t o n i u m i s n e v e r d i s t r i b u t e d i n a p e r f e c t l y u n i -
f o r m f a s h i o n i n t h e l u n g a s r a p i d f o r m a t i o n o f h y d r o x i d e s a s s o c i a t e d w i t h
a r a p i d r i s e o f t h e pH r e s u l t s i n p a r t i c l e f o r m a t i o n . D e p o s i t i o n s
o c c u r r i n g i n t h i s w a y l e a d t o h i g h l o c a l d o s e s , f a r e x c e e d i n g t h e d o s e
a v e r a g e d o v e r t h e t o t a l l u n g ( M o s k a l e v , 1 9 7 2 ) . More s o l u b l e a c t i n i d e s a r e
m o r e u n i f o r m l y d i s t r i b u t e d t h r o u g h o u t t h e l u n g . T h i s i s t r u e f o r e x a m p l e
o f r e s u l t s w i t h a m e r i c i u m - 2 1 + 1 > c u r i u m - 2 l i U * e i n s t e i n i u m - 2 5 3 > e v e n i n t h e i r
o x i d i z e d f o r m s ( C h a p t e r s 2 a n d i i ) . F o r t h i s r e a s o n a n a n a l y s i s o f t h e
r e s u l t s o b t a i n e d w i t h r e l a t i v e l y t r a n s p o r t a b l e a c t i n i d e s a s s u m e s s p e c i a l
i m p o r t a n c e . A c o m p a r i s o n w i t h p l u t o n i u m i s n o t w h o l l y v a l i d , f o r t w o
v a r i a b l e s a r e i n v o l v e d : f i r s t l y , a f a i r l y u n i f o r m d i s t r i b u t i o n , a n d
s e c o n d l y , c l e a r a n c e r a t e s t h a t v a r y f r o m o n e e l e m e n t t o a n o t h e r a n d s o
p r o d u c e v a r i a t i o n s i n t h e d o s e r a t e s ( f o r a g i v e n d o s e r e c e i v e d ) . The t w o
150
f o r m s o f a m e r i c i u m , o x i d e a n d n i t r a t e , p r o d u c e h i g h f r e q u e n c i e s o f l u n g
c a n c e r , i e , amer i c ium-2 l4 .1 n i t r a t e : a b o u t 20% f o r 5 0 0 r a d ( 5 G y ) a n d 80% f o r
l e s s t h a n 2 5 0 0 r a d ( 2 $ G y ) ; f o r a m e r i c i u m - 2 1 + 1 d i o x i d e : t h e r e s p o n s e o c c u r s
a t much l o w e r l e v e l s , 50% f o r l e s s t h a n 5 0 0 r a d ( 5 G y ) , 70% f o r 1 ^ 0 0 r a d
0 5 Gy) ( L a f u m a e t a l , 1 9 7 5 , 1 9 7 6 ; M o r i n e t a l , 1 9 7 6 , 1 9 7 7 ) . The h i g h
r a d i o t o x i c i t y i n o t h e r r a t t i s s u e s o f c u r i u m a n d e i n s t e i n i u m ( T a b l e 6 . 2 )
may a c c o u n t f o r t h e l o w e r f r e q u e n c i e s o f l u n g c a n c e r o b s e r v e d w i t h t h e s e
e l e m e n t s ( L a f u m a e t a l , 1 9 7 5 ; B a l l o u e t a l , 1 9 7 5 ) ; h o w e v e r , f o r a m e r i c i u m -
2l+1 t h e f r e q u e n c y o f p u l m o n a r y c a n c e r s i s h i g h e r a n d p e a k - f r e q u e n c y i s
o b t a i n e d a t a p p r e c i a b l y s m a l l e r d o s e s t h a n i n t h e c a s e o f t h e i n s o l u b l e
f o r m s o f p l u t o n i u m . The s h o r t h a l f - l i f e o f e i n s t e i n i u m - 2 5 3 a n d i t s r a p i d
d i f f u s i b i l i t y make a c o m p a r i s o n w i t h t h i s e l e m e n t v e r y d i f f i c u l t .
The c o m b i n a t i o n o f t h e r e s u l t s o f t h e s e many e x p e r i m e n t a l r e s e a r c h
p r o j e c t s u s i n g v e r y d i f f e r e n t a p p r o a c h e s a n d t e c h n i q u e s , g i v e s g r o u n d s f o r
t h i n k i n g t h a t d e p o s i t i o n i n t h e l u n g o f i n s o l u b l e a l p h a - e m i t t i n g p a r t i c l e s
d o e s n o t p r e s e n t a g r e a t e r r i s k o f l u n g c a n c e r t h a n d e p o s i t i o n o f t h e same
a l p h a a c t i v i t y d i s t r i b u t e d i n a m o r e u n i f o r m f a s h i o n i n t h e p u l m o n a r y
p a r e n c h y m a ( A l b e r t e t a l , 1 9 7 6 ; B a i r e t a l , 1 9 7 U ; NCRP U 6 , 1 9 7 5 ; D o l p h i n
e t a l , 1 9 7 J + ; M . R . C . , 1 9 7 5 ; I CEP 1 1 + , 1 9 6 9 ; M o s k a l e v , 1 9 7 2 ; Lafuma e t a l ,
1 9 7 5 ; M o r i n e t a l , 1 9 7 7 ) .
3 . O b s e r v a t i o n s o n Man
The number o f w o r k e r s e x p o s e d t o p l u t o n i u m o r t o t r a n s u r a n i u m e l e m e n t s
i s more t h a n s e v e r a l t h o u s a n d t h r o u g h o u t t h e w o r l d . A c e r t a i n p r o p o r t i o n
o f t h i s n u m b e r h a s i n c o r p o r a t e d a p p r e c i a b l e q u a n t i t i e s o f t h e s e a c t i n i d e s ,
s o m e t i m e s w i t h d o s e l e v e l s h i g h e r t h a n t h e s t a t u t o r y l i m i t s ; t h e t i m e t h a t
h a s e l a p s e d s i n c e c o n t a m i n a t i o n h a s i n many c a s e s b e e n m o r e t h a n 2 5 y e a r s
a n d a l l o w s c e r t a i n c o n c l u s i o n s t o b e d r a w n .
Some g r o u p s o f c o n t a m i n a t e d w o r k e r s a r e w e l l known ( R o s s , 1 9 6 8 ;
Hempelmann e t a l , 1 9 7 3 , 1 9 7 U ; B a i r e t a l , 1 9 7 U ; S c h o f i e l d a n d D o l p h i n ,
1 9 7 U ) • The g r o u p w h i c h h a s b e e n s t u d i e d m o s t i s t h a t o f t w e n t y - f i v e w o r k e r s
o n t h e " M a n h a t t a n P r o j e c t " ( C h a p t e r 3 ) - Of t h e s e 2 5 w o r k e r s , 11+ s t i l l h a v e
i n t e r n a l d e p o s i t i o n s o f p l u t o n i u m - 2 3 9 a m o u n t i n g t o b e t w e e n 0 . 0 0 5 a n d O.k +iCi
( 0 . 2 a n d 1 5 k B q ) a b o u t t h i r t y y e a r s a f t e r c o n t a m i n a t i o n . B a i r e t a l , ( 1 9 7 U )
h a v e c o m p a r e d t h e n u m b e r o f c a n c e r s a r r i v e d a t b y t h e v a r i o u s t h e o r e t i c a l
c a l c u l a t i o n s a n d t h e n u m b e r t h a t h a v e a c t u a l l y b e e n o b s e r v e d : ( a ) b a s e d o n
U . S . a g e s p e c i f i c m o r t a l i t y d a t a t h e number o f c a n c e r s e x p e c t e d i n t h i s
g r o u p w o u l d b e O . 7 6 f o r t h e l u n g , 0 . 1 5 f o r t h e l i v e r , 0 . 0 U f o r t h e b o n e ;
( b ) t h e n u m b e r , o n t h e p e s s i m i s t i c a s s u m p t i o n o f a r i s k e q u a l t o 5 x 1 0 ^
151
p e r p a r t i c l e ( T a m p l i n a n d C o c h r a n , 1 9 7 4 ) a n d a s s u m i n g 1 $ % o f t h e m a s s o f
t h e l u n g t o b e a f f e c t e d b y t h e p a r t i c l e s , w o u l d b e 2 0 0 m a l i g n a n t t u m o u r s
p e r i n d i v i d u a l , o r 5 0 0 0 i n t h e g r o u p ; ( c ) t h e n u m b e r o f c a n c e r s , o n t h e
same a s s u m p t i o n s b u t o n l y t a k i n g i n t o a c c o u n t t h e q u a n t i t i e s o f p l u t o n i u m
p r e s e n t i n t h e l u n g 30 y e a r s a f t e r c o n t a m i n a t i o n , w o u l d s t i l l b e 3 p e r
p e r s o n ; ( d ) t h e a c t u a l n u m b e r o b s e r v e d i n m o r e t h a n 30 y e a r s i s n i l .
A l t h o u g h n e g a t i v e r e s u l t s s h o u l d a l w a y s b e a n a l y s e d w i t h t h e g r e a t e s t c a r e ,
i t d o e s s e e m t h a t i f r a d i a t i o n f r o m p a r t i c u l a t e f o r m s o f p l u t o n i u m w a s
e x c e p t i o n a l l y h a z a r d o u s , some m a l i g n a n c i e s w o u l d a l r e a d y h a v e m a n i f e s t e d
t h e m s e l v e s .
A t u m o u r a l l e s i o n a r i s i n g f r o m c o n t a c t w i t h a c h i p o f m e t a l l i c
p l u t o n i u m b u r i e d i n t h e h a n d o f a w o r k e r h a s b e e n c l a s s i f i e d a s a " p r e -
c a n c e r o u s " s t a t e ( T a m p l i n a n d C o c h r a n , 1 9 7 4 ) ; t h e d o s e a r o u n d t h i s p i e c e
o f m e t a l w a s v e r y h i g h , b e i n g e s t i m a t e d a t 7 5 x 1 0 ^ r a d ( 7 5 x 1 0 ^ G y ) i n
a l i t t l e m o r e t h a n 4 y e a r s ( L u s h b a u g h e t a l , 1 9 & 2 , 1 9 ^ 7 ) . The e x c i s i o n o f
t h e l e s i o n w a s n o t f o l l o w e d b y a n y o f t h e s e c o n d a r y m a n i f e s t a t i o n s t h a t a r e
u s u a l w i t h c a n c e r o u s l e s i o n s . I n f a c t , t h i s u n i q u e c a s e , i n s o f a r a s i t i s
o n e o f a r e a l p r e - c a n c e r o u s c h a n g e , d o e s n o t p r o v i d e a n y p r e c i s e i n f o r m a t i o n :
t h e c o n c e p t o f r a d i a t i o n - i n d u c e d c a n c e r d o e s n o t n e e d f u r t h e r s u p p o r t i n g
a r g u m e n t s ; i n n o w a y d o e s t h i s human e x a m p l e d e m o n s t r a t e t h a t p l u t o n i u m i n
p a r t i c u l a t e f o r m i s p a r t i c u l a r l y d a n g e r o u s .
4 - Summary
W i t h t h e a i d o f a l l t h e r e c e n t d a t a f r o m v a r i o u s s o u r c e s i t i s e a s y t o
r e f u t e t h e a n a l y s e s o f e x p e r i m e n t s o r o f t h e o r e t i c a l s t u d i e s t n a t
t e n d t o t h e c o n c l u s i o n t h a t t h e r e i s a p a r t i c u l a r l y h i g h r i s k f r o m
n o n - u n i f o r m d i s t r i b u t i o n o f p l u t o n i u m i n t h e l u n g a s c o m p a r e d w i t h
u n i f o r m d i s t r i b u t i o n . The p r o b a b i l i t y t h a t a m a l i g n a n t t u m o u r w i l l
o c c u r i n a t i s s u e d e p e n d s o n t h e v o l u m e o f t h e i r r a d i a t e d t i s s u e a n d
h e n c e o n t h e n u m b e r o f c e l l s d i r e c t l y e x p o s e d t o r i s k w i t h o u t p r e -
j u d g i n g t h e m e c h a n i s m s i n i t i a t i n g a n d p r o m o t i n g t h e c a n c e r o u s p r o c e s s .
T h i s f a c t o r i s r e l a t e d t o t h e w a y i n w h i c h t h e a l p h a e m i t t e r i s
d i s p e r s e d i n t h e o r g a n . N o t o n l y d o e s i t a p p e a r t h a t t h e l o c a l r i s k
o f c a n c e r - f o r m a t i o n i s n o g r e a t e r i n t h e c a s e o f i n h a l a t i o n o f
a c t i n i d e s d i s t r i b u t e d i n a f i n i t e n u m b e r o f " h o t p a r t i c l e s " t h a n
i t i s i n t h e c a s e o f i n h a l a t i o n o f a d i s p e r s e d f o r m d i s t r i b u t e d i n a
l e s s h e t e r o g e n e o u s o r , i n d e e d , w h o l l y u n i f o r m w a y , b u t i t a l s o s e e m s
t h a t t h i s r i s k may b e s m a l l e r .
Chapter 8
T R E A T M E N T FOR ACCIDENTAL INTAKES
1 . I n t r o d u c t i o n
T r e a t m e n t s t h a t may b e u s e d t o a c c e l e r a t e t h e r a t e o f e l i m i n a t i o n o f
a c t i n i d e s f r o m t h e b o d y d e p e n d c o n s i d e r a b l y u p o n t h e s i t e o f d e p o s i t i o n ,
t h e p h y s i c o - c h e m i c a l f o r m i n v o l v e d a n d i n p a r t i c u l a r w h e t h e r t h e m a t e r i a l
i s s o l u b l e ( e g , p l u t o n i u m n i t r a t e o r c i t r a t e ) o r i n s o l u b l e ( e g , p l u t o n i u m
d i o x i d e ) •
2 . T r e a t m e n t f o r i n t a k e s o f i n s o l u b l e f o r m s o f a c t i n i d e s
2 . 1 D e p o s i t s i n t h e l u n g
F o l l o w i n g t h e a c c i d e n t a l i n h a l a t i o n o f p l u t o n i u m d i o x i d e a n y p a r t i c l e s
d e p o s i t e d i n t h e u p p e r r e g i o n s o f t h e l u n g s a r e r a p i d l y c l e a r e d u p t h e
c i l i a r y e s c a l a t o r . Any p a r t i c l e s r e m a i n i n g i n t h e l u n g s a f t e r t h i s e a r l y
c l e a r a n c e p h a s e a r e m a i n l y a c c u m u l a t e d b y m a c r o p h a g e s . Any t r e a t m e n t m u s t ,
t h e r e f o r e , a i m t o r e d u c e t h e l e v e l o f a c t i v i t y i n t h e l u n g b y r e m o v i n g
t h e s e c e l l s . The o n l y a p p r o a c h t h a t h a s b e e n d e m o n s t r a t e d t o b e p o t e n t i a l l y
o f v a l u e i s b r o n c h o p u l m o n a r y l a v a g e .
The p r o c e d u r e u s e d i n man a n d l a r g e a n i m a l s ( d o g s a n d b a b o o n s ) i n v o l v e s
p a s s i n g a c u f f e d d o u b l e - l u m e n t u b e t h r o u g h t h e m o u t h a n d i n t o t h e t r a c h e a o f
a n a n a e s t h e t i s e d s u b j e c t . The t u b e i s p o s i t i o n e d s o t h a t e a c h l u n g i s
i n d e p e n d e n t l y i n t u b a t e d a n d t h e s u b j e c t i s a l l o w e d t o b r e a t h e p u r e o x y g e n
t h r o u g h i t . One l u n g i s t h e n m a i n t a i n e d o n o x y g e n w h i l s t t h e o t h e r i s
f i l l e d w i t h s a l i n e w h i c h i s t h e n d r a i n e d o u t . The p r o c e d u r e i s r e p e a t e d a
n u m b e r o f t i m e s . A t t h e e n d o f t h i s " u n i l a t e r a l " l a v a g e t h e o p p o s i t e l u n g
c a n b e s i m i l a r l y l a v a g e d c o m p l e t i n g a " b i l a t e r a l l a v a g e " . S a l i n e i s
n o r m a l l y u s e d f o r l u n g w a s h i n g a s i t h a s b e e n s h o w n t o b e m o r e e f f e c t i v e
t h a n b a l a n c e d s a l t s o l u t i o n s i n r e m o v i n g p u l m o n a r y m a c r o p h a g e s ( N o l i b e e t a l ,
1 9 7 7 a ) . The p r e s e n c e o f C a + + a n d Mg"*^ i n h i b i t s t h e r e l e a s e o f m a c r o p h a g e s
f r o m t h e a l v e o l a r w a l l ( B r a i n a n d C o r k e r y , 1 9 7 7 ) .
O v e r t h e l a s t 1 0 y e a r s a s e r i e s o f s t u d i e s o n t h e u s e o f l a v a g e f o r
r e m o v i n g i n s o l u b l e r a d i o a c t i v e p a r t i c l e s f r o m t h e l u n g s o f a n i m a l s h a v e
b e e n r e p o r t e d f r o m F r a n c e , t h e U n i t e d S t a t e s a n d t h e U n i t e d K i n g d o m .
T a b l e 8 . 1 g i v e s some r e s u l t s o b t a i n e d i n man a n d k m a m m a l i a n s p e c i e s . I n
b o t h d o g s ( S i l b a u g h e t a l , 1 9 7 5 ) a n d b a b o o n s ( N o l i b e e t a l , 1 9 7 6 ) 5 0 - 6 0 %
o f a n i n h a l e d i n s o l u b l e a e r o s o l h a s b e e n r e m o v e d b y r e p e a t e d l a v a g e s c a r r i e d
o u t o v e r a p e r i o d o f 1 2 w e e k s a f t e r e x p o s u r e t o t h e a e r o s o l . B e t w e e n 8 5 a n d
90% o f t h e i n i t i a l l u n g c o n t e n t o f 2 ^ P u 0 9 h a s b e e n r e m o v e d f r o m h a m s t e r s
153
15U
g i v e n 7 s u c c e s s i v e l a v a g e s d u r i n g a 6 w e e k p e r i o d a f t e r e x p o s u r e , B r i g h t w e l l
a n d E l l e n d e r ( 1 9 7 7 ) . I n t h i s l a t t e r s t u d y t h e f i r s t 3 l a v a g e s r e m o v e d 7 3 %
o f t h e e s t i m a t e d i n i t i a l l u n g c o n t e n t . The s e v e n t h l a v a g e r e m o v e d o n l y
2 . 0 % o f t h e i n i t i a l l u n g c o n t e n t b u t t h i s w a s s t i l l a b o u t 20% o f t h e l u n g
c o n t e n t a t t h e t i m e o f t r e a t m e n t . I n r o d e n t s i t i s n o t p r a c t i c a b l e t o
w a s h o u t e a c h l u n g s e p e r a t e l y a n d t h e t e c h n i q u e u s e d i n v o l v e d a l t e r n a t i v e l y
f l o o d i n g b o t h l u n g s w i t h a v o l u m e o f s a l i n e r a t h e r l e s s t h a n t h e t o t a l
l u n g v o l u m e a n d t h e n d r a i n i n g t h e l u n g s .
B r o n c h o p u l m o n a r y l a v a g e h a s b e e n u s e d w i t h p a r t i a l s u c c e s s o n a man
who h a d i n h a l e d p l u t o n i u m f o l l o w i n g a g l o v e b o x a c c i d e n t ( M c C l e l l a n e t a l ,
1 9 7 2 b ) . A b o u t 1 3 % o f t h e i n i t i a l l u n g c o n t e n t w a s r e m o v e d i n t h e l a v a g e
f l u i d ( T a b l e 8 , 1 ) a n d t h e r e w a s some i n c r e a s e i n f a e c a l e x c r e t i o n t h a t
c o u l d h a v e r e s u l t e d f r o m t h e t r e a t m e n t . I n t h i s c a s e o n e l u n g w a s l a v a g e d
t w i c e a n d t h e o t h e r l u n g o n c e o n l y . The a c c u m u l a t e d e v i d e n c e f r o m a n i m a l
e x p e r i m e n t s s u g g e s t s t h a t m o r e l a v a g e s w o u l d h a v e f u r t h e r r e d u c e d t h e l u n g
c o n t e n t o f p l u t o n i u m .
N o l i b e e t a l , ( 1 9 7 7 a ) h a v e d e s c r i b e d t h e p a t h o l o g i c a l e f f e c t s o f
l a v a g e i n b a b o o n s . I m m e d i a t e l y a n d a f e w h o u r s a f t e r t r e a t m e n t t h e e f f e c t s
o n l u n g h i s t o l o g y i n c l u d e d h a e m o r r h a g e , p e r i b r o n c h i a l a n d p e r i v a s c u l a r
o e d e m a , a n d i n f i l t r a t i o n o f n e u t r o p h i l i c g r a n u l o c y t e s . C h a n g e s i n u l t r a -
s t r u c t u r e w e r e a l s o n o t e d i n c l u d i n g t h e s w e l l i n g o f some a l v e o l a r w a l l c e l l s ,
a n d i n p l a c e s t h e i r c o m p l e t e l o s s l e a v i n g a b a r e b a s a l m e m b r a n e . T w e n t y -
f o u r h o u r s a f t e r l a v a g e some a l v e o l i w e r e f i l l e d w i t h a f i b r i n o u s e x u d a t e
a n d f o a m y m a c r o p h a g e s , t h i s , w a s a s s o c i a t e d w i t h a n i n f i l t r a t i o n o f g r a n -
u l o c y t e s a n d o f t e n m e g a k a r y o c y t e s . N o n e o f t h e s e c h a n g e s w e r e e x t e n s i v e .
By 2 d a y s t h e r e w a s a l a r g e r e g r e s s i o n o f t h e s e p a t h o l o g i c a l c h a n g e s a n d
a f t e r h d a y s t h e l u n g s w e r e n o r m a l . No e v i d e n c e o f c h r o n i c l u n g p a t h o l o g y
w a s n o t e d s e v e r a l m o n t h s a f t e r a s c h e d u l e o f 1 5 l a v a g e s . S i m i l a r c h a n g e s
h a v e b e e n r e p o r t e d i n b e a g l e d o g s f o l l o w i n g l a v a g e t r e a t m e n t ( M u g g e n b u r g
e t a l , 1 9 7 2 ) .
A l t h o u g h t h e p r o c e d u r e h a s b e e n u s e d o n l y o n c e i n man f o r t h e r e m o v a l
o f i n h a l e d r a d i o a c t i v e m a t e r i a l i t h a s b e e n u s e d f r e q u e n t l y f o r t h e t r e a t -
m e n t o f a l v e o l a r p r o t e i n o s i s , b r o n c h i a l a s t h m a , c y s t i c f i b r o s i s , c h r o n i c
b r o n c h i t i s , a n d b r o n c h i e c t a s i s . I n a r e v i e w o f e x p e r i e n c e w i t h b r o n c h o -
p u l m o n a r y l a v a g e i n man R o g e r s e t a l , ( 1 9 7 2 ) s h o w e d t h a t i n 8 2 p a t i e n t s
g i v e n 2i+0 l a v a g e s o n l y o n e d e a t h d u r i n g o r p o s t - l a v a g e w a s r e p o r t e d . T h i s
w a s d u e t o a p u l m o n a r y e m b o l i s m w h i c h i s d i f f i c u l t t o r e l a t e t o t h e p r o c e d -
u r e p e r s e . A n u m b e r o f d e a t h s h a v e b e e n r e p o r t e d i n a n i m a l s t r e a t e d w i t h
l a v a g e ( N o l i b e e t a l , 1 9 7 6 , M u g g e n b u r g e t a l , 1 9 7 6 ) . H o w e v e r , t h e d e a t h s
h a v e o c c u r r e d p r e d o m i n a n t l y a s a r e s u l t o f e x p e r i m e n t a l e r r o r s a n d n o t
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b e c a u s e o f a n y a d v e r s e e f f e c t s o f l a v a g e u p o n t h e r e s p i r a t o r y s y s t e m .
I n c o n c l u s i o n , b r o n c h o p u l m o n a r y l a v a g e i s t h e o n l y e f f e c t i v e t r e a t m e n t
f o r r e m o v i n g i n h a l e d i n s o l u b l e r a d i o a c t i v e m a t e r i a l s . I t a p p e a r s t o b e a
s a f e p r o c e d u r e . The m a i n r i s k i s l i k e l y t o b e t h a t o f t h e r e p e a t e d
a n a e s t h e s i a r e q u i r e d r a t h e r t h a n t h e p r o c e d u r e i t s e l f . The o n l y l i m i t a t i o n
i n t h e u s e o f t h i s p r o c e d u r e f o r r e m o v i n g r a d i o a c t i v e m a t e r i a l s f r o m t h e
l u n g a p p e a r s t o b e t h e n u m b e r o f l a v a g e s r e q u i r e d a s e a c h l a v a g e may r e m o v e
o n l y 20% o r l e s s o f t h e l u n g c o n t e n t . The v a l u e o f t h e t e c h n i q u e w o u l d b e
i n c r e a s e d c o n s i d e r a b l y i f t h e e f f i c i e n c y c o u l d b e i m p r o v e d .
2 . 2 D e p o s i t s i n w o u n d s
D e p o s i t s o f p l u t o n i u m o r h i g h e r a c t i n i d e s i n w o u n d s i t e s c a n n o r m a l l y
b e r e m o v e d b y s u r g i c a l e x c i s i o n . S c h o f i e l d 0976) h a s r e p o r t e d t h a t a t
BNFL W i n d s c a l e p l u t o n i u m d e p o s i t s a r e s u r g i c a l l y e x c i s e d w h e n e v e r p o s s i b l e
i f t h e a c t i v i t y a t t h e s i t e i s i n e x c e s s o f a b o u t k n C i ( 0 . 1 5 k B q ) . E x c i s i o n
i s n o r m a l l y c o m b i n e d w i t h t h e u s e o f d i e t h y l e n e t r i a m i n e p e n t a a c e t i c a c i d
(DTPA) t o a c c e l e r a t e t h e e x c r e t i o n o f a n y s o l u b l e a c t i n i d e s t h a t h a v e
e n t e r e d t h e c i r c u l a t i o n o r r e m a i n a t t h e wound s i t e .
3 . T r e a t m e n t f o r i n t a k e s o f s o l u b l e f o r m s o f a c t i n i d e s
3 . 1 I n t r a v e n o u s a d m i n i s t r a t i o n o f DTPA
I n t a k e s o f a c t i n i d e s f r e q u e n t l y i n v o l v e c o m p o u n d s w i t h h e t e r o g e n e o u s
p h y s i c o c h e m i c a l p r o p e r t i e s . H o w e v e r a f r a c t i o n o f t h e d e p o s i t e d m a t e r i a l
w i l l b e h a v e i n a s o l u b l e m a n n e r ( t r a n s p o r t a b l e ) a n d t h e r e m a i n d e r a s
i n s o l u b l e ( n o n - t r a n s p o r t a b l e ) . I n t h e c a s e o f i n s o l u b l e f o r m s s u c h a s
p l u t o n i u m d i o x i d e t h e t r a n s p o r t a b l e f r a c t i o n may b e l e s s t h a n 0 . 1 % o f t h e
d e p o s i t b u t f o r s o l u b l e f o r m s ( n i t r a t e o r c i t r a t e ) i t may b e a t h i r d o r
m o r e ( C h a p t e r h)»
F o r i n c r e a s i n g t h e r a t e o f e l i m i n a t i o n o f t h e t r a n s p o r t a b l e f r a c t i o n
o f a n i n t a k e t h e c u r r e n t l y a c c e p t e d t r e a t m e n t i s t h e i n t r a v e n o u s a d m i n i s -
t r a t i o n o f t h e c a l c i u m s a l t o f t h e c h e l a t i n g a g e n t DTPA ( N o r w o o d , 1 9 6 2 ,
N o r w o o d a n d F u q u a , 1 9 6 9 , S c h o f i e l d a n d L y n n , 1 9 7 3 , S c h o f i e l d e t a l , 1 9 7 U ) .
The c h e l a t e c o m p l e x f o r m e d b e t w e e n a n y a v a i l a b l e p l u t o n i u m a n d DTPA i s
r a p i d l y a n d a l m o s t q u a n t i t a t i v e l y e x c r e t e d f r o m t h e b o d y ( N e n o t e t a l , 1 9 7 2 ,
S t a t h e r a n d H o w d e n , 1 9 7 5 ) . The d o s e u s e d i n man i s n o r m a l l y 3 . 5 t o 1 i + m g k g ~ " \
The v a l u e a n d l i m i t a t i o n s i n t h e u s e o f DTPA f o r t r e a t i n g a c c i d e n t a l
i n t a k e s o f p l u t o n i u m o r o t h e r a c t i n i d e s h a s r e c e n t l y b e e n r e v i e w e d b y
D o l p h i n ( 1 9 7 6 a ) . The m a i n d i s a d v a n t a g e a s s o c i a t e d w i t h t h e u s e o f DTPA i s
t h a t i t c a n o n l y p e n e t r a t e t h e c e l l s o f t h e b o d y t o a v e r y l i m i t e d e x t e n t
157
a n d t h e r e f o r e i n p r a c t i c e i s m a i n l y e f f e c t i v e i n r e m o v i n g p l u t o n i u m f r o m t h e
e x t r a c e l l u l a r s p a c e o r some o f t h a t w h i c h h a s r e c e n t l y b e e n d e p o s i t e d o n
b o n e o r l i v e r s u r f a c e s . As t h e r a t e o f c l e a r a n c e o f a m a j o r p o r t i o n o f
p l u t o n i u m f r o m t h e b l o o d i s r a p i d ( C h a p t e r h) i t i s i m p o r t a n t t o a d m i n i s t e r
DTPA a s s o o n a s p o s s i b l e a f t e r a s u s p e c t e d o r known i n t a k e o f a c t i n i d e s . A
n u m b e r o f s t u d i e s h a v e s h o w n t h a t t h e e f f e c t i v e n e s s o f t r e a t m e n t w i t h DTPA
d e p e n d s b o t h u p o n t h e t i m e o f a d m i n i s t r a t i o n a n d t h e a m o u n t . W i t h p r o m p t
t r e a t m e n t i t s e f f e c t i v e n e s s i n c r e a s e s w i t h t h e a m o u n t a d m i n i s t e r e d b u t a t
l a t e r t i m e s t h i s e f f e c t i s l e s s m a r k e d ( C a t s c h , 1 9 7 6 , S t a t h e r e t a l , 1 9 7 6 ) .
A m e r i c i u m a n d c u r i u m a r e c l e a r e d m o r e r a p i d l y f r o m t h e s y s t e m i c
c i r c u l a t i o n t h a n p l u t o n i u m ( C h a p t e r l i )» I t m i g h t b e e x p e c t e d , t h e r e f o r e ,
t h a t DTPA w o u l d b e l e s s e f f e c t i v e i n i n c r e a s i n g t h e e l i m i n a t i o n o f t h e s e
t r a n s p l u t o n i c e l e m e n t s c o m p a r e d w i t h p l u t o n i u m i f g i v e n a f e w h o u r s a f t e r
a n i n t a k e . No c o m p a r a t i v e d a t a a p p e a r t o b e a v a i l a b l e a t t h e s e t i m e s b u t
V o l f e t a l , ( 1 9 7 7 ) h a v e s h o w n t h a t t h e p r o m p t t r e a t m e n t w i t h t h e c a l c i u m
s a l t ( 1 5 \i m o l e k g 1 * a d m i n i s t e r e d 1 , 5 m i n u t e s a f t e r i s o t o p e i n j e c t i o n ) w a s
m o r e e f f e c t i v e i n r e d u c i n g t i s s u e l e v e l s o f a m e r i c i u m - 2 l ± 1 a n d c u r i u m - 2 l i 2
c o m p a r e d w i t h p l u t o n i u m - 2 3 9 * L e v e l s o f p l u t o n i u m i n t h e s k e l e t o n a n d l i v e r
w e r e r e d u c e d t o a b o u t 5 7 % o f t h e c o n t r o l s a t o n e w e e k w h e r e a s c u r i u m a n d
a m e r i c i u m l e v e l s i n t h e s k e l e t o n w e r e r e d u c e d t o a b o u t 27% o f c o n t r o l s a n d
i n t h e l i v e r t o 1 9 % . I f r e p e a t e d i n j e c t i o n s w e r e g i v e n a t l a t e r t i m e s
( 6 t h , 8 t h a n d 1 1 t h d a y a f t e r i s o t o p e i n j e c t i o n ) b u t a t a c o n s i d e r a b l y —1 —1
h i g h e r d o s e ( 1 m m o l e k g d a y ) , t h e e f f e c t o f t h e c a l c i u m s a l t i n
r e d u c i n g l e v e l s o f a c t i v i t y i n t h e s k e l e t o n w a s s i m i l a r f o r a l l t h r e e
r a d i o n u c l i d e s ( 7 7 % o f c o n t r o l s a t 1 3 d a y s a f t e r i s o t o p e a d m i n i s t r a t i o n ) b u t
w a s m o r e e f f e c t i v e a t r e d u c i n g a m e r i c i u m a n d c u r i u m i n t h e l i v e r (8% o f
c o n t r o l s ) t h a n p l u t o n i u m (20% o f c o n t r o l s ) ( S e i d e l a n d V o l f , 1 9 7 2 ) . The
i n c r e a s e d e f f e c t i v e n e s s o f DTPA i n r e d u c i n g t i s s u e l e v e l s o f t h e t r a n s -
p l u t o n i c e l e m e n t s p r o b a b l y r e s u l t s f r o m t h e i r w e a k e r b i n d i n g t o p r o t e i n s
i n t h e b l o o d a n d o t h e r t i s s u e c o m p o n e n t s .
I n a n i m a l e x p e r i m e n t s t h e e f f e c t i v e n e s s o f t r e a t m e n t c a n b e r e a d i l y
m e a s u r e d a s t h e a n i m a l s a r e n o r m a l l y k i l l e d a t t h e e n d o f t h e s t u d y . I t
i s c o n s i d e r a b l y l e s s e a s y t o e v a l u a t e t h e b e n e f i t s o f t r e a t m e n t i n man . An
e s t i m a t e o f t h e d e g r e e o f d e c o n t a m i n a t i o n a c h i e v e d d e p e n d s u p o n a k n o w l e d g e
b o t h o f t h e a m o u n t o f a c t i v i t y i n t h e b o d y s o o n a f t e r e x p o s u r e a n d t h e t o t a l
a m o u n t e x c r e t e d . T h e s e v a l u e s may n o t b e known w i t h a n y d e g r e e o f a c c u r a c y .
A n a l y s i s o f t h e a c t i v i t y e x c r e t e d i n t h e u r i n e o v e r a p e r i o d o f w e e k s
* 2 8 |i m o l e k g " DTPA = 1li mg k g " DTPA
158
p r o v i d e s p r o b a b l y t h e b e s t , b u t n o t a l w a y s a n a c c u r a t e e s t i m a t e o f t h e
e f f e c t i v e n e s s o f t r e a t m e n t . S p o o r ( 1 9 7 7 ) h a s r e v i e w e d 3 1 c a s e h i s t o r i e s
o f p e r s o n s t r e a t e d w i t h DTPA a f t e r a c c i d e n t a l i n t a k e s o f p l u t o n i u m ,
a m e r i c i u m o r c u r i u m c o m p o u n d s . Out o f t h e s e c a s e s t h e u s e o f DTPA w a s
c o n s i d e r e d t o h a v e h a d a n e g l i g i b l e e f f e c t i n a b o u t o n e t h i r d o f t h e c a s e s ,
a s l i g h t e f f e c t i n a f u r t h e r t h i r d a n d a c o n s i d e r a b l e e f f e c t i n t h e r e -
m a i n i n g c a s e s . I t w a s n o t e w o r t h y t h a t i n many c a s e s t h e u s e o f DTPA
e n h a n c e d t h e r a t e o f u r i n a r y e x c r e t i o n b y a f a c t o r o f 3 0 t o 1±0 o v e r t h e
v a l u e e x p e c t e d w i t h o u t t r e a t m e n t . D e s p i t e t h i s b e c a u s e t r e a t m e n t w a s
o f t e n i n i t i a t e d t o o l a t e o r b e c a u s e t h e o r i g i n a l i n t a k e i n v o l v e d p l u t o n i u m
d i o x i d e t h e o v e r a l l e f f e c t o f t h e t r e a t m e n t i n r e d u c i n g t h e b o d y a c t i v i t y
w a s i n many c a s e s s m a l l .
The e f f e c t i v e n e s s o f DTPA i s l i m i t e d b y i t s i n a b i l i t y t o r e m o v e
p l u t o n i u m t h a t h a s b e e n a c c u m u l a t e d b y c e l l s o r i n c o r p o r a t e d i n b o n e
m i n e r a l . R e c e n t l y , h o w e v e r , i t h a s b e e n r e p o r t e d t h a t a l i p o p h i l i c
d e r i v a t i v e o f DTPA (now t e r m e d P u c h e l ) h a s b e e n p r e p a r e d t h a t i s a b l e t o
r e m o v e 85% o f t h e l i v e r c o n t e n t o f p l u t o n i u m i n r o d e n t s ( B u l m a n e t a l ,
1 9 7 7 ) - T h i s m a t e r i a l w i l l n e e d e x t e n s i v e t o x i c o l o g i c a l t e s t i n g b e f o r e
i t c a n b e c o n s i d e r e d f o r u s e i n man .
3 . 2 E f f e c t s o f DTPA a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n
T h e r e i s n o e v i d e n c e o f DTPA t o x i c i t y i n man p r o v i d e d i t i s g i v e n a s
s i n g l e i n t r a v e n o u s i n j e c t i o n s n o t e x c e e d i n g 11+ mg k g " 1 b o d y w e i g h t a t
i n t e r v a l s o f 2i+ h o u r s o r m o r e ( N o r w o o d a n d P u q u a , 1 9 ^ 9 ) • M o r g a n a n d S m i t h
( 1 9 7 U ) f a i l e d t o d e m o n s t r a t e a n y t o x i c e f f e c t s o f t h e c a l c i u m s a l t i n
a n i m a l s u n d e r a l l l i k e l y c o n d i t i o n s o f u s e . T h e r e i s e v i d e n c e f r o m a n i m a l
e x p e r i m e n t s o f l e t h a l a n d n o n - l e t h a l t o x i c e f f e c t s o r d e a t h w h e n t h e c a l c i u m
s a l t i s g i v e n a s m u l t i p l e i n j e c t i o n s ( 5 t i m e s a d a y ) o v e r a p e r i o d o f 2 l i
h o u r s f o r a f e w d a y s e v e n t h o u g h t h e a m o u n t i n j e c t e d d o e s n o t e x c e e d 1 l i mg
k g " d a y " ( T a y l o r e t a l , 1 9 7 U ) • I t i s t h o u g h t t h a t t h e a d v e r s e e f f e c t s
a r e c a u s a l l y r e l a t e d t o t h e r e m o v a l o f e s s e n t i a l t r a c e m e t a l s , m a i n l y Zn a n d
Mh ( G a b a r d , 1 9 7 U ; P l a n a s - B o h n e a n d O l i n g e r , 1 9 7 ^ ) • T h i s v i e w i s s u p p o r t e d
b y s t u d i e s w h i c h show t h a t t o x i c i t y c a n b e c o n s i d e r a b l y r e d u c e d b y t h e u s e
o f t h e z i n c s a l t ( T a y l o r e t a l , 1 9 7 U > C a t s c h a n d W e d e l s t a e d t , 1 9 6 5 * S e i d e l
a n d V o l f , 1 9 7 2 ) .
A d i s a d v a n t a g e i n t h e u s e o f t h e z i n c s a l t i s t h a t i t i s l e s s e f f e c t -
i v e t h a n t h e c a l c i u m s a l t i n r e m o v i n g i n t e r n a l l y d e p o s i t e d t r a n s u r a n i c
e l e m e n t s , w h e n t h e c h e l a t e i s a d m i n i s t e r e d w i t h i n a f e w d a y s a f t e r i n c o r p -
o r a t i o n o f t h e r a d i o n u c l i d e ( V o l f a n d S e i d e l , 1 9 7 4 , V o l f , 1 9 7 6 , C a t s c h ,
159
1 9 7 ^ , S m i t h e t a l , 1 9 7 6 ) . A d m i n i s t e r e d a t a l a t e r t i m e b o t h t h e c a l c i u m
a n d z i n c s a l t s a p p e a r t o b e e q u a l l y e f f e c t i v e ( L l o y d e t a l , 1 9 7 6 , S e i d e l
a n d V o l f , 1 9 7 2 , S e i d e l , 1 9 7 6 ) .
3 # 3 A e r o s o l a d m i n i s t r a t i o n o f DTPA
DTPA i s n o r m a l l y g i v e n b y i n t r a v e n o u s i n j e c t i o n b e c a u s e a b s o r p t i o n
f r o m t h e g a s t o - i n t e s t i n a l t r a c t i s l o w ( F o r e m a n e t a l , 1 9 5 6 ) . H o w e v e r , i t
i s n o t a l w a y s p r a c t i c a b l e t o i n j e c t DTPA s o o n a f t e r a n a c c i d e n t a n d a n u m b e r
o f a u t h o r s h a v e s u g g e s t e d t h a t i t c o u l d b e s e l f - a d m i n i s t e r e d a s a n a e r o s o l
( L y u b c h a n s k i i , 1 9 6 6 , N e n o t e t a l , 1 9 7 1 a , N e n o t e t a l , 1 9 7 1 h , J o l l y e t a l ,
1 9 7 2 , S m i t h e t a l , 1 9 7 6 , S t a t h e r e t a l , 1 9 7 6 ) . S t a t h e r e t a l , ( 1 9 7 6 ) h a v e
s h o w n t h a t t h e a d m i n i s t r a t i o n o f t h e c a l c i u m s a l t e i t h e r b y p u l m o n a r y i n -
t u b a t i o n o r b y i n t r a v e n o u s i n j e c t i o n w a s e q u a l l y e f f e c t i v e i n r e d u c i n g t i s s u e
l e v e l s o f p l u t o n i u m a d m i n i s t e r e d i n t r a v e n o u s l y a s c i t r a t e . S m i t h e t a l ,
( 1 9 7 6 ) h a v e s h o w n t h a t i n t r a v e n o u s DTPA ( 3 5 u m o l e k g " ) a n d i n h a l e d DTPA
a p p e a r t o b e t h e r a p e u t i c a l l y e q u i v a l e n t f o l l o w i n g i n t r a m u s c u l a r a d m i n i s t r a -
t i o n o f p l u t o n i u m n i t r a t e . I n t h e c a s e o f s o l u b l e f o r m s o f p l u t o n i u m
d e p o s i t e d i n t h e r e s p i r a t o r y s y s t e m e a r l y a d m i n i s t r a t i o n o f DTPA c a n b e
c o n s i d e r a b l y m o r e e f f e c t i v e t h a n i n t r a v e n o u s a d m i n i s t r a t i o n i n r e d u c i n g
t i s s u e d e p o s i t s o f p l u t o n i u m . F o r e x a m p l e w h e n r a t s w e r e e x p o s e d t o a e r o -
s o l s o f t h e c a l c i u m s a l t (5»U mg k g " ) U 5 m i n u t e s a f t e r t h e p u l m o n a r y
d e p o s i t i o n o f p l u t o n i u m c i t r a t e t h e l u n g c o n t e n t o f p l u t o n i u m m e a s u r e d a
w e e k l a t e r w a s r e d u c e d t o 8 . 5 % o f c o n t r o l a n i m a l s . I n a d d i t i o n t h e t o t a l
a c t i v i t y d e p o s i t e d i n t i s s u e s o t h e r t h a n t h e l u n g s w a s 60% o f c o n t r o l
a n i m a l s . F o l l o w i n g t h e i n t r a v e n o u s i n j e c t i o n o f s i m i l a r a m o u n t s o f DTPA
t h e c o m p a r a b l e f i g u r e s w e r e 96% a n d 68% r e s p e c t i v e l y ( S t a t h e r e t a l , 1 9 7 6 ) .
I f t r e a t m e n t i s d e l a y e d DTPA i s l e s s e f f e c t i v e . I n r a t s e x p o s e d t o a n
a e r o s o l o f t h e c a l c i u m s a l t ( 3 m g / r a t / e x p o s u r e ) 2 0 d a y s a f t e r i n h a l a t i o n o f
p l u t o n i u m n i t r a t e a n d a t f i v e s u b s e q u e n t w e e k l y i n t e r v a l s t h e r e w a s l i t t l e
e f f e c t o n p l u t o n i u m c l e a r a n c e f r o m t h e l u n g a l t h o u g h d e p o s i t i o n i n t h e
s k e l e t o n a n d l i v e r w a s r e d u c e d b y a b o u t 20% ( B a l l o u e t a l , 1 9 7 7 ) .
P a s q u i e r a n d D u c o u s s o ( 1 9 7 6 ) h a v e d e s c r i b e d a p e r s o n a l i n h a l a t i o n
s y s t e m f o r s e l f a d m i n i s t r a t i o n o f t h e c a l c i u m s a l t .
3 .U E f f e c t s o f DTPA a f t e r a e r o s o l a d m i n i s t r a t i o n
H i s t o l o g i c a l e x a m i n a t i o n h a s b e e n made o f t h e l u n g s o f r a t s a t i n t e r -
v a l s b e t w e e n 1 a n d 5 8 d a y s a f t e r e x p o s u r e t o a n a e r o s o l i s e d f o r m o f t h e
c a l c i u m s a l t o f DTPA (5.1+ mg k g " ) ( S t a t h e r e t a l , 1 9 7 6 ) . T h e r e w a s n o
e v i d e n c e o f a n y a b n o r m a l i t y i n t h e l u n g t i s s u e . T h i s i s i n c o n t r a s t t o
s t u d i e s r e p o r t e d b y S m i t h e t a l , (l3lG\ who d e s c r i b e d a t r a n s i t o r y
160
v e s i c u l a r e m p h y s e m a w i t h c o m p l e t e r e c o v e r y i n r a t s a n d h a m s t e r s e x p o s e d t o
a e r o s o l s o f t h e c a l c i u m s a l t f o r e i t h e r 1 o r 2 h o u r s 3 t i m e s i n 1 w e e k .
The d o s e i n t h e s e s t u d i e s r a n g e d f r o m 1 l i t o 2l± mg k g " 1 a t e a c h e x p o s u r e a n d
t h e t o t a l a m o u n t i n h a l e d i s a f a c t o r o f 8 t o 1 3 a b o v e t h e s t u d y b y S t a t h e r
e t a l , ( 1 9 7 6 ) . The r a t l u n g c a n r e c o v e r f r o m e v e n l a r g e r d o s e s o f t h e
c a l c i u m s a l t a s w a s s h o w n b y B a l l o u a n d B u s c h ( 1 9 7 2 ) who u s e d i n t r a t r a c h e a l - 1
i n j e c t i o n t o a d m i n i s t e r d o s e s o f b e t w e e n 1 7 0 a n d 3 9 0 mg k g t o r a t s . No
d e a t h s o c c u r r e d f r o m U d a i l y i n j e c t i o n s o f 1 7 0 mg k g . A t a c o n c e n t r a t i o n
o f 2 6 0 mg k g 90% s u r v i v e d e i t h e r t h e c a l c i u m o r z i n c s a l t o f DTPA; a t
d o s e s i n e x c e s s o f 2 6 0 mg k g " s u r v i v a l w a s a b o u t 50% a f t e r 3 d a i l y t r e a t -
m e n t s w i t h e i t h e r s a l t . A f t e r ii w e e k s r e c o v e r y , n o h i s t o l o g i c a l a l t e r a t i o n
w a s o b s e r v e d i n t h e l u n g s .
I n a f u r t h e r s t u d y ( S m i t h e t a l , 1 9 7 6 ) , d o g s w e r e e x p o s e d t o a n a e r o s o l
o f t h e c a l c i u m s a l t a t a n a v e r a g e e x p o s u r e d o s e o f 5 6 mg kg"" 1 g i v e n d a i l y f o r
5 d a y s . G r o u p s o f d o g s w e r e s a c r i f i c e d a t 1 , l i , 8 a n d 1 8 w e e k s a f t e r t h e
l a s t e x p o s u r e . H y p e r p l a s i a o f t h e g a s t r i c s u b m u c o s a l l y m p h o i d f o l l i c l e s
w a s o b s e r v e d i n 3 o u t o f k a n i m a l s t r e a t e d a t 1 w e e k f o l l o w i n g t h e l a s t
DTPA e x p o s u r e . No c h a n g e s w e r e s e e n a t l a t e r t i m e s a n d n o s i m i l a r c h a n g e s
w e r e s e e n i n c o n t r o l a n i m a l s . No e m p h y s e m a o f t h e t y p e o b s e r v e d i n r a t s
a n d h a m s t e r s w a s s e e n i n t h e d o g s a n d n o o t h e r s i g n i f i c a n t c h a n g e s w e r e
n o t e d .
I n human c a s e s i n w h i c h a e r o s o l DTPA h a s b e e n a d m i n i s t e r e d n o a d v e r s e
r e a c t i o n s h a v e b e e n n o t e d ( S a n d e r s , 1 9 7 4 a , J o l l y e t a l , 1 9 7 2 ) .
3 . 5 L o c a l t r e a t m e n t o f c o n t a m i n a t e d w o u n d s w i t h DTPA
F o r t h e t r e a t m e n t o f d e p o s i t s o f a c t i n i d e s i n wound s i t e s DTPA i s
u s u a l l y a d m i n i s t e r e d i n t r a v e n o u s l y . The p o s s i b i l i t y o f a g r e a t e r e f f e c t
a f t e r l o c a l a d m i n i s t r a t i o n i n c a s e s o f wound c o n t a m i n a t i o n h a s b e e n c o n -
s i d e r e d i n a n u m b e r o f e x p e r i m e n t a l s t u d i e s .
T a y l o r a n d Sowby ( 1 9 6 2 ) c o m p a r e d t h e e f f e c t o f i n t r a p e r i t o n e a l
i n j e c t i o n a n d l o c a l i n j e c t i o n o f DTPA o n t h e c l e a r a n c e o f P u - 2 3 9 f r o m a n
i n t r a m u s c u l a r s i t e o f i n j e c t i o n i n t h e h i n d l e g o f r a t s . DTPA ( 7 5 mg kg"" 1 )
w a s a d m i n i s t e r e d a t 1 h o u r a n d 21+ h o u r s a f t e r i n j e c t i o n o f 0 . 1 {iCi
( 3 . 7 k B q ) o f p l u t o n i u m - 2 3 9 n i t r a t e . The a m o u n t o f p l u t o n i u m - 2 3 9 r e m a i n i n g
a t t h e i n j e c t i o n s i t e a f t e r 7 d a y s w a s 63% o f c o n t r o l s a f t e r i n t r a -
p e r i t o n e a l i n j e c t i o n o f DTPA a n d 1 5 % o f c o n t r o l s a f t e r i n t r a m u s c u l a r
i n j e c t i o n . H o w e v e r , w h i l e s k e l e t a l u p t a k e w a s r e d u c e d t o 1 5 % o f c o n t r o l s
a f t e r l o c a l i n j e c t i o n c o m p a r e d w i t h 27% a f t e r s y s t e m i c i n j e c t i o n , l i v e r
161
u p t a k e w a s 58% o f c o n t r o l c o m p a r e d w i t h 2 1 % a f t e r s y s t e m i c i n j e c t i o n .
T h e s e r e s u l t s l e d t h e a u t h o r s t o d o u b t t h e v a l u e o f l o c a l i n j e c t i o n o f
DTPA.
More r e c e n t l y , V o l f ( 1 9 7 U > 1 9 7 5 ) h a s a d v o c a t e d t h e l o c a l
a d m i n i s t r a t i o n o f DTPA f o r t h e t r e a t m e n t o f p l u t o n i u m c o n t a m i n a t e d w o u n d s
o n t h e b a s i s o f f u r t h e r e x p e r i m e n t s w i t h r a t s . DTPA c a u s e d a n e n h a n c e d
c l e a r a n c e o f p l u t o n i u m f r o m t h e s i t e o f d e p o s i t i o n a n d a l o w e r l e v e l o f
d e p o s i t i o n i n o t h e r t i s s u e s i n a s e r i e s o f e x p e r i m e n t s . F o r i n s t a n c e ,
l o c a l i n j e c t i o n o f DTPA ( 5 0 0 mg k g " ) i n t o t h e t h i g h m u s c l e a t 1 h o u r a f t e r
i n j e c t i o n o f 0 . 5 \i0± ( 1 8 k B q ) o f p l u t o n i u m - 2 3 9 n i t r a t e r e s u l t e d i n a l e v e l
o f r e t e n t i o n a t t h e i n j e c t i o n s i t e a f t e r 8 d a y s o f 1 9 % o f c o n t r o l s a n d
l i v e r a n d s k e l e t a l u p t a k e o f 11+% a n d 16% o f c o n t r o l s , r e s p e c t i v e l y . Some
c o m b i n a t i o n s o f c h e l a t i n g a g e n t s w e r e f o u n d t o b e m o r e e f f e c t i v e t h a n DTPA
a l o n e . DTPA a n d c i t r a t e p r o v e d t h e m o s t e f f e c t i v e c o m b i n a t i o n t e s t e d i n
r e d u c i n g t h e o v e r a l l b o d y b u r d e n o f p l u t o n i u m - 2 3 9 * T h e i r i n j e c t i o n
( 2 5 0 mg kg"^ e a c h ) 1 h o u r a f t e r i n j e c t i o n o f 0 . 5 n-Ci ( 1 8 k B q ) o f p l u t o n i u m -
2 3 9 n i t r a t e r e s u l t e d i n r e t e n t i o n a t t h e i n j e c t i o n s i t e a f t e r 8 d a y s e q u a l
t o 1 2 % o f c o n t r o l s a n d l i v e r a n d s k e l e t a l u p t a k e o f 8% a n d 11% o f c o n t r o l s
r e s p e c t i v e l y .
S t u d i e s b y H a r r i s o n a n d D a v i d (19*77) u s i n g t h e c a l c i u m s a l t a t c o n -
c e n t r a t i o n s e q u i v a l e n t t o t h o s e u s e d i n human a c c i d e n t c a s e s h a v e a l s o s h o w n
t h a t l o c a l a d m i n i s t r a t i o n c a n b e m o r e e f f e c t i v e t h a n s y s t e m i c a d m i n i s t r a t i o n .
DTPA ( 1 5 mg k g " ; 0.1+ m l ) i n j e c t e d i n t o t h e t h i g h m u s c l e o f h a m s t e r s 1 5
m i n u t e s a f t e r i n j e c t i o n o f 8 n C i ( 3 0 0 B q ) o f p l u t o n i u m - 2 3 9 n i t r a t e r e d u c e d
t h e a c t i v i t y a t t h e s i t e o f i n j e c t i o n a t 7 d a y s t o 36% o f c o n t r o l s c o m p a r e d
w i t h 9l4% a f t e r i n t r a p e r i t o n e a l i n j e c t i o n . R e t e n t i o n i n t h e l i v e r a n d
s k e l e t o n w a s 65% a n d 38% o f c o n t r o l s , r e s p e c t i v e l y , c o m p a r e d w i t h 1 0 0 % a n d
66%, r e s p e c t i v e l y , a f t e r i n t r a p e r i t o n e a l i n j e c t i o n . The e f f e c t o f l o c a l
i n j e c t i o n w a s f o u n d t o b e much m o r e v a r i a b l e w h e n t h e same d o s e o f DTPA
w a s g i v e n i n a s m a l l e r v o l u m e o f s o l u t i o n ( 0 . 1 ml c o m p a r e d w i t h 0.1+ m l ) ,
p r e s u m a b l y d u e t o i n c o m p l e t e i n f i l t r a t i o n o f t h e p l u t o n i u m - 2 3 9 d e p o s i t b y
t h e DTPA. V o l f ( 1 9 7 6 ) h a s a l s o r e p o r t e d t h a t f o r t h e l o c a l a d m i n i s t r a t i o n
o f DTPA t o b e m a x i m a l l y e f f e c t i v e i t m u s t c o m p l e t e l y i n f i l t r a t e t h e wound
s i t e .
l+. Summary
B r o n c h o p u l m o n a r y l a v a g e i s t h e o n l y m e t h o d o f t r e a t m e n t t h a t h a s b e e n
s h o w n t o b e o f v a l u e f o r r e m o v i n g i n s o l u b l e r a d i o a c t i v e p a r t i c l e s
d e p o s i t e d i n t h e l u n g s . The t r e a t m e n t h a s b e e n s h o w n t o b e e f f e c t i v e
i n a n i m a l e x p e r i m e n t s b u t h a s b e e n u s e d o n l y o n c e i n man . The m a i n
l i m i t a t i o n i n t h e u s e o f t h i s t e c h n i q u e i s t h a t e a c h l a v a g e may r e m o v e
162
o n l y 20% o r l e s s o f t h e l u n g c o n t e n t . The v a l u e o f t h e t e c h n i q u e
w o u l d b e i n c r e a s e d c o n s i d e r a b l y i f t h e e f f i c i e n c y c o u l d b e i m p r o v e d .
F o r r e m o v i n g a c t i v i t y d e p o s i t e d a t a w o u n d s i t e t h e m o s t s a t i s f a c t o r y
t r e a t m e n t i s e x c i s i o n o f t h e c o n t a m i n a t e d t i s s u e .
I n t r a v e n o u s i n j e c t i o n o f DTPA i s t h e o n l y a c c e p t e d t h e r a p e u t i c m e t h o d
f o r r e m o v i n g s o l u b l e f o r m s o f a c t i n i d e s f r o m t h e b o d y . I t w i l l
e f f e c t i v e l y c l e a r a c t i n i d e s f r o m t h e s y s t e m i c c i r c u l a t i o n a n d some t h a t
h a s r e c e n t l y d e p o s i t e d i n b o n e a n d o t h e r t i s s u e s . I t i s u n a b l e t o
r e m o v e i n t r a c e l l u l a r d e p o s i t s o r a c t i v i t y t h a t h a s b e e n b u r i e d i n b o n e
a n d m u s t t h e r e f o r e b e a d m i n i s t e r e d s o o n a f t e r a n i n t a k e . The u s e o f
a n a e r o s o l i s e d f o r m o f DTPA may b e a c o n s i d e r a b l e a d v a n t a g e i n r e d u c i n g
t h e t i m e b e f o r e t r e a t m e n t i s g i v e n a n d f o r r e m o v i n g l u n g d e p o s i t s o f
s o l u b l e f o r m s o f a c t i n i d e s . L o c a l i n j e c t i o n o f DTPA i n t o c o n t a m i n a t e d
w o u n d s c a n r e m o v e m o r e p l u t o n i u m f r o m t h e b o d y t h a n t h e same a m o u n t
g i v e n i n t r a v e n o u s l y p r o v i d e d t h e DTPA c o m p l e t e l y i n f i l t r a t e s t h e wound
s i t e . A m e t h o d f o r r e m o v i n g b o t h i n t r a c e l l u l a r a n d s k e l e t a l d e p o s i t s
o f a c t i n i d e s i n man i s u r g e n t l y r e q u i r e d .
$ . A c k n o w l e d g e m e n t
The a u t h o r s w o u l d l i k e t o t h a n k D r . J . B r i g h t w e l l a n d D r . J . H a r r i s o n
f o r t h e i r h e l p i n t h e p r e p a r a t i o n o f t h i s C h a p t e r .
Chapter 9
A Q U A N T I T A T I V E ASSESSMENT OF T H E BIOLOGICAL CONSEQUENCES OF HUMAN EXPOSURE T O P L U T O N I U M , AMERICIUM
AND CURIUM
1 . I n t r o d u c t i o n
A p o p u l a t i o n may b e e x p o s e d t o p l u t o n i u m , a m e r i c i u m a n d c u r i u m i n
v a r i o u s w a y s f o l l o w i n g t h e i r r e l e a s e i n t o t h e e n v i r o n m e n t . P a r t i c l e s
c o n t a i n i n g t h e s e a c t i n i d e s c o u l d b e i n h a l e d , e i t h e r a s a r e s u l t o f
a i r b o r n e r e l e a s e s o r f o l l o w i n g t h e i r r e s u s p e n s i o n , o r c o n t a m i n a t e d f o o d -
s t u f f s o r w a t e r may b e c o n s u m e d . T h i s w o u l d r e s u l t i n i r r a d i a t i o n o f
e i t h e r t h e l u n g s o r g u t . A f r a c t i o n o f t h e s e i n c o r p o r a t e d r a d i o n u c l i d e s
w o u l d b e s o l u b l e i n t h e b o d y f l u i d s a n d t r a n s l o c a t e f r o m t h e s i t e o f e n t r y
t o b e d e p o s i t e d i n a n d i r r a d i a t e o t h e r t i s s u e s o f t h e b o d y i n p a r t i c u l a r t h e
l i v e r a n d s k e l e t o n . I n d i v i d u a l s a c c i d e n t a l l y e x p o s e d i n t h e c o u r s e o f t h e i r
w o r k may a l s o i n h a l e o r i n g e s t t h e s e a c t i n i d e s a n d i n some c a s e s t h e y may
e n t e r t h e b o d y t h r o u g h c u t s , a b r a s i o n s o r o t h e r w o u n d s .
D e p e n d i n g u p o n t h e r a d i a t i o n d o s e , b o t h e a r l y a n d l a t e s o m a t i c damage
c o u l d o c c u r i n t h e e x p o s e d p o p u l a t i o n , a n d h e r e d i t a r y e f f e c t s may o c c u r i n
t h e i r d e c e n d a n t s . T h i s d e v e l o p m e n t o f d o s e - e f f e c t r e l a t i o n s h i p s i s b a s e d
u p o n t h e l i m i t e d a m o u n t o f i n f o r m a t i o n a v a i l a b l e o n humans e x p o s e d t o
r a d i a t i o n s u p p l e m e n t e d b y e x p e r i m e n t a l d a t a o b t a i n e d f r o m a n i m a l s .
The s e v e r i t y o f damage t o t i s s u e s d e p e n d s u p o n t h e t y p e o f r a d i a t i o n .
The b i o l o g i c a l e f f e c t i v e n e s s o f r a d i a t i o n s w i t h a h i g h l i n e a r e n e r g y
t r a n s f e r (LET) ( e g , a l p h a p a r t i c l e s ) i s g e n e r a l l y g r e a t e r t h a n r a d i a t i o n s
w i t h a l o w LET ( e g , (3 p a r t i c l e s o r Y - r a y s ) . The r e l a t i v e b i o l o g i c a l
e f f e c t i v e n e s s (RBE) o f h i g h LET r a d i a t i o n c o m p a r e d w i t h l o w LET r a d i a t i o n
v a r i e s w i t h t h e s p e c i e s a n d t h e b i o l o g i c a l t e s t s y s t e m u s e d b u t i n g e n e r a l
i t i n c r e a s e s w i t h d e c r e a s i n g d o s e a n d d o s e r a t e ( I C R P , 1 9 7 2 ) . F o r t h e
c a l c u l a t i o n o f d o s e e q u i v a l e n t i n t i s s u e s f o r r a d i o l o g i c a l p r o t e c t i o n
p u r p o s e s t h e ICRP ( 1 9 7 7 ) h a s r e c o m m e n d e d t h a t t h e a b s o r b e d d o s e f r o m a l p h a
r a d i a t i o n s h o u l d b e m u l t i p l i e d b y a m o d i f y i n g f a c t o r ( q u a l i t y f a c t o r = Q)
o f 2 0 . A l t h o u g h t h i s m o d i f y i n g f a c t o r c a n n o t b e u s e d f o r a s s e s s i n g t h e
l i k e l y c o n s e q u e n c e s o f s e v e r e a c c i d e n t a l e x p o s u r e s , i t i s t o b e a p p l i e d f o r
e s t i m a t i n g t h e i n c i d e n c e o f b o t h l a t e e f f e c t s a n d h e r e d i t a r y e f f e c t s .
163
16k
2 . E a r l y s o m a t i c e f f e c t s
A i r b o r n e r e l e a s e s o f l a r g e a m o u n t s o f a c t i n i d e s may r e s u l t i n s e v e r e
l u n g d a m a g e . T h e r e a p p e a r s t o b e a t h r e s h o l d d o s e e q u i v a l e n t t o a n a v e r a g e
l u n g d o s e o f a b o u t 2000 r a d s (20 G y ; ( a l p h a ) i n a y e a r b e l o w w h i c h d e a t h
w o u l d n o t b e e x p e c t e d . Lung d o s e s i n excess o f t h i s may c a u s e o e d e m a , p n e u -
m o n i t i s a n d f i b r o s i s a n d e v e n t u a l l y r e s u l t i n d e a t h . D o s e s o f t h i s m a g n i t u d e
w o u l d n o t o c c u r e x c e p t a s a r e s u l t o f m a j o r a c c i d e n t a l r e l e a s e s a n d a r e
t h e r e f o r e n o t c o n s i d e r e d f u r t h e r . More i n f o r m a t i o n i s g i v e n i n C h a p t e r 6
o n t h e e a r l y e f f e c t s o f i n h a l e d a c t i n i d e s .
F o r d e p o s i t s o f a c t i n i d e s i n w o u n d s i t e s t h e r e i s i n s u f f i c i e n t i n f o r m -
a t i o n t o b e a b l e t o p r e d i c t t h e e f f e c t s t h a t may o c c u r a t t h e s i t e o f
d e p o s i t i o n . F i b r o u s n o d u l e s a r e t h e o n l y p a t h o l o g i c a l c h a n g e s t h a t h a v e
b e e n o b s e r v e d i n man a t s i t e s o f p l u t o n i u m d e p o s i t s i n w o u n d s o f b e t w e e n
a b o u t k a n d 200 n C i ( 0 . 1 5 kBq a n d 7 k B q ) ( C h a p t e r 3 ) .
3 . L a t e s o m a t i c e f f e c t s
3.1 I n t r o d u c t i o n
The m a j o r l a t e s o m a t i c e f f e c t o f r a d i a t i o n i n man i s c a n c e r . No
c l i n i c a l d i s t i n c t i o n c a n b e made b e t w e e n c a n c e r s i n d u c e d i n t h e p o p u l a t i o n
b y r a d i a t i o n a n d t h o s e r e s u l t i n g f r o m o t h e r c a u s e s .
The r i s k o f r a d i a t i o n - i n d u c e d m a l i g n a n t d i s e a s e h a s b e e n s u m m a r i s e d
i n v a r i o u s r e v i e w s ( I C R P , 1966c; D o l p h i n a n d M a r l e y , 1969; BEIR, 1972;
N a t i o n a l Academy o f S c i e n c e s , 197U; R a s m u s s e n , 1975; NCRP, 1975; MRC,
1975; T h o m e a n d V e n n a r t , 1976; S m i t h a n d S t a t h e r , 1976; ICRP, 1 9 7 7 ) .
T h e r e a r e c o n s i d e r a b l e d i f f i c u l t i e s i n v o l v e d i n a t t e m p t i n g t o e s t a b l i s h
e s t i m a t e s o f r i s k o f p r o d u c i n g c a n c e r i n d i f f e r e n t t i s s u e s . No d e f i n i t i v e
i n f o r m a t i o n i s a v a i l a b l e o n t h e m e c h a n i s m o f c a r c i n o g e n e s i s i n man a n d t h e
d a t a a v a i l a b l e o n c a n c e r i n c i d e n c e u s u a l l y r e l a t e t o r e l a t i v e l y s m a l l
g r o u p s o f p e o p l e e x p o s e d t o h i g h d o s e s o f r a d i a t i o n a t h i g h d o s e r a t e s .
I n m o s t c a s e s , t h e r e f o r e , i t i s n e c e s s a r y t o e x t r a p o l a t e t h e d a t a t o o b t a i n
some a s s e s s m e n t o f t h e a n t i c i p a t e d r i s k o f c a n c e r f r o m e x p o s u r e o f
r e l a t i v e l y l a r g e p o p u l a t i o n s t o l o w d o s e s o f r a d i a t i o n a t l o w d o s e r a t e s .
I n t h i s r e p o r t a l i n e a r , n o - t h r e s h o l d m o d e l h a s b e e n a d o p t e d i n w h i c h t h e
p r o b a b i l i t y o f c a n c e r d e a t h i s c o n s i d e r e d t o b e d i r e c t l y p r o p o r t i o n a l t o
t h e t o t a l d o s e ( I C R P , 1 9 7 7 ) .
N u m e r i c a l e s t i m a t e s o f r i s k a r e e x p r e s s e d i n a b s o l u t e t e r m s . The
a b s o l u t e r i s k i s t h e d i f f e r e n c e b e t w e e n t h e r i s k i n t h e i r r a d i a t e d p o p u l a -
t i o n a n d t h e r i s k i n a c o m p a r a b l e n o n - i r r a d i a t e d p o p u l a t i o n . U s i n g t h e
l i n e a r , n o - t h r e s h o l d , d o s e - i n c i d e n c e m o d e l , t h e a b s o l u t e c a n c e r r i s k c a n
165
b e e x p r e s s e d a s e i t h e r t h e n u m b e r o f e x c e s s c a n c e r s d e v e l o p i n g p e r u n i t o f
t i m e i n a n e x p o s e d p o p u l a t i o n p e r u n i t o f d o s e ( e g , c a n c e r s p e r 1 0 ^ man r a d
p e r y e a r ) o r t h e t o t a l n u m b e r o f e x c e s s c a n c e r s t h a t w o u l d b e e x p e c t e d t o
d e v e l o p d u r i n g t h e r e s t o f t h e i r r a d i a t e d p e r s o n ' s e x p e c t e d l i f e s p a n
( e g , c a n c e r s p e r 1 0 ^ man r a d ) . A l i m i t a t i o n o f t h i s a p p r o a c h i s t h a t i t
a s s u m e s t h a t t h e r e i s n o s y n e r g i s t i c e f f e c t b e t w e e n t h e r a d i a t i o n a n d a n y
o t h e r c a n c e r - i n i t i a t i n g o r p r o m o t i n g a g e n t . H o w e v e r , a b s o l u t e r i s k e s t i -
m a t e s p r o v i d e t h e m o s t a p p r o p r i a t e i n d i c a t i o n o f t h e i m p a c t o n a p o p u l a t i o n
r e s u l t i n g f r o m e x p o s u r e t o r a d i a t i o n b e c a u s e t h e y s p e c i f y d i r e c t l y t h e
n u m b e r o f p e r s o n s a f f e c t e d ( I C R P , 1 9 ^ 9 ) .
T h e r e i s e x t e n s i v e i n f o r m a t i o n a v a i l a b l e i n t h e l i t e r a t u r e o n c a n c e r
i n c i d e n c e i n a n i m a l s f o l l o w i n g e x p o s u r e t o r a d i a t i o n . H o w e v e r , a s t h e
h i s t o l o g i c a l t y p e s o f c a n c e r t h a t o c c u r i n e x p e r i m e n t a l a n i m a l s may d i f f e r
f r o m t h o s e c o m m o n l y s e e n i n m a n , a n d a s t h e r e a r e s p e c i e s d i f f e r e n c e s i n
r a d i o s e n s i t i v i t y , a n i m a l d a t a t o e s t i m a t e r i s k s f o r man m u s t b e u s e d w i t h
e x t r e m e c a u t i o n . O n l y human d a t a h a v e t h e r e f o r e b e e n u s e d f o r c a l c u l a t i n g
r i s k c o e f f i c i e n t s f o r l a t e s o m a t i c e f f e c t s o f r a d i a t i o n . T h e r e a r e n o d a t a
o n t h e d e v e l o p m e n t o f c a n c e r i n humans a s a r e s u l t o f i n c o r p o r a t i o n o f
p l u t o n i u m , a m e r i c i u m o r c u r i u m i s o t o p e s . E s t i m a t e s o f r i s k h a v e t h e r e f o r e
b e e n b a s e d m a i n l y o n t h e r e s u l t s o f e p i d e m i o l o g i c a l s t u d i e s o n humans
e x p o s e d t o e x t e r n a l r a d i a t i o n . Some i n f o r m a t i o n i s a l s o a v a i l a b l e o n t h e
d e v e l o p m e n t o f b o n e a n d l i v e r c a n c e r s a s a r e s u l t o f i n t a k e s o f a l p h a
e m i t t e r s .
E s t i m a t e s o f r i s k c o e f f i c i e n t s h a v e b e e n made f o r r a d i a t i o n - i n d u c e d
d e a t h s f r o m l e u k a e m i a a n d c a n c e r s o f l u n g , b o n e , l i v e r a n d g a s t r o i n t e s t i n a l
t r a c t . I n g e n e r a l , t h e v a l u e s g i v e n a r e r o u n d e d s o a s n o t t o i m p l y
g r e a t e r a c c u r a c y t h a n t h e d a t a a v a i l a b l e j u s t i f y . B e c a u s e o f t h e
l a c k o f human d a t a n o c o r r e c t i o n s a r e r e c o m m e n d e d f o r a n y p o s s i b l e
v a r i a t i o n i n e f f e c t i v e n e s s o f r a d i a t i o n w i t h d i f f e r e n t d o s e s a n d d o s e
r a t e s ( T a b l e 9 . 1 ) •
3 . 2 L e u k a e m i a
The i n d u c t i o n o f l e u k a e m i a b y i o n i s i n g r a d i a t i o n s h a s b e e n d e m o n s t r a t e d
i n a n u m b e r o f e p i d e m i o l o g i c a l s t u d i e s i n man.
I n t h e J a p a n e s e s u r v i v o r s , a t H i r o s h i m a a n d N a g a s a k i , J a b l o n a n d K a t o
( 1 9 7 2 ) f o u n d a n e x c e s s o f l e u k a e m i a s w a s a p p a r e n t b y 5 y e a r s a f t e r e x p o s u r e
s o t h a t t h e l a t e n t p e r i o d f o r r a d i a t i o n - i n d u c e d l e u k a e m i a i s 5 y e a r s o r
p o s s i b l y l e s s . B a s e d o n a n RBE o f 5 f o r n e u t r o n s , a r i s k e s t i m a t e
166
T a b l e 9 , 1
R i s k c o e f f i c i e n t s f o r d e a t h s f r o m c a n c e r
T i s s u e a t R i s k E f f e c t C a n c e r d e a t h s p e r
10° man r a d a l p h a
Lung
L i v e r
C e l l s o n e n d o s t e a l s u r f a c e s 1
B o n e marrow
G . I . t r a c t
Lung C a n c e r
L i v e r C a n c e r
B o n e C a n c e r
L e u k a e m i a
G . I . t r a c t c a n c e r
1*00°
1 0 0 d
1 0 0 d
1+00°
1+00°
a . T h e s e r i s k c o e f f i c i e n t s c a n b e c o n s i d e r e d t o a p p l y t o d o s e s r e c e i v e d o v e r a s h o r t p e r i o d ( e g , 1 y e a r ) c o m p a r e d w i t h t h e p l a t e a u p e r i o d f o r c a n c e r i n d u c t i o n .
b # The r i s k c o e f f i c i e n t a p p l i e s t o d o s e s t o t h e o s t e o -p r o g e n i t o r c e l l s , a s s u m e d t o b e w i t h i n 10 im o f t h e e n d o s t e a l s u r f a c e o f b o n e .
c . D e r i v e d f r o m f o l l o w - u p s t u d i e s o n humans e x p o s e d p r e d o m i n a n t l y t o l o w LET r a d i a t i o n . The r i s k c o e f f i c i e n t s c a l c u l a t e d h a v e b e e n m u l t i p l i e d b y a q u a l i t y f a c t o r o f 20 f o r a l p h a r a d i a t i o n .
d . D e r i v e d f r o m f o l l o w - u p s t u d i e s o n humans e x p o s e d p r e d o m i n a n t l y t o a l p h a i r r a d i a t i o n .
e . R i s k c o e f f i c i e n t s f o r d e a t h s f r o m c a n c e r s o f t h e l u n g , c e l l s o n e n d o s t e a l s u r f a c e s a n d b o n e marrow a r e c o n s i s t e n t w i t h t h o s e g i v e n i n ICRP P u b l i c a t i o n 2 6 , 1 9 7 7 * No s p e c i f i c r i s k c o e f f i c i e n t s a r e g i v e n b y ICRP f o r t h e l i v e r a n d t h e g a s t r o i n t e s t i n a l t r a c t .
167
e q u i v a l e n t t o a b o u t o n e l e u k a e m i a p e r y e a r p e r 1 0 ^ man r a d ( 1 0 ^ man Gy)
( l o w LET) o v e r a 2 0 - y e a r p e r i o d h a s b e e n c a l c u l a t e d ( B E I R , 1 9 7 2 ) . G o s s
( 1 9 7 U ) h a s c a l c u l a t e d a r i s k c o e f f i c i e n t o f 30 l e u k a e m i a s p e r 1 0 ^ man r a d
( 1 0 ^ man Gy) ( l o w LET) f o r a p o p u l a t i o n w i t h a s t a n d a r d a g e d i s t r i b u t i o n .
I n a s t u d y o f p a t i e n t s t r e a t e d w i t h X - r a y s f o r a n k y l o s i n g s p o n d y l i t i s ,
a n e x c e s s o f l e u k a e m i a w a s o b s e r v e d ( C o u r t Brown a n d D o l l , 1 9 6 5 ) . The
p e r i o d o f f o l l o w - u p r a n g e d u p t o 2 7 y e a r s w i t h a m e a n t i m e o f 1 1 . 5 y e a r s .
B a s e d o n a m e a n d o s e t o li0% o f t h e s p i n a l marrow o f a b o u t 8 8 0 r a d ( 8 . 8 G y )
( l o w L E T ) , a r i s k o f a b o u t 1 0 l e u k a e m i a s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w
LET) h a s b e e n c a l c u l a t e d ( D o l p h i n a n d M a r l e y , 1 9 6 9 ) . T h i s e s t i m a t e w o u l d
b e e x p e c t e d t o i n c r e a s e w i t h a l o n g e r f o l l o w - u p . An e x c e s s o f l e u k a e m i a s
h a s a l s o b e e n f o u n d i n p a t i e n t s t r e a t e d b y X - i r r a d i a t i o n t o i n d u c e
a r t i f i c i a l m e n o p a u s e o r f o r o t h e r g y n a e c o l o g i c a l c o n d i t i o n s , S m i t h a n d
D o l l ( 1 9 7 6 ) . Prom t h e d a t a t h e y e s t i m a t e d a n e x c e s s r a t e o f l e u k a e m i a i n
women i n t h e f i r s t 2 0 y e a r s a f t e r t r e a t m e n t o f a b o u t 2 2 p e r 1 0 ^ man r a d
( 1 0 ^ man G y ) ( l o w L E T ) .
A l l t h e s e s t u d i e s a r e i n r e a s o n a b l e a g r e e m e n t a n d i n d i c a t e a r i s k
c o e f f i c i e n t o f a b o u t 2 0 l e u k a e m i a s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w L E T ) .
F o r a l p h a i r r a d i a t i o n t h i s e s t i m a t e c o u l d b e m u l t i p l i e d b y 2 0 ( = Q)
3 . 3 Lung c a n c e r
The BEIR r e p o r t ( 1 9 7 2 ) g i v e s a n e s t i m a t e o f a b o u t 1 . 2 c a s e s o f l u n g
c a n c e r p e r 1 0 ^ p e r r a d ( 1 0 ^ p e r Gy) ( l o w LET) p e r y e a r f o r p a t i e n t s
t r e a t e d f o r a n k y l o s i n g s p o n d y l i t i s w i t h a m e a n f o l l o w - u p t i m e o f 1 1 . 5
y e a r s . I n f o r m a t i o n i s a l s o a v a i l a b l e o n r a d i a t i o n i n d u c e d l u n g c a n c e r i n
J a p a n e s e s u r v i v o r s . I n H i r o s h i m a a l l d o s e g r o u p s a b o v e 1 0 r a d s h a d h i g h e r
m o r t a l i t y r a t i o s t h a n t h e 0 - 9 r a d ( 0 - 0 . 0 9 Gy) d o s e g r o u p b u t i n N a g a s a k i
t h e 0 - 9 r a d ( 0 - 0 . 0 9 G y ) d o s e g r o u p h a d m o r t a l i t y f a r i n e x c e s s o f
e x p e c t a t i o n a t n a t i o n a l r a t e s ( a n i n c r e a s e o f 72%) a n d t h e r e w e r e n o
s i g n i f i c a n t d i f f e r e n c e s among t h e d o s e g r o u p s . I n t h e a b s e n c e o f d a t a o n
s m o k i n g a n d o n t h e e f f e c t s o f h i g h LET n e u t r o n i r r a d i a t i o n o n t h e r e s p i r a -
t o r y s y s t e m , t o w h i c h t h e p o p u l a t i o n a t H i r o s h i m a w a s e x p o s e d , i t i s t h e r e -
f o r e d i f f i c u l t t o i n t e r p r e t t h e d a t a . The BEIR r e p o r t ( 1 9 7 2 ) g i v e s a n
e s t i m a t e o f 0 . 6 c a s e s p e r 1 0 ^ p e r r a d ( 1 0 ^ p e r G y ) ( l o w LET) p e r y e a r
( b a s e d o n a n RBE f o r n e u t r o n s o f 5 ) f o r t h e J a p a n e s e s u r v i v o r s , i n r e a s o n -
a b l e a g r e e m e n t w i t h t h e e s t i m a t e o f 1 2 - i i O c a s e s p e r 1 0 ^ p e r r a d ( 1 0 ^ p e r
G y ) ( l o w LET) o v e r 2 5 y e a r s g i v e n i n t h e UNSCEAR r e p o r t ( 1 9 7 2 ) f o r
J a p a n e s e s u r v i v o r s .
168
R a d i a t i o n - i n d u c e d l u n g c a n c e r i n man h a s a l s o b e e n o b s e r v e d i n s t u d i e s
o n m i n e r s e x p o s e d t o r a d o n a n d i t s d a u g h t e r s ( A r c h e r a n d L u n d i n , 1967 , S e v c
e t a l , 1 9 7 6 ) . H o w e v e r , t h e r e a r e c o n s i d e r a b l e d i f f i c u l t i e s i n e s t i m a t i n g
r i s k c o e f f i c i e n t s f r o m t h e s e d a t a b e c a u s e o f p r o b l e m s i n a s s e s s i n g w h a t
e x p o s u r e s t o r a d o n d a u g h t e r s h a v e a c t u a l l y o c c u r r e d a n d b e c a u s e c a n c e r r i s k
i s u s u a l l y e x p r e s s e d i n t e r m s o f t h e d o s e t o t h e b r o n c h i a l e p i t h e l i u m
r a t h e r t h a n a v e r a g e l u n g d o s e . The i n c i d e n c e o f l u n g c a n c e r i n man i s a l s o
i n f l u e n c e d b y t o b a c c o s m o k i n g ( A r c h e r e t a l , 1973) a n d b y t h e i n h a l a t i o n o f
o t h e r e n v i r o n m e n t a l c o n t a m i n a n t s s u c h a s b e n z p y r e n e o r o c c u p a t i o n a l e x p o s u r e
t o a s b e s t o s f i b r e , a r s e n i c , n i c k e l , o r i r o n a n d i r o n o x i d e s ( S p e n c e r , 1 9 7 3 ) .
F u r t h e r m o r e , t h e h i s t o l o g i c a l t y p e s o f c a n c e r f o u n d i n t h e m i n e r s show a n
i n c r e a s e d i n c i d e n c e o f t h e s m a l l c e l l a n d u n d i f f e r e n t i a t e d t y p e s ( S a c c o m a n n o
e t a l , 1971) w h e r e a s t h o s e f o u n d i n t h e J a p a n e s e s u r v i v o r s a r e m a i n l y
s q u a m o u s c a r c i n o m a a n d a d e n o c a r c i n o m a s (UNSCEAR, 19^2) • I t i s n o t known
w h e t h e r l u n g t u m o u r s i n man i n d u c e d b y i n h a l e d a c t i n i d e s w o u l d o c c u r m a i n l y
i n t h e p e r i p h e r y o f t h e l u n g a s o c c u r s i n d o g s a n d r o d e n t s o r i n t h e m a i n
b r o n c h i , b u t r i s k c o e f f i c i e n t s b a s e d o n f o l l o w u p s t u d i e s i n m i n e r s a r e n o t
a p p r o p r i a t e f o r e s t i m a t i n g r i s k c o e f f i c i e n t s f o r t h e l u n g t h a t c a n b e
a p p l i e d t o a v e r a g e l u n g d o s e s c a l c u l a t e d f o r i n h a l e d l o n g - l i v e d r a d i o -
n u c l i d e s d e p o s i t e d i n t h e p u l m o n a r y r e g i o n o f t h e l u n g .
B a s e d o n t h e d a t a f r o m t h e J a p a n e s e s u r v i v o r s a n d p a t i e n t s t r e a t e d f o r
a n k y l o s i n g s p o n d y l i t i s , a r i s k c o e f f i c i e n t o f 20 c a n c e r s p e r 10^ man r a d
(10^ man Gy) ( l o w LET) i s r e c o m m e n d e d , a l t h o u g h i t i s p o s s i b l e t h a t t h i s
v a l u e may i n c r e a s e w i t h a l o n g e r f o l l o w - u p o f t h e e x p o s e d p o p u l a t i o n s . F o r
a l p h a i r r a d i a t i o n t h i s e s t i m a t e c o u l d b e m u l t i p l i e d b y 20 ( = Q ) .
3«U B o n e c a n c e r
Human d a t a o n b o n e c a n c e r i n d u c e d b y a l p h a i r r a d i a t i o n i s a v a i l a b l e
f r o m l o n g - t e r m s t u d i e s o n o v e r 1700 p e o p l e e x p o s e d t o r a d i u m b e t w e e n a b o u t
1910 a n d 1930 . The f o l l o w - u p o n t h e s e c a s e s now e x t e n d s t o m o r e t n a n 50
y e a r s a f t e r t h e i n i t i a l i n t a k e . I n t h e s t u d y p o p u l a t i o n , 5U b o n e c a n c e r s
a n d 27 c a n c e r s o f t h e p a r a n a s a l s i n u s e s o r m a s t o i d s h a v e o c c u r r e d ( f i v e
p e r s o n s d e v e l o p e d b o t h ) ( R o w l a n d , 1 9 7 5 ) . A l t h o u g h t h e r e a r e d i f f i c u l t i e s
i n e s t i m a t i n g t h e d o s e t o t h e s k e l e t o n f r o m d e p o s i t e d r a d i u m ( I C R P , 1968)
t h e d a t a h a v e b e e n i n t e r p r e t e d b y R o w l a n d (1975) u s i n g t h e N o r r i s r e t e n t i o n
f u n c t i o n (1955) a n d a v e r a g e b o n e d o s e s h a v e b e e n c a l c u l a t e d .
D o l p h i n (1976b) s h o w e d t h a t w h e n t h e d a t a a r e g r o u p e d i n t o d o s e r a n g e s
t h e r i s k c o e f f i c i e n t f o r b o n e c a n c e r i n t h o s e p e o p l e w i t h a n a v e r a g e b o n e
d o s e o v e r 1 0 , 0 0 0 r a d (100 G y ) ( a l p h a ) w a s a b o u t h a l f t h a t o f t h o s e i n t h e
l o w e r d o s e g r o u p . T h i s r e d u c t i o n c o u l d b e d u e t o t h e l o s s o f r e p r o d u c t i v e
169
c a p a c i t y o f p o t e n t i a l l y m a l i g n a n t c e l l s . By f i t t i n g a l i n e a r f u n c t i o n t o
t h e d a t a g i v e n b y R o w l a n d ( 1 9 7 5 ) o n a v e r a g e d o s e t o b o n e a n d b o n e s a r c o m a
i n c i d e n c e f o r t h e c a s e s w i t h a v e r a g e b o n e d o s e s b e l o w 1 0 , 0 0 0 r a d ( 1 0 0 Gy)
( a l p h a ) a r i s k c o e f f i c i e n t o f 5 3 b o n e s a r c o m a s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy)
( a l p h a ) w a s o b t a i n e d . T h i s v a l u e i s i n a g r e e m e n t w i t h t h e v a l u e q u o t e d b y
Mays e t a l , ( 1 9 7 6 ) a n d i s e q u i v a l e n t t o a r i s k o f a b o u t 1 0 6 b o n e s a r c o m a s
p e r 1 0 ^ man r a d ( 1 0 ^ man G y ) ( a l p h a ) i f t h e r i s k c o e f f i c i e n t i s b a s e d o n
t h e d o s e t o t h e s e n s i t i v e c e l l s a d j a c e n t t o t h e e n d o s t e a l s u r f a c e o f b o n e
w h i c h r e c e i v e d a b o u t h a l f t h e a v e r a g e b o n e d o s e ( I C R P , 1 9 6 8 ) . W i t h a l o n g e r
f o l l o w - u p f u r t h e r t u m o u r s may o c c u r . H o w e v e r , m o r e t h a n 90% o f t h e 5 0 - y e a r
d o s e f r o m r a d i u m - 2 2 8 i s r e c e i v e d b y 1 5 y e a r s a f t e r e x p o s u r e a n d , i n t h e
c a s e o f r a d i u m - 2 2 6 , a b o u t o n e - t h i r d o f t h e 5 0 - y e a r d o s e i s r e c e i v e d i n t h e
f i r s t 8 y e a r s a n d a b o u t o n e - h a l f i n t h e f i r s t 1 5 y e a r s ( A d a m s , 1 9 7 6 ) . The
a p p e a r a n c e o f f u r t h e r c a n c e r s w o u l d t h e r e f o r e b e u n l i k e l y t o h a v e a s i g n i -
f i c a n t e f f e c t o n t h e o v e r a l l r i s k c o e f f i c i e n t . B a s e d o n t h e i n f o r m a t i o n
c u r r e n t l y a v a i l a b l e a r i s k c o e f f i c i e n t f o r b o n e c a n c e r o f 1 0 0 c a n c e r s p e r
1 0 ^ man r a d ( 1 0 ^ man G y ) ( a l p h a ) i s t h e r e f o r e r e c o m m e n d e d . I t s h o u l d b e
n o t e d t h a t t h e d o s e i s c a l c u l a t e d f o r t h e o s t e o p r o g e n i t o r c e l l s a s s u m e d
t o b e w i t h i n 1 0 ^m o f t h e e n d o s t e a l s u r f a c e s o f b o n e .
3 . 5 L i v e r c a n c e r
D a t a o n l i v e r c a n c e r i n d u c t i o n a s a r e s u l t o f a l p h a i r r a d i a t i o n i s
a v a i l a b l e f r o m p a t i e n t s t r e a t e d w i t h a n a q u e o u s s u s p e n s i o n o f t h e o x i d e s
o f t h o r i u m - 2 3 2 e n r i c h e d w i t h t h o r i u m - 2 3 0 ( T h o r o t r a s t ) . T h e s e d a t a c a n b e
u s e d t o o b t a i n a p r o v i s i o n a l e s t i m a t e o f l i v e r c a n c e r r i s k . T h o r o t r a s t
d o s i m e t r y i s a p r o b l e m o f g r e a t c o m p l e x i t y d u e t o i n c o m p l e t e k n o w l e d g e o f
t h e p h y s i c o c h e m i c a l a n d b i o l o g i c a l f a c t o r s a f f e c t i n g r a d i a t i o n d o s e t o t h e
l i v e r c e l l s . K a u l ( 1 9 7 3 ) h a s e s t i m a t e d m e a n o r g a n d o s e r a t e s i n man
f o l l o w i n g t h e i n j e c t i o n o f v a r y i n g v o l u m e s o f T h o r o t r a s t w h i c h make
a l l o w a n c e f o r s e l f - a b s o r p t i o n i n t h e T h o r o t r a s t p a r t i c l e s . F a b e r ( 1 9 7 3 a ,
1 9 7 3 ° ) n a s p u b l i s h e d d a t a o n a s e r i e s o f D a n i s h p a t i e n t s t r e a t e d w i t h
T h o r o t r a s t . A t o t a l o f 2 8 l i v e r c a n c e r s ( 1 7 h e p a t o c a r c i n o m a s a n d 1 1
h a e m a n g i © e n d o t h e l i o m a s ) w e r e r o u n d i n 7 5 6 p a t i e n t s w h e r e a s o n l y o n e w a s
e x p e c t e d . The a v e r a g e f o l o w - u p t i m e i n t h e s t u d y w a s a b o u t 30 y e a r s . The
r i s k o f d e v e l o p i n g l i v e r c a n c e r i n t h e s t u d y p o p u l a t i o n h a s b e e n c a l c u l a t e d
a s Ik c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( a l p h a ) ( S m i t h a n d S t a t h e r ,
1 9 7 6 ) .
B e c a u s e o f t h e p r o t r a c t e d d o s e f r o m T h o r o t r a s t , f u r t h e r c a n c e r s may
o c c u r w i t h a l o n g e r f o l l o w - u p t i m e . H o w e v e r , b e c a u s e o f t h e p r o g r e s s i v e
a g g r e g a t i o n o f T h o r o t r a s t p a r t i c l e s a n d t h e c o n s e q u e n t r e d u c t i o n i n t h e
170
m e a n a l p h a d o s e r a t e t o t h e l i v e r w i t h t i m e , a b o u t 65% o f t h e 2 0 - y e a r d o s e
i s a c c u m u l a t e d o v e r t h e f i r s t 1 0 y e a r s a f t e r a d m i n i s t r a t i o n ( K a u l , 1 9 6 ! + ) .
A f u r t h e r i m p o r t a n t f a c t o r i s t h a t e s t i m a t e s o f r i s k may b e f a l s e l y h i g h
i f t h e c h e m i c a l p r o p e r t i e s o f t h o r i u m make i t c a r c i n o g e n i c . I n v i e w o f t h i s
c o n s i d e r a t i o n , t o g e t h e r w i t h c o n s i d e r a b l e u n c e r t a i n t i e s i n T h o r o t r a s t d o s i -
m e t r y a n d t h e l a c k o f i n f o r m a t i o n o n t h e l a t e n t p e r i o d f o r r a d i a t i o n -
i n d u c e d l i v e r c a n c e r ( p o s s i b l y 1 0 - 2 0 y e a r s ) , a r i s k c o e f f i c i e n t w i t h a
r o u n d e d v a l u e o f 1 0 0 c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man G y ) ( a l p h a ) i s
r e c o m m e n d e d .
3 . 6 G a s t r o i n t e s t i n a l t r a c t c a n c e r
V e r y l i t t l e i n f o r m a t i o n i s a v a i l a b l e o n w h i c h t o e s t i m a t e t h e r i s k o f
c a n c e r i n t h e g a s t r o i n t e s t i n a l t r a c t .
B a s e d o n a f o l l o w - u p s t u d y o n t h e J a p a n e s e s u r v i v o r s , a r i s k c o e f f i -
c i e n t f o r t h e s t o m a c h a n d l a r g e b o w e l o f 0 . 5 2 c a n c e r s p e r y e a r p e r 1 0 ^ man
r a d ( 1 0 ^ man G y ) ( l o w LET) ( a s s u m i n g a n RBE f o r n e u t r o n s o f 5 ) h a s b e e n
c a l c u l a t e d ( B E I R , 1 9 7 2 ) . T h i s w o u l d b e e q u i v a l e n t t o a b o u t 1 3 c a n c e r s p e r
1 0 ^ man r a d ( 1 0 ^ man G y ) ( l o w LET) o v e r 2 5 y e a r s .
S m i t h a n d D o l l ( 1 9 7 6 ) h a v e r e p o r t e d a n e x c e s s o f c a n c e r s o f t h e
i n t e s t i n e s , e x c l u d i n g r e c t u m , i n a f o l l o w - u p s t u d y o n women t r e a t e d b y
X - i r r a d i a t i o n o f t h e l o w e r a b d o m e n t o i n d u c e m e n o p a u s e . No t i s s u e d o s e s
w e r e c a l c u l a t e d b u t a m e a n d o s e o f a b o u t 6 0 0 r a d ( 6 G y ) ( l o w LET) ( D o l l
a n d S m i t h , 1 9 6 8 ) , p o s s i b l y t o a b o u t o n e - t h i r d o f t h e i n t e s t i n e , g i v e s a n
e s t i m a t e d r i s k o f a b o u t 21+ c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w LET)
( S m i t h a n d S t a t h e r , 1 9 7 6 ) .
B r i n k l e y a n d H a y b i t t l e ( 1 9 6 9 ) o b s e r v e d e x c e s s d e a t h s f r o m t u m o u r s o f
t h e r e c t u m a n d i n t e s t i n e i n a f o l l o w - u p o f p a t i e n t s g i v e n p r e v i o u s t h e r a -
p e u t i c i r r a d i a t i o n f o r t h e i n d u c t i o n o f a r t i f i c i a l m e n o p a u s e . B a s e d o n a n
e s t i m a t e d m e a n e x p o s u r e o f 8 0 0 r a d ( 8 Gy) t o t h e r e c t u m a n d o n e - h a l f o f
t h i s d o s e t o t h e l a r g e i n t e s t i n e , P o c h i n ( 1 9 7 2 ) h a s e s t i m a t e d a r i s k o f 2 7
c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man G y ) ( l o w L E T ) . F o r t h e r e c t u m a l o n e
( t h r e e o b s e r v e d c a s e s , 0 . 5 e x p e c t e d ) a n y e s t i m a t e w o u l d b e v e r y i m p r e c i s e .
S m i t h a n d D o l l ( 1 9 7 6 ) f o u n d a n e x c e s s o f c a n c e r s o f t h e r e c t u m i n a
f o l l o w - u p o f p a t i e n t s t r e a t e d b y X - i r r a d i a t i o n t o i n d u c e a r t i f i c i a l m e n o -
p a u s e . B a s e d o n a n e s t i m a t e d m e a n e x p o s u r e d o s e t o t h e r e c t u m o f a b o u t
6 0 0 r a d ( 6 Gy) ( D o l l a n d S m i t h , 1 9 6 8 ) , t h i s c o r r e s p o n d s t o a p o s s i b l e r i s k
o f a b o u t t w o c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man G y ) ( l o w LET) ( S m i t h a n d
S t a t h e r , 1 9 7 7 ) .
171
The e v i d e n c e o n w h i c h t o b a s e e s t i m a t e s o f t h e r i s k c o e f f i c i e n t f o r
r a d i a t i o n - i n d u c e d c a n c e r o f t h e g a s t r o i n t e s t i n a l t r a c t i s t h e r e f o r e very -
l i m i t e d . H o w e v e r , t h e s e d a t a w o u l d s u g g e s t t h a t , u n t i l f u r t h e r e v i d e n c e
i s a v a i l a b l e , i t w o u l d b e a p p r o p r i a t e t o u s e a v a l u e o f 2 0 c a n c e r s p e r 1 0
man r a d ( 1 0 ^ man G y ) ( l o w L E T ) . F o r a l p h a i r r a d i a t i o n t h i s e s t i m a t e c o u l d
b e m u l t i p l i e d b y 2 0 ( = Q ) . D o s e s a r e t h o s e a b s o r b e d b y t h e m u c o s a l c e l l
l a y e r . F o r a l p h a a c t i v i t y i n t h e g u t l u m e n t h e d o s e t o t h e m u c o s a l l a y e r
may b e t a k e n t o b e 1 % o f t h a t a t t h e s u r f a c e o f t h e g u t c o n t e n t s . A l t h o u g h
t h i s i s a r a t h e r a r b i t r a r y v a l u e t h e r e i s some e x p e r i m e n t a l e v i d e n c e t h a t
i t s u s e i s w a r r a n t e d ( S u l l i v a n e t a l , i 9 6 0 ) .
1+. H e r e d i t a r y E f f e c t s
i | . 1 The o c c u r r e n c e o f h e r e d i t a r y d i s e a s e s
Damage t o t h e g e r m c e l l s c a n r e s u l t i n s p o n t a n e o u s a b o r t i o n o r
h e r e d i t a r y d i s e a s e . The r i s k o f a b o r t i o n i s d i f f i c u l t t o q u a n t i f y b e c a u s e
many o c c u r s o e a r l y i n p r e g n a n c y a s t o b e u n d e t e c t a b l e . F o r t h i s r e a s o n ,
a b o r t i o n s a r e n o t c o n s i d e r e d i n t h i s r e p o r t . H e r e d i t a r y d i s e a s e s may b e
c l a s s i f i e d i n t o t h r e e t y p e s w h i c h a r e a s s o c i a t e d w i t h damage t o s i n g l e
g e n e s , s e v e r a l g e n e s o r c h r o m o s o m e s .
Damage t o a s i n g l e g e n e may a p p e a r a s a m u t a t i o n ( d o m i n a n t o r
r e c e s s i v e ) o n e i t h e r n o n - s e x c h r o m o s o m e s ( a u t o s o m e s ) o r s e x c h r o m o s o m e s .
D o m i n a n t m u t a t i o n s c a n b e t r a n s m i t t e d t o c h i l d r e n b y e i t h e r p a r e n t a n d t h e
f r e q u e n c y o f t h e o b s e r v e d d i s e a s e i s t h o u g h t t o b e d i r e c t l y p r o p o r t i o n a l t o
t h e m u t a t i o n r a t e . B a s e d u p o n a n i m a l s t u d i e s , i t h a s b e e n c a l c u l a t e d t h a t
a b o u t o n e - f i f t h o f t h e s e m u t a t i o n s a p p e a r a s d i s e a s e i n t h e f i r s t g e n e r a t i o n
a n d t h e y a r e e l i m i n a t e d a t t h e r a t e o f a b o u t 20% i n e a c h s u c c e e d i n g
g e n e r a t i o n ( B E I R , 1 9 7 2 ) . T h e r e c e s s i v e m u t a t i o n i s a l s o t r a n s m i t t e d b u t
a p p e a r s a s d i s e a s e o n l y i f b o t h p a r e n t s c o n t r i b u t e t h e same t y p e o f
d e f e c t i v e g e n e . L i t t l e i s k n o w n a b o u t t h e i n c i d e n c e o f r e c e s s i v e - l i n k e d
d i s e a s e s e x c e p t t h a t t h e y a r e l o w ( l e s s t h a n 0 . 1 % ( S a n k a r a n a r a y a n a n , 1 9 7 6 ) )
a n d may n o t b e c o m e a p p a r e n t f o r many g e n e r a t i o n s . D i s e a s e s l i n k e d t o
d a m a g e d g e n e s i n s e x c h r o m o s o m e s s h o w a p a t t e r n s i m i l a r t o t h a t o b s e r v e d
i n t h e a u t o s o m a l d o m i n a n t d i s e a s e s b u t t h e i r i n c i d e n c e i s a b o u t o n e - t e n t h
o f t h a t o f t h e d o m i n a n t d i s e a s e s . The g r o u p o f s i n g l e g e n e ( m o n o g e n i c )
d i s e a s e s , o f w h i c h t h e a u t o s o m a l d o m i n a n t d i s e a s e s a r e t h e m o s t common,
o c c u r w i t h a f r e q u e n c y o f a b o u t 1 % o f a l l l i v e b i r t h s ( S t e v e n s o n , 1 9 5 9 ,
BEIR, 1 9 7 2 ) .
A n o t h e r g r o u p o f h e r e d i t a r y d i s e a s e s , t h e m u l t i - g e n e o r p o l y g e n i c
d i s e a s e s , a r e m u c h m o r e c o m p l e x i n a e t i o l o g y . T h e y r e f l e c t damage t o m o r e
172
t h a n o n e g e n e a n d t h e i r i n c i d e n c e i s e s t i m a t e d t o b e a b o u t k% o f a l l l i v e
b i r t h s ( B E I R , 1 9 7 2 ) , Some o f t h e s e d i s e a s e s a r e s e e n a s m a l f o r m a t i o n s a t
b i r t h , b u t o t h e r s a p p e a r i n l a t e r l i f e . T h e y c o u l d i n c l u d e m a j o r c a t e g o r i e s
o f c o n s t i t u t i o n a l a n d d e g e n e r a t i v e d i s e a s e s u c h a s d i a b e t e s , s c h i z o p h r e n i a
a n d h e a r t d i s e a s e . H o w e v e r t h e r e l a t i o n s h i p b e t w e e n t h e i r i n c i d e n c e a n d
m u t a t i o n r a t e i s n o t u n d e r s t o o d ; some g e n e t i c i s t s b e l i e v e t h a t t h e y a r e
m a i n t a i n e d m a i n l y b y s e l e c t i o n a n d t h a t a n i n c r e a s e i n m u t a t i o n r a t e w o u l d
n o t i n f l u e n c e t h e p r e v a l e n c e o f t h e s e d i s e a s e s . The m u t a t i o n a l c o m p o n e n t
i s u n l i k e l y t o b e m o r e t h a n 50% a n d i s p r o b a b l y much l o w e r ( B E I R , 1 9 7 2 ) .
I t i s a s s u m e d t h a t s e l e c t i o n i s t h e m a i n m e c h a n i s m o f t r a n s m i s s i o n a n d t h a t
o n l y 5% o f t h e d i s e a s e s a r e m a i n t a i n e d b y m u t a t i o n . The m a g n i t u d e o f
i n d i v i d u a l g e n e e f f e c t s c a u s i n g d i s e a s e i s l i k e l y t o b e l e s s t h a n t h a t o f
t h e s i n g l e g e n e d o m i n a n t m u t a t i o n s a n d a s m a l l e r f r a c t i o n o f t h e t o t a l
i m p a c t w o u l d t h e r e f o r e b e e x p e c t e d i n t h e f i r s t g e n e r a t i o n . I t may t h e r e -
f o r e b e a s s u m e d t h a t 10% o f p o l y g e n i c d i s e a s e s w i l l a p p e a r i n t h e f i r s t
g e n e r a t i o n a n d t h e r a t e o f e l i m i n a t i o n w i l l b e 10% i n e a c h s u c c e e d i n g
g e n e r a t i o n (BEIR, 1 9 7 2 ) .
The t h i r d g r o u p o f h e r e d i t a r y d i s e a s e s i s a s s o c i a t e d w i t h a b e r r a t i o n s
i n t h e c h r o m o s o m e s . T h i s damage m a n i f e s t s i t s e l f a s c h a n g e s i n t h e n u m b e r
o r s t r u c t u r e o f t h e C h r o m o s o m e s . M o s t c h r o m o s o m e a b e r r a t i o n s t e r m i n a t e i n
a b o r t i o n . T h o s e e n d i n g i n a s u c c e s s f u l p r e g n a n c y p r o d u c e c h i l d r e n w h o , i f
t h e y s u r v i v e t h r o u g h a d o l e s c e n c e , a r e m a i n l y s t e r i l e . T h u s , f o r p r a c t i c a l
p u r p o s e s , d i s e a s e s l i n k e d t o c h r o m o s o m e a b e r r a t i o n s a r e e l i m i n a t e d i n t h e
f i r s t a n d s e c o n d g e n e r a t i o n s . T h e i r i n c i d e n c e i s e s t i m a t e d t o b e a b o u t
0.6% o f a l l l i v e b i r t h s ( N e i l s e n a n d S i l l e s e n , 1 9 7 5 ) .
The s e v e r i t y o f h e r e d i t a r y d i s e a s e i s a f a c t o r w h i c h c a n n o t b e
m e a s u r e d . I t may v a r y f r o m d e a t h i n e a r l y c h i l d h o o d t o d i s e a s e s w h i c h a r e
l a t e n t t h r o u g h o u t l i f e a n d c a n b e d e t e c t e d o n l y b y s o p h i s t i c a t e d l a b o r a t o r y
t e s t s .
l i . 2 R a d i a t i o n - i n d u c e d e f f e c t s
R a d i a t i o n - i n d u c e d h e r e d i t a r y d i s e a s e d i f f e r s i n n o known w a y f r o m
h e r e d i t a r y d i s e a s e w h i c h o c c u r s s p o n t a n e o u s l y . The g e n e t i c c o n s e q u e n c e s o f
r a d i a t i o n h a v e b e e n d i s c u s s e d i n r e c e n t r e v i e w s (UNSCEAR, 1972; BEIR, 1972;
R a s m u s s e n , 1975; S a n k a r a n a r a y a n a n , 1976; S m i t h a n d S t a t h e r , 1976; ICRP,
1 9 7 7 ) .
T h e r e i s n o i n f o r m a t i o n o n r a d i a t i o n - i n d u c e d h e r e d i t a r y d i s e a s e i n man
o r a n i m a l s r e s u l t i n g f r o m t h e d e p o s i t i o n o f a c t i n i d e s i n t h e g o n a d s . The
g e n e t i c c o n s e q u e n c e s o f a c t i n i d e a c c u m u l a t i o n i n t h e g o n a d s m u s t t h e r e f o r e
173
b e e x t r a p o l a t e d f r o m i n f o r m a t i o n o n t h e e f f e c t s o f l o w LET r a d i a t i o n .
I n a s t a n d a r d p o p u l a t i o n e x p o s e d t o i o n i s i n g r a d i a t i o n s f r o m r a d i o -
a c t i v i t y r e l e a s e d i n t o t h e e n v i r o n m e n t a t o t a l o f 5 7 c a s e s o f s e r i o u s
h e r e d i t a r y d i s e a s e p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w LET) h a v e b e e n
p r e d i c t e d o v e r many g e n e r a t i o n s ( S m i t h a n d S t a t h e r , 1 9 7 6 ) o f w h i c h 1 5 a n d
9 c a s e s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w LET) w o u l d a p p e a r i n t h e f i r s t
a n d s e c o n d g e n e r a t i o n s r e s p e c t i v e l y . The j u s t i f i c a t i o n f o r t h e s e v a l u e s i s
b a s e d u p o n s t u d i e s c a r r i e d o u t m a i n l y i n t h e m o u s e b e c a u s e t h e r e i s l i t t l e
d i r e c t e v i d e n c e o f t h e e f f e c t s o f r a d i a t i o n - i n d u c e d h e r e d i t a r y d i s e a s e i n
man . T h e s e v a l u e s a r e b r o a d l y c o n s i s t e n t w i t h t h o s e g i v e n i n ICRP
P u b l i c a t i o n 2 6 ( 1 9 7 7 ) f o r o c c u p a t i o n a l l y e x p o s e d w o r k e r s a n d f o r m e m b e r s
o f t h e g e n e r a l p u b l i c . The v a l u e s g i v e n b y ICRP a r e 1+0 c a s e s o f h e r e d i t a r y
d i s e a s e p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) f o r t h e f i r s t t w o g e n e r a t i o n s a n d a
f u r t h e r 1+0 c a s e s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) f o r a l l f u t u r e g e n e r a t i o n s .
B a s e d o n a q u a l i t y f a c t o r o f 2 0 f o r a l p h a i r r a d i a t i o n t h e o v e r a l l r i s k
w o u l d b e e q u i v a l e n t t o 111+0 c a s e s o f s e r i o u s h e r e d i t a r y d i s e a s e p e r 1 0 ^ man
r a d a l p h a (10^" man G y ) . D e r i v e d v a l u e s f o r t h e n u m b e r s o f r a d i a t i o n i n d u c e d
s i n g l e g e n e , m u l t i g e n e a n d c h r o m o s o m e d i s o r d e r s nxe g i v e n i n T a b l e 9 . 2 .
No e s t i m a t e s o f r i s k o f s p o n t a n e o u s a b o r t i o n s h a v e b e e n made f o r
a l t h o u g h t h e y may b e a s o u r c e o f human d i s t r e s s t h e y w i l l b e o f much l e s s
c o n c e r n t h a n c o n g e n i t a l a b n o r m a l i t i e s i n t h e l i v e - b o m a n d w i l l n o t h a v e
a n a p p r e c i a b l e e f f e c t o n human w e l l - b e i n g .
5 . B i o l o g i c a l e f f e c t s i n man
I n o r d e r t o a s s e s s t h e b i o l o g i c a l c o n s e q u e n c e s o f i n t a k e s o f a c t i n i d e s
b y e i t h e r i n d i v i d u a l s o f p o p u l a t i o n s t h e r i s k c o e f f i c i e n t s f o r b o t h r a d -
i a t i o n i n d u c e d c a n c e r a n d h e r e d i t a r y d i s e a s e s m u s t b e w e i g h t e d b y t h e d o s e s
a c c u m u l a t e d b y t h e v a r i o u s t i s s u e s o f t h e b o d y . B e c a u s e o f t h e l o n g h a l f -
t i m e o f r e t e n t i o n o f a c t i n i d e s i n t i s s u e s t h e d o s e s r e c e i v e d w i l l d e p e n d
u p o n t h e a g e a t e x p o s u r e . F u r t h e r m o r e r a d i a t i o n i n d u c e d c a n c e r s d e v e l o p
f o l l o w i n g a l a t e n t p e r i o d a f t e r e x p o s u r e w h e n n o e f f e c t i s s e e n . The l e n g t h
o f b o t h t h e l a t e n t p e r i o d a n d t h e s u b s e q u e n t p e r i o d o f r i s k w i l l t h e r e f o r e
a l s o i n f l u e n c e t h e c o n s e q u e n c e s o f e x p o s u r e . An i d e a l i s e d m o d e l may b e
u s e d f o r c a l c u l a t i n g c a n c e r m o r t a l i t y i n a p o p u l a t i o n f r o m e s t i m a t e d v a l u e s
o r r i s k c o e f f i c i e n t s . I n t h i s m o d e l t h e l a t e n t p e r i o d , i n w h i c h t h e r e i s
a n e g l i g i b l e i n c r e a s e i n c a n c e r i n c i d e n c e , i s f o l l o w e d b y a p e r i o d w i t h a n
i n c r e a s e d i n c i d e n c e o f c a n c e r a t a u n i f o r m r a t e w h i c h l a s t s f o r a n u m b e r
o f y e a r s . F o r l e u k a e m i a i t may b e a s s u m e d t h a t n o n e o c c u r d u r i n g t h e f i r s t
5 y e a r s a f t e r i r r a d i a t i o n a n d t h a t t h e r e i s a c o n s t a n t i n c i d e n c e d u r i n g t h e
Ilk
N u m b e r s i ^ 6 p e r 1 0 man r a d a l p h a e
C l a s s o f d i s e a s e F i r s t
g e n e r a t i o n S e c o n d
g e n e r a t i o n T o t a l f o r
a l l g e n e r a t i o n s
S i n g l e g e n e 0
( m a i n l y a u t o s o m a l d o m i n a n t ) 1 6 0 11+0 81+0
M u l t i - g e n e 0 2 0 2 0 1 6 0
Chromosome^" 1 2 0 2 0 1 4 0
TOTAL 300 1 8 0 111+0
N o t e s : a . B a s e d u p o n 4 2 0 , 0 0 0 l i v e b i r t h s p e r 1 0 p o p u l a t i o n i n o n e g e n e r a t i o n ( 3 0 y e a r s ) .
b . The r a d i a t i o n d o s e r e c e i v e d i n o n e y e a r .
c . A d o u b l i n g d o s e o f 1 0 0 r a d ( l o w LET) t o t h e s p e r m a t o c y t e i s a s s u m e d i n t h e c a l c u l a t i o n s .
d . C o n f i n e d t o t r a n s l o c a t i o n - l i n k e d d i s e a s e s b a s e d u p o n a n i n d u c t i o n r a t e o f 7 7 0 b a l a n c e d t r a n s l o c a t i o n s p e r 1 0 man r a d ( l o w LET) a n d e q u a l s e n s i t i v i t y o f t h e s p e r m a -t o x y t e a n d o o c y t e .
e . B a s e d o n a q u a l i t y f a c t o r o f 2 0 f o r a l p h a r a d i a t i o n .
R e f e r e n c e : S m i t h a n d S t a t h e r ( 1 9 7 6 ) .
R i s k c o e f f i c i e n t s f o r h e r e d i t a r y d i s e a s e s 8 * '
T a b l e 9 . 2
175
n e x t 2 0 y e a r s . F o r a l l o t h e r c a n c e r s t h e i n i t i a l p e r i o d o f n o r i s k c a n b e
t a k e n t o b e 1 5 y e a r s f o l l o w e d b y a p e r i o d o f 3 0 y e a r s a t c o n s t a n t r i s k . I t
i s t h e r e f o r e o n l y a p p r o p r i a t e t o a p p l y t h e f u l l r i s k c o e f f i c i e n t s t o r a d -
i a t i o n d o s e s r e c e i v e d e a r l y i n l i f e .
F o r r a d i a t i o n i n d u c e d h e r e d i t a r y d i s e a s e s t h e e f f e c t o f a n i n t a k e o f
a c t i n i d e s w i l l a l s o d e p e n d u p o n t h e a g e a t e x p o s u r e . R e p r o d u c t i v e l i f e i s
n o r m a l l y a s s u m e d t o c e a s e a t a n a v e r a g e a g e o f 3 0 a n d a n y r a d i a t i o n d o s e
r e c e i v e d b y t h e g o n a d s a f t e r t h i s a g e w i l l h a v e n o e f f e c t o n f u t u r e
g e n e r a t i o n s .
T a b l e 9 * 3 s h o w s t h e 5 0 y e a r c o m m i t t e d d o s e t o t h e t i s s u e s o f i n t e r e s t
f o l l o w i n g t h e i n h a l a t i o n o f 1 u C i ( 3 7 kBq.) o f e i t h e r i n s o l u b l e o r s o l u b l e
c o m p o u n d s o f p l u t o n i u m . The t i s s u e d o s e s h a v e b e e n c a l c u l a t e d ( A d a m s , 1 9 7 8 )
u s i n g t h e m e t h o d s a n d t r a n s f e r f a c t o r s a d o p t e d b y ICRP C o m m i t t e e I I i n
t h e i r f o r t h c o m i n g r e p o r t ( ICRP i n p r e s s ) . The e n d o s t e a l c e l l s o n t h e
s u r f a c e o f t h e b o n e r e c e i v e t h e h i g h e s t d o s e . The d o s e s t o t h e g o n a d s a n d
t o t h e m u c o s a l c e l l l a y e r a r e o n l y a b o u t 1 % a n d 0 . 0 0 2 % o f t h e d o s e t o t h e
e n d o s t e u m .
T a b l e 9»U g i v e s t h e 5 0 y e a r c o m m i t t e d d o s e t o t h e t i s s u e s o f i n t e r e s t
f o l l o w i n g t h e i n g e s t i o n o f 1 u C i ( 3 7 kBq.) o f e i t h e r i n s o l u b l e o r s o l u b l e
p l u t o n i u m c o m p o u n d s . B e c a u s e o f t h e l o w a b s o r p t i o n f r o m t h e g u t t h e t i s s u e
d o s e s a r e c o n s i d e r a b l y l e s s t h a n t h o s e o b t a i n e d f o l l o w i n g i n h a l a t i o n . The
e n d o s t e a l c e l l l a y e r a g a i n r e c e i v e s t h e h i g h e s t d o s e w h i l s t t h e l o w e s t i s
r e c e i v e d b y t h e g o n a d s .
The d o s e s g i v e n i n T a b l e s 9 * 3 a n d 9 * 4 a r e c l e a r l y t h e maximum d o s e s
t h a t a r e l i k e l y t o b e r e c e i v e d . The a c t u a l d o s e s a n d t h e c o n s e q u e n c e s o f
e x p o s u r e w i l l d e p e n d u p o n t h e a g e o f t h e i n d i v i d u a l o r t h e a g e d i s t r i b u t i o n
o f t h e p o p u l a t i o n . The d a t a i n T a b l e s 9 * 3 a n d 9 * 4 d o d e m o n s t r a t e h o w e v e r
t h a t f o l l o w i n g t h e i n h a l a t i o n o f a c t i n d e s t h e t i s s u e s r e c e i v i n g t h e h i g h e s t
d o s e s a r e t h e l u n g , t h e e n d o s t e a l c e l l s o f b o n e , t h e b o n e marrow a n d l i v e r .
The d o s e s t o t h e s e t i s s u e s f o l l o w i n g i n g e s t i o n o f p l u t o n i u m c o m p o u n d s a r e
a b o u t a t h o u s a n d t h o f t h o s e r e c e i v e d f o l l o w i n g t h e i n h a l a t i o n o f c o m p a r a b l e
a m o u n t s o f a c t i v i t y .
6. Efamrnary
To p r o v i d e a b a s i s f o r a n a s s e s s m e n t o f t h e e f f e c t s o n a p o p u l a t i o n o f
e x p o s u r e t o a c t i n i d e s , e s t i m a t e s o f r i s k c o e f f i c i e n t s h a v e b e e n made
f o r a l p h a r a d i a t i o n - i n d u c e d d e a t h s f r o m l e u k a e m i a (1+00 c a s e s p e r 1 0 ^
man r a d a l p h a (1+00 p e r 1 0 ^ man G y ) ) a n d f r o m c a n c e r s o f t h e b o n e ( 1 0 0
c a n c e r s p e r 1 0 ^ man r a d a l p h a ( 1 0 0 p e r 10^" man G y ) ) , l i v e r ( 1 0 0 c a n c e r s
176
p e r 10^ man r a d a l p h a (100 p e r 10^ man G y ) ) , l u n g (1+00 c a n c e r s p e r W
man r a d a l p h a (1+.00 p e r 10^ man G y ) ) a n d g a s t r o i n t e s t i n a l t r a c t (1+00
c a s e s p e r 10^ man r a d a l p h a (1+00 p e r 10^ man G y ) ) , T a b l e 9,1. F o r
s e r i o u s h e r e d i t a r y d i s e a s e s a t o t a l o f 111+0 c a s e s p e r 10^ man r a d
a l p h a (111+0 p e r 10^ man Gy) i s p r e d i c t e d o v e r many g e n e r a t i o n s ( T a b l e
9.2). T h e s e v a l u e s a r e b a s e d o n t h e u s e o f a q u a l i t y f a c t o r o f 20
f o r a l p h a r a d i a t i o n .
ITT
T a b l e 9 . 3
T i s s u e
- 1 r a d u C i i n h a l e d
T i s s u e C l a s s Y
( i n s o l u b l e ) C l a s s W
( s o l u b l e )
b L u n g 5 . 9 E 01 3 . 1 E 00
L i v e r ' 3 . 9 E 01 9 , 8 E 01
E n d o s t e a l c e l l s 0 ' 6 1 . 8 E 0 2 1+.6 E 0 2
B o n e marrow 1.1+ E 01 3 . 7 E 01
f L o w e r l a r g e i n t e s t i n e 5 . 9 E - 0 3 5.U ^ 0 3
G o n a d s 0 ' ^ 2 . 2 E 0 0 5 . 9 E 0 0
L u n g d e p o s i t i o n a n d c l e a r a n c e p a r a m e t e r s a s d e f i n e d i n t h e ICRP
T a s k Group L u n g M o d e l ( ICRP 1 9 6 6 a , 1 9 7 2 ) .
A v e r a g e d o s e t o l u n g a n d a s s o c i a t e d l y m p h n o d e s ( I C R P , 1 9 7 7 ) .
A s s u m e s t h a t o f t h e a c t i v i t y e n t e r i n g t h e b l o o d 1+5% i s d e p o s i t e d i n t h e s k e l e t o n (T£ 100 y e a r s ) 45% i n t h e l i v e r (T£ 1+0 y e a r s ) 0.011% i n t h e o v a r i e s a n d 0.035% i n t h e t e s t e s . The a c t i v i t y d e p o s i t e d i n t h e g o n a d s i s a s s u m e d t o b e r e t a i n e d i n d e f i n i t e l y .
A v e r a g e o r g a n d o s e s .
D o s e c a l c u l a t e d t o t h e o s t e o p r o g e n i t o r c e l l s a s s u m e d t o b e w i t h i n 1 0 urn o f t h e e n d o s t e a l s u r f a c e o f d o s e ( ICRP 1 9 7 7 ) .
A v e r a g e d o s e a b s o r b e d b y t h e m u c o s a l c e l l l a y e r t a k e n t o b e 1 % o f t h a t a t t h e s u r f a c e o f t h e g u t c o n t e n t s .
R e f e r e n c e Adams 1 9 7 8 .
a )
b )
o )
d )
e )
f )
50 y e a r c o m m i t t e d d o s e t o t i s s u e s i n man f o l l o w i n g i n h a l a t i o n o f p l u t o n i u m a e r o s o l s ^AMAD 1 u m j 3 ^ "
178
T a b l e 9.1+
T i s s u e
r a d u C i " 1
i n g e s t e d
T i s s u e cidjs -f-
( i n s o l u b l e ) C l a s s W b
( s o l u b l e )
L i v e r 7
E n d o s t e a l c e l l s 0
B o n e marrow
L o w e r l a r g e i n t e s t
G o n a d s 0 ' d
8 . 1 E - 0 3
3 . 9 E - 0 2
3 . 1 E - 0 3
i n e 1 . 0 E - 0 2
J+.8 E-01+
8 . 1 E - 0 2
3 . 9 E - 0 1
3 . 1 E - 0 2
1 . 0 E - 0 2
1+.8 E - 0 3
0 . 0 0 1 % a b s o r b e d .
0 . 0 1 % a b s o r b e d .
A s s u m e s t h a t o f t h e a c t i v i t y e n t e r i n g t h e b l o o d 1+5% i s d e p o s i t e d i n t h e s k e l e t o n (T£ 1 0 0 y e a r s ) 1+5% i n t h e l i v e r ( T j 1+0 y e a r s ) 0 . 0 1 1 % i n t h e o v a r i e s a n d 0 . 0 3 5 % i n t h e t e s t e s . The a c t i v i t y d e p o s i t e d i n t h e g o n a d s i s a s s u m e d t o b e r e t a i n e d i n d e f i n i t e l y .
A v e r a g e o r g a n d o s e s .
D o s e c a l c u l a t e d t o t h e o s t e o p r o g e n i t o r c e l l s a s s u m e d t o b e w i t h i n 1 0 urn o f t h e e n d o s t e a l s u r f a c e o f b o n e ( ICRP 1 9 7 7 ) .
R e f e r e n c e Adams , 1 9 7 8 .
a )
b )
c )
a)
e )
5 0 y e a r c o m m i t t e d d o s e t o t i s s u e s i n man f o l l o w i n g i n g e s t i o n o f p l u t o n i u m
Chapter 10
S U M M A R Y A N D C O N C L U S I O N S
1 . I n t r o d u c t i o n
The o b j e c t o f t h i s r e v i e w h a s b e e n t o s u m m a r i s e t h e a v a i l a b l e i n f o r m a -
t i o n o n t h e m e t a b o l i s m a n d b i o l o g i c a l e f f e c t s o f t h e a c t i n i d e s p l u t o n i u m ,
a m e r i c i u m a n d c u r i u m r e l e v a n t t o a n a s s e s s m e n t o f t h e r a d i o l o g i c a l h e a l t h
p r o b l e m s r e s u l t i n g f r o m t h e u s e o f m i x e d o x i d e f u e l s o f p l u t o n i u m a n d
u r a n i u m i n l i g h t w a t e r r e a c t o r s .
2. M e t a b o l i s m
2.1 M e t a b o l i s m a t t h e s i t e o f e n t r y
A c t i n i d e s may e n t e r t h e b o d y b y i n h a l a t i o n , t h r o u g h c u t s , a b r a s i o n s o r
o t h e r w o u n d s , o r b y i n g e s t i o n . I f d e p o s i t e d e i t h e r a t a w o u n d s i t e o r i n
t h e r e s p i r a t o r y s y s t e m t h e r e i s a l w a y s a t r a n s p o r t a b l e ( s o l u b l e ) f r a c t i o n
o f m a t e r i a l t h a t r a p i d l y e n t e r s t h e s y s t e m i c c i r c u l a t i o n a n d i s e i t h e r
d e p o s i t e d i n t i s s u e s o r e x c r e t e d . A s e c o n d f r a c t i o n f o r m e d e i t h e r b y r a p i d
h y d r o l y s i s a n d p o l y m e r i s a t i o n o f s o l u b l e a c t i n i d e c o m p o u n d s o r r e s u l t i n g
f r o m a n i n t a k e o f i n s o l u b l e p a r t i c l e s o r c o l l o i d s r e m a i n s a t t h e s i t e o f
e n t r y * Much o f t h i s s e c o n d ( i n s o l u b l e ) f r a c t i o n i s e n g u l f e d b y m a c r o p h a g e s
a n d e v e n t u a l l y may e i t h e r b e t r a n s l o c a t e d t o r e g i o n a l l y m p h a t i c t i s s u e o r i n
t h e c a s e o f d e p o s i t s i n t h e l u n g c l e a r e d u p t h e m u c o c i l i a r y e s c a l a t o r ,
s w a l l o w e d a n d e x c r e t e d i n t h e f a e c e s . Some i n s o l u b l e p a r t i c l e s w i l l a l s o
b e d i s s o l v e d i n b i o l o g i c a l f l u i d s a n d g r a d u a l l y e n t e r t h e s y s t e m i c c i r c u l a -
t i o n . F o r a n y i n t a k e t h e r e l a t i v e p r o p o r t i o n s o f t h e s e t w o f r a c t i o n s d e p e n d
u p o n t h e m a t e r i a l i n i t i a l l y d e p o s i t e d . F o r e x a m p l e , i n t h e c a s e o f a p o l y -
d i s p e r s e a e r o s o l o f h i g h t e m p e r a t u r e c a l c i n e d p l u t o n i u m d i o x i d e d e p o s i t e d i n
t h e l u n g s t h e a m o u n t r a p i d l y m o v i n g t o b l o o d i s n o r m a l l y l e s s t h a n 0.1+%
w h e r e a s f o r a p l u t o n i u m c i t r a t e a e r o s o l i t may b e g r e a t e r t h a n 1+0%.
2.2 E n t r y b y i n h a l a t i o n
A m o d e l f o r t h e d e p o s i t i o n a n d r e t e n t i o n o f i n h a l e d a e r o s o l s i n t h e
human r e s p i r a t o r y t r a c t w a s d e s c r i b e d i n t h e R e p o r t o f t h e T a s k G r o u p o n
Lung I t y n a m i c s (1966) f o r C o m m i t t e e 2 o f t h e I n t e r n a t i o n a l C o m m i s s i o n o n
R a d i o l o g i c a l P r o t e c t i o n a n d m o d i f i e d i n ICRP P u b l i c a t i o n 19> 1972 . I n t h e
m o d e l t h e r e s p i r a t o r y t r a c t h a s b e e n d i v i d e d i n t o t h r e e r e g i o n s ; t h e n a s o -
p h a r y n x , t h e t r a c h e o b r o n c h i a l r e g i o n a n d t h e p u l m o n a r y r e g i o n . The r e g i o n a l
d e p o s i t i o n o f a n i n h a l e d a e r o s o l i s c o n s i d e r e d t o b e p r i m a r i l y a f u n c t i o n o f
t h e p a r t i c l e s i z e d i s t r i b u t i o n . The c h e m i c a l f o r m o f t h e c o m p o u n d i n h a l e d
i n f l u e n c e s t h e s u b s e q u e n t c l e a r a n c e f r o m t h e l u n g . I n t h e m o d e l r e t e n t i o n
179
180
i n t h e l u n g c a n b e f o r d a y s ( C l a s s D ) , w e e k s ( C l a s s W) o r y e a r s ( C l a s s Y ) .
The T a s k G r o u p Lung M o d e l p r e d i c t s t h a t f o l l o w i n g t h e i n h a l a t i o n o f a n
a e r o s o l o f a r e l a t i v e l y s o l u b l e ( C l a s s W) c o m p o u n d ( p a r t i c l e s i z e d i s t r i b u -
t i o n 1 [im AMAD), 1 2 % o f t h e a c t i v i t y w i l l e v e n t u a l l y b e t r a n s f e r r e d t o t h e
b l o o d , a n d f o r a l e s s s o l u b l e ( C l a s s Y) c o m p o u n d 5%. R e t e n t i o n i s e x p o n e n -
t i a l w i t h h a l f - t i m e s o f r e t e n t i o n o f t h e l o n g t e r m c o m p o n e n t i n t h e l u n g o f
$ 0 a n d 5 0 0 d a y s f o r C l a s s W a n d C l a s s Y c o m p o u n d s r e s p e c t i v e l y .
S t u d i e s i n a n i m a l s h a v e s h o w n t h a t p l u t o n i u m c o m p o u n d s g e n e r a l l y c o n -
f o r m t o t h i s c l a s s i f i c a t i o n - o x i d e s a r e C l a s s Y , n i t r a t e s a r e C l a s s W a n d
p l u t o n i u m c o m p l e x e d w i t h t h e c h e l a t i n g a g e n t d i e t h y l e n e t r i a m i n e p e n t a a c e t i c
a c i d (DTPA) i s C l a s s D .
E x p e r i m e n t a l s t u d i e s h a v e a l s o s h o w n t h a t a l l c o m p o u n d s o f a m e r i c i u m
a n d c u r i u m , e x c e p t C l a s s D , b u t i n c l u d i n g t h e o x i d e s , a r e r e t a i n e d i n t h e
l u n g w i t h h a l f - t i m e s o f a f e w w e e k s o r m o n t h s a n d s h o u l d b e c o n s i d e r e d t o
b e C l a s s W.
F o l l o w i n g t h e i n h a l a t i o n o f p a r t i c l e s c o n s i s t i n g o f m i x t u r e s o f
a c t i n i d e s o r a c t i n i d e s i n c o m b i n a t i o n w i t h o t h e r e l e m e n t s t h e r e t e n t i o n i n
t h e l u n g o f t h e i n d i v i d u a l a c t i n i d e s w i l l b e s i m i l a r t o t h a t o f t h e m a t e r i a l
p r e s e n t i n t h e i n h a l e d p a r t i c l e s i n g r e a t e s t m a s s .
2 . 3 E n t r y t h r o u g h c u t s a n d w o u n d s
The b e h a v i o u r o f a c t i n i d e c o m p o u n d s i n c o n t a m i n a t e d w o u n d s d e p e n d s o n
p h y s i c o - c h e m i c a l c h a r a c t e r i s t i c s s u c h a s c h e m i c a l f o r m , p a r t i c l e s i z e , m a s s
i n j e c t e d a n d s p e c i f i c a c t i v i t y a s w e l l a s b i o l o g i c a l f a c t o r s s u c h a s t h e
d e p t h a n d s i t e o f d e p o s i t i o n , t h e t y p e o f t i s s u e , t i s s u e f l u i d f l o w p a s t
t h e d e p o s i t a n d t h e d i s p e r s i o n w i t h i n t h e t i s s u e . I n g e n e r a l t e r m s , s o l u b l e
c o m p o u n d s a r e c l e a r e d m o r e r e a d i l y t h a n i n s o l u b l e c o m p o u n d s , s u b c u t a n e o u s
d e p o s i t s m o r e r e a d i l y t h a n i n t r a m u s c u l a r d e p o s i t s a n d a m e r i c i u m a n d c u r i u m
m o r e r e a d i l y t h a n p l u t o n i u m .
2 .1+ I n g e s t i o n
S t u d i e s i n a n i m a l s o n t h e a b s o r p t i o n o f p l u t o n i u m , f r o m t h e g a s t r o -
i n t e s t i n a l t r a c t , h a v e s h o w n t h a t t h i s i s n o t a s i g n i f i c a n t r o u t e o f u p t a k e
i n t h e a d u l t . F o r s o l u b l e p l u t o n i u m c o m p o u n d s t h a t h a v e e n t e r e d t h e g u t t h e
i n s o l u b l e p l u t o n i u m d i o x i d e p a r t i c l e s 1 x 1 0 y o . P l u t o n i u m i n p a r t i c l e s o f
t h e d i o x i d e l e s s t h a n a b o u t 5 nm i n d i a m e t e r s h o u l d b e t r e a t e d a s s o l u b l e .
I n some c i r c u m s t a n c e s i n g e s t i o n may b e a s i g n i f i c a n t r o u t e o f e n t r y
i n t o t h e b o d y . A m e r i c i u m a n d c u r i u m a r e a b s o r b e d m o r e r e a d i l y f r o m t h e
a m o u n t o f p l u t o n i u m a b s o r b e d may b e a s s u m e d t o b e a b o u t 1 x 1 0 " ^ % a n d f o r
181
g a s t r o i n t e s t i n a l t r a c t t h a n p l u t o n i u m a n d f o r a l l c o m p o u n d s t h e a m o u n t
a b s o r b e d c a n b e t a k e n t o b e a b o u t 5 x 1 0 ~ 2 % . I n y o u n g a n i m a l s a b s o r p t i o n
o f p l u t o n i u m , a m e r i c i u m a n d c u r i u m i s e n h a n c e d r e l a t i v e t o t h e a d u l t . Some
s t u d i e s o n a c t i n i d e s i n c o r p o r a t e d i n t o p l a n t a n d a n i m a l t i s s u e s h a v e s h o w n
t h a t t h e y may b e a b s o r b e d m o r e r e a d i l y t h a n i n o r g a n i c c o m p o u n d s b u t t h e
r e s u l t s t h a t h a v e b e e n o b t a i n e d s o f a r a r e f r a g m e n t a r y a n d v a r i a b l e . More
s t u d i e s a r e n e e d e d o n t h i s r o u t e o f i n t a k e .
2 . 5 T r a n s p o r t i n t h e b l o o d a n d d e p o s i t i o n i n t i s s u e s
A f t e r t h e e n t r y o f p l u t o n i u m i n t o t h e b l o o d m o s t o f i t i s r a p i d l y b o u n d
t o t r a n s f e r r i n , a p r o t e i n t h a t n o r m a l l y t r a n s p o r t s i r o n i n t h e b o d y . The
r e m a i n d e r i s b o u n d t o a s m a l l e r m o l e c u l e w h i c h i s p r o b a b l y c i t r a t e . I t i s
p r o b a b l e t h a t a m e r i c i u m a n d c u r i u m b e h a v e s i m i l a r l y o n e n t r y i n t o t h e b l o o d .
The t i s s u e d i s t r i b u t i o n o f a c t i n i d e s f o l l o w i n g t h e i r e n t r y i n t o t h e
b l o o d i s l a r g e l y i n d e p e n d e n t o f t h e i n i t i a l p h y s i c o - c h e m i c a l f o r m t a k e n i n t o
t h e b o d y . F o r a n a s s e s s m e n t o f t h e c o n s e q u e n c e s o f human e x p o s u r e t o t h e s e
a c t i n i d e s t h e r e a r e t h r e e i m p o r t a n t s i t e s o f d e p o s i t i o n : t h e l i v e r , b o n e
a n d g o n a d s . A p a r t f r o m t h e s e t h r e e t i s s u e s a c t i n i d e s a r e d e p o s i t e d i n a l l
t h e o t h e r t i s s u e s o f t h e b o d y b u t b e c a u s e o f t h e g e n e r a l l y l o w r a d i a t i o n
d o s e s i n v o l v e d t h e y n e e d n o t b e c o n s i d e r e d a s c r i t i c a l t i s s u e s .
The l i v e r a n d b o n e t o g e t h e r a c c u m u l a t e a b o u t 90% o f t h e s y s t e m i c
d e p o s i t a l t h o u g h t h e d i s t r i b u t i o n o f a c t i v i t y b e t w e e n t h e m i s v e r y v a r i a b l e .
O v e r a l l 1+5% o f t h e s y s t e m i c a c t i v i t y c a n b e c o n s i d e r e d t o d e p o s i t i n e a c h
t i s s u e . R e t e n t i o n i s e x p o n e n t i a l w i t h h a l f - t i m e s i n human b o n e a n d l i v e r
e s t i m a t e d t o b e 1 0 0 a n d 1+0 y e a r s r e s p e c t i v e l y .
B e c a u s e o f t h e p o t e n t i a l g e n e t i c r i s k t h e t h i r d i m p o r t a n t s i t e o f
d e p o s i t i o n f r o m t h e b l o o d i s t h e g o n a d s . B a s e d u p o n b o t h a n i m a l a n d human
d a t a i t h a s b e e n e s t i m a t e d t h a t t h e human t e s t e s w i l l a c c u m u l a t e 3 x 1 0 " ^ %
o f a c t i v i t y e n t e r i n g t h e b l o o d a n d t h e o v a r i e s 1 x 10~"^%. A l t h o u g h d a t a o n
t h e r e t e n t i o n o f a c t i n i d e s i n t h e g o n a d s i s v e r y l i m i t e d a n i m a l s t u d i e s
s u g g e s t t h a t t h e y a r e r e t a i n e d i n d e f i n i t e l y .
2 . 6 E x c r e t i o n
A c t i n i d e s i n c o r p o r a t e d i n t o t h e b o d y a r e e x c r e t e d b o t h i n t h e f a e c e s
a n d i n t h e u r i n e . F a e c a l e x c r e t i o n r e s u l t s f r o m a c t i n i d e s e n t e r i n g t h e g u t
e i t h e r i n m u c o u s c l e a r e d f r o m t h e r e s p i r a t o r y s y s t e m o r i n g u t s e c r e t i o n s .
U r i n a r y e x c r e t i o n i s d u e t o u l t r a f i l t r a t i o n t h r o u g h t h e k i d n e y o f a c t i n i d e -
c i t r a t e c o m p l e x e s f o r m e d i n t h e b l o o d .
A n i m a l s t u d i e s h a v e s h o w n t h a t m o r e a m e r i c i u m a n d c u r i u m a r e e x c r e t e d
182
i n t h e u r i n e t h a n p l u t o n i u m . The a p p l i c a t i o n o f u r i n a r y e x c r e t i o n d a t a f o r
p l u t o n i u m i n man t o t h e s e h i g h e r a c t i n i d e s i s t h e r e f o r e l i k e l y t o o v e r -
e s t i m a t e s y s t e m i c d e p o s i t s .
3 - B i o l o g i c a l E f f e c t s
From t h e s m a l l n u m b e r s o f w o r k e r s who h a v e i n c o r p o r a t e d p l u t o n i u m o r
o t h e r a c t i n i d e s t h e r e i s n o e v i d e n c e o f l i f e s h o r t e n i n g o r m a l i g n a n t d i s e a s e
w h i c h c a n b e a t t r i b u t e d t o t h e s e i n t a k e s . E x t e n s i v e a n i m a l s t u d i e s h a v e
d e m o n s t r a t e d t h a t b i o l o g i c a l e f f e c t s may o c c u r p r e d o m i n a n t l y i n t h e l u n g ,
b o n e , l i v e r , b l o o d a n d l y m p h n o d e s b u t g e n e r a l l y a t h i g h e r l e v e l s o f
i n c o r p o r a t i o n t h a n h a v e b e e n o b s e r v e d i n man . E f f e c t s h a v e a l s o o c c u r r e d a t
w o u n d s i t e s c o n t a m i n a t e d w i t h a c t i n i d e s . No e f f e c t s h a v e b e e n s e e n i n t h e
g a s t r o - i n t e s t i n a l t r a c t a s a r e s u l t o f i n g e s t i o n o r i n h a l a t i o n o f a c t i n i d e s .
3 . 1 Lung
E a r l y e f f e c t s o f r a d i a t i o n r e s u l t i n g i n d e a t h w i t h i n a b o u t a y e a r h a v e
b e e n s e e n i n d o g s a n d r o d e n t s t h a t h a v e i n h a l e d l a r g e a m o u n t s o f p l u t o n i u m -
2 3 9 d i o x i d e e q u i v a l e n t t o m o r e t h a n a b o u t 100 uCi ( 3 - 7 MBq) i n man . T h e s e
c h a n g e s i n c l u d e o e d e m a , p n e u m o n i t i s a n d f i b r o s i s . A t l o w e r i n t a k e s
( e q u i v a l e n t t o a b o v e a b o u t 1 jiCi ( 3 7 k B q ) i n man) l u n g c a n c e r s h a v e b e e n
o b s e r v e d a s t h e m a i n l a t e e f f e c t o f i n h a l e d p l u t o n i u m - 2 3 9 d i o x i d e . S i m i l a r
e f f e c t s h a v e b e e n s e e n f o r t h e h i g h e r a c t i n i d e s r e t a i n e d i n t h e l u n g s
a l t h o u g h b e c a u s e o f t h e m o r e u n i f o r m d i s t r i b u t i o n o f t h e a m e r i c i u m a n d
c u r i u m i n t h e l u n g e f f e c t s h a v e b e e n p r o d u c e d a t l o w e r t i s s u e d o s e s . I n
g e n e r a l c a n c e r s o b s e r v e d i n e x p e r i m e n t a l a n i m a l s o c c u r i n t h e p e r i p h e r a l
r e g i o n o f t h e l u n g s . I n man n a t u r a l l y o c c u r r i n g c a n c e r s o r c a n c e r s o c c u r r -
i n g a f t e r e x p o s u r e t o t o b a c c o smoke o r t o r a d o n a n d i t s d a u g h t e r s i n m i n e s
a r e f o u n d m a i n l y i n t h e p r i m a r y a n d s e g m e n t a l b r o n c h i . I t i s n o t k n o w n
w h e t h e r p l u t o n i u m i n d u c e d c a n c e r i n man w o u l d o c c u r p e r i p h e r a l l y o r i n t h e
m a i n b r o n c h i . Much w o r k h a s s t i l l t o b e d o n e i n d e f i n i n g t h e l u n g c e l l s
m o s t a t r i s k .
3 . 2 B l o o d a n d b o n e m a r r o w
C h a n g e s i n c i r c u l a t i n g b l o o d c e l l s h a v e b e e n s e e n a f t e r t h e i n h a l a t i o n
o r i n t r a v e n o u s i n j e c t i o n o f p l u t o n i u m c o m p o u n d s . The m o s t f r e q u e n t c h a n g e
s e e n h a s b e e n a c h r o n i c r e d u c t i o n i n l y m p h o c y t e c e l l c o u n t . L y m p h o p o e n i a
h a s o c c u r r e d i n d o g s f o l l o w i n g t h e i n h a l a t i o n o f q u a n t i t i e s o f p l u t o n i u m
e q u i v a l e n t t o m o r e t h a n a b o u t 1 [iCi ( 3 7 k B q ) i n man. The s i g n i f i c a n c e o f
t h i s i s n o t k n o w n . I t m i g h t b e a n t i c i p a t e d t h a t b e c a u s e p l u t o n i u m d e p o s i t s
i n b o n e a n d l y m p h n o d e s , b l o o d s t e m c e l l n e o p l a s i a s h o u l d b e a c o n s e q u e n c e
o f p l u t o n i u m c o n t a m i n a t i o n . L e u k a e m i a h a s h o w e v e r b e e n f o u n d r a r e l y i n
183
a n i m a l s a n d a l m o s t e x c l u s i v e l y i n r o d e n t s a d m i n i s t e r e d w i t h l a r g e a m o u n t s o f
a c t i v i t y . B e c a u s e o f t h e o b s e r v e d i n c r e a s e d i n c i d e n c e o f l e u k a e m i a i n
h u m a n s e x p o s e d t o e x t e r n a l r a d i a t i o n t h e b o n e m a r r o w i n man m u s t b e c o n s i d -
e r e d p o t e n t i a l l y a t r i s k f r o m e x p o s u r e t o a l p h a i r r a d i a t i o n f r o m a c t i n i d e s
d e p o s i t e d i n b o n e .
3 . 3 B o n e a n d l i v e r
B o n e f r a c t u r e s h a v e b e e n o b s e r v e d i n a n i m a l s g i v e n i n t r a v e n o u s i n j e c -
t i o n s o f l a r g e d o s e s o f p l u t o n i u m - 2 3 9 ( e q u i v a l e n t t o m o r e t h a n 7 0 +iCi
( 2 . 6 MBq) i n m a n ) . A t l o w e r d o s e s s t u d i e s i n a n i m a l s h a v e s h o w n t h a t b o n e
c a n c e r i s t h e m o s t f r e q u e n t f o r m o f m a l i g n a n c y i n d u c e d b y p l u t o n i u m - 2 3 9 t h a t
h a s e n t e r e d t h e s y s t e m i c c i r c u l a t i o n . I n g e n e r a l t h e a p p e a r a n c e t i m e o f
t h e s e c a n c e r s i s d e p e n d e n t u p o n t h e a m o u n t o f p l u t o n i u m d e p o s i t e d i n b o n e .
A v a r i a t i o n i n s e n s i t i v i t y b e t w e e n d i f f e r e n t a n i m a l s p e c i e s h a s b e e n d e m o n -
s t r a t e d a n d t h e r e a r e t h e r e f o r e p r o b l e m s i n e x t r a p o l a t i n g t h e s e r e s u l t s t o
man. B o n e c a n c e r s h a v e a l s o o c c u r r e d i n d o g s g i v e n i n t r a v e n o u s i n j e c t i o n s
o f a m e r i c i u m - 2 1 + 1 , i n d o g s t h a t h a d i n h a l e d p l u t o n i u m - 2 3 8 o x i d e , a n d i n r a t s
t h a t h a d i n h a l e d a m e r i c i u m a n d c u r i u m c o m p o u n d s .
L i v e r c a n c e r s h a v e b e e n o b s e r v e d i n d o g s g i v e n i n t r a v e n o u s i n j e c t i o n s
o f p l u t o n i u m - 2 3 9 b u t t h e y h a v e o c c u r r e d m u c h l e s s f r e q u e n t l y t h a n b o n e
c a n c e r s . D e s p i t e t h e l o w i n c i d e n c e o f l i v e r c a n c e r s f o u n d i n a n i m a l s t h i s
t i s s u e m u s t b e c o n s i d e r e d p o t e n t i a l l y a t r i s k i n man u n t i l s h o w n t o b e
o t h e r w i s e .
3»U Lvmph n o d e s
Some o f t h e p l u t o n i u m o r o t h e r a c t i n i d e s d e p o s i t e d e i t h e r i n t h e l u n g s
o r a t a w o u n d s i t e may b e t r a n s l o c a t e d t o r e g i o n a l l y m p h a t i c t i s s u e .
B e c a u s e o f t h e i r s m a l l m a s s t h e r a d i a t i o n d o s e t o t h e s e n o d e s may g r e a t l y
e x c e e d t h a t t o t h e s i t e o f i n t a k e o r t o o t h e r t i s s u e s . H o w e v e r , e v i d e n c e
f r o m s t u d i e s i n e x p e r i m e n t a l a n i m a l s i s t h a t t h e o n l y s i g n i f i c a n t damage
t h a t o c c u r s i n t h i s t i s s u e i s f i b r o s i s o r n e c r o s i s a n d t h a t t h e y a r e n o t
a p r i m a r y s i t e f o r t h e d e v e l o p m e n t o f r a d i a t i o n i n d u c e d m a l i g n a n t d i s e a s e .
Prom t h i s r e a s o n l y m p h a t i c t i s s u e s h o u l d n o t b e c o n s i d e r e d a c r i t i c a l t i s s u e
f o r i n t a k e s o f a c t i n i d e s .
3 - 5 Gut
No e f f e c t s o n t h e g a s t r o - i n t e s t i n a l t r a c t h a v e b e e n o b s e r v e d e i t h e r
i n man o r a n i m a l s f o l l o w i n g e x p o s u r e t o a c t i n i d e s . I t i s u n l i k e l y , b u t
n e v e r t h e l e s s p o s s i b l e , t h a t c a n c e r s o f t h e g a s t r o - i n t e s t i n a l t r a c t c o u l d
o c c u r a s a r e s u l t o f i n g e s t i o n o f l a r g e a m o u n t s o f a c t i n i d e s .
181;
3 . 6 G o n a d s
No t u m o u r s o r e v i d e n c e o f h e r e d i t a r y e f f e c t s r e s u l t i n g f r o m t h e
i n c o r p o r a t i o n o f a c t i n i d e s i n t h e g o n a d s h a s b e e n d e m o n s t r a t e d i n a n y o f
t h e a n i m a l s p e c i e s s t u d i e d . I n o r d e r t o a s s e s s t h e h e r e d i t a r y e f f e c t s o f
a c t i n i d e s i n c o r p o r a t e d i n t h e g o n a d s i t i s t h e r e f o r e n e c e s s a r y t o e x t r a -
p o l a t e f r o m s t u d i e s o n a n i m a l s e x p o s e d t o e x t e r n a l r a d i a t i o n .
3 . 7 Wounds
The o n l y c l i n i c a l o r p a t h o l o g i c a l c h a n g e r e p o r t e d i n man h a s b e e n t h e
d e v e l o p m e n t a f t e r a f e w m o n t h s o r y e a r s o f f i b r o u s n o d u l e s a r o u n d t h e s i t e
o f p l u t o n i u m d e p o s i t s o f b e t w e e n k a n d 200 n C i (0.15 a n d 7 -4 k B q ) .
3 . 8 The h o t p a r t i c l e p r o b l e m
The h y p o t h e s i s t h a t n o n - u n i f o r m i r r a d i a t i o n o f t h e l u n g b y p a r t i c l e s o f
p l u t o n i u m o r o t h e r a c t i n i d e s i s l i k e l y t o b e m o r e c a r c i n o g e n i c t h a n u n i f o r m
i r r a d i a t i o n o f t h e l u n g i s n o t s u p p o r t e d b y t h e e v i d e n c e a v a i l a b l e . F o r a
g i v e n a m o u n t o f a c t i v i t y u n i f o r m i r r a d i a t i o n o f t h e l u n g i n c r e a s e s t h e
n u m b e r o f c e l l s a t r i s k a n d i s p o t e n t i a l l y m o r e c a r c i n o g e n i c .
U. T h e r a p y
B r o n c h o p u l m o n a r y l a v a g e i s t h e o n l y m e t h o d o f t r e a t m e n t t h a t h a s b e e n
s h o w n t o b e e f f e c t i v e i n a n i m a l s f o r r e m o v i n g i n s o l u b l e r a d i o a c t i v e p a r t i -
c l e s d e p o s i t e d i n t h e l u n g s . The t r e a t m e n t h a s b e e n u s e d o n l y o n c e i n man
f o r r e m o v i n g a n i n t a k e o f p l u t o n i u m a n d w a s n o t v e r y e f f e c t i v e . The
a c c u m u l a t e d e v i d e n c e f r o m a n i m a l e x p e r i m e n t s s u g g e s t s t h a t e x t e n d i n g t h e
c o u r s e o f t r e a t m e n t w o u l d h a v e f u r t h e r r e d u c e d t h e l u n g c o n t e n t o f p l u t o n i u m .
F o r r e m o v i n g a c t i v i t y d e p o s i t e d a t a wound s i t e t h e m o s t s a t i s f a c t o r y
t r e a t m e n t i s e x c i s i o n o f a s much o f t h e c o n t a m i n a t e d t i s s u e a s p o s s i b l e .
I n t r a v e n o u s i n j e c t i o n o f t h e c a l c i u m s a l t o f t h e c h e l a t i n g a g e n t
d i e t h y l e n e t r i a m i n e p e n t a a c e t i c a c i d (DTPA) i s t h e o n l y p r e s e n t l y u s e d
m e t h o d f o r r e m o v i n g s o l u b l e f o r m s o f a c t i n i d e f r o m t h e b o d y . I t w i l l
e f f e c t i v e l y c l e a r a c t i n i d e s f r o m t h e b l o o d a n d e x t r a c e l l u l a r f l u i d a n d some
t h a t h a s r e c e n t l y d e p o s i t e d i n b o n e a n d o t h e r t i s s u e s . I t i s u n a b l e t o
r e m o v e i n t r a c e l l u l a r d e p o s i t s o r a c t i v i t y t h a t h a s b e e n b u r i e d i n b o n e a n d
m u s t t h e r e f o r e b e a d m i n i s t e r e d s o o n a f t e r a n i n t a k e . The u s e o f a n a e r o s o l -
i s e d f o r m o f DTPA may b e a c o n s i d e r a b l e a d v a n t a g e i n r e d u c i n g t h e t i m e
b e f o r e t r e a t m e n t i s g i v e n a n d f o r r e m o v i n g l u n g d e p o s i t s o f s o l u b l e f o r m s o f
a c t i n i d e s . L o c a l i n j e c t i o n o f DTPA i n t o c o n t a m i n a t e d w o u n d s c a n r e m o v e m o r e
p l u t o n i u m f r o m t h e b o d y t h a n t h e same a m o u n t g i v e n i n t r a v e n o u s l y p r o v i d e d
t h e DTPA c o m p l e t e l y i n f i l t r a t e s t h e w o u n d s i t e . A m e t h o d f o r r e m o v i n g b o t h
185
i n t r a c e l l u l a r a n d s k e l e t a l d e p o s i t s o f a c t i n i d e s i s u r g e n t l y r e q u i r e d .
5 . H e a l t h E f f e c t s i n Man
A s t h e h i s t o l o g i c a l t y p e s o f c a n c e r s e e n i n e x p e r i m e n t a l a n i m a l s
may d i f f e r f r o m t h o s e c o m m o n l y s e e n i n man a n d a s t h e r e a r e s p e c i e s
d i f f e r e n c e s i n r a d i o s e n s i t i v i t y , o n l y human d a t a h a v e b e e n u s e d f o r
c a l c u l a t i n g r i s k c o e f f i c i e n t s f o r l a t e s o m a t i c e f f e c t s o f r a d i a t i o n .
T h e r e a r e n o d a t a o n t h e d e v e l o p m e n t o f c a n c e r s i n h u m a n s a s a r e s u l t
o f i n c o r p o r a t i o n o f p l u t o n i u m , a m e r i c i u m o r c u r i u m i s o t o p e s . E s t i m a t e s
o f r i s k h a v e t h e r e f o r e b e e n b a s e d m a i n l y o n t h e r e s u l t s o f e p i d e m i l o g i c a l
s t u d i e s o n h u m a n s e x p o s e d t o e x t e r n a l r a d i a t i o n . Some i n f o r m a t i o n i s
a l s o a v a i l a b l e o n t h e d e v e l o p m e n t o f b o n e a n d l i v e r c a n c e r s a s a r e s u l t
o f i n t a k e s o f o t h e r a l p h a e m i t t e r s .
To p r o v i d e a b a s i s f o r a n a s s e s s m e n t o f t h e e f f e c t s o n a p o p u l a t i o n
o f e x p o s u r e t o a c t i n i d e s , e s t i m a t e s o f r i s k c o e f f i c i e n t s h a v e b e e n made
f o r a l p h a r a d i a t i o n - i n d u c e d d e a t h s f r o m l e u k a e m i a (1+00 c a s e s p e r 10^ man
r a d a l p h a (1+00 p e r 10^ man G y ) ) a n d f r o m c a n c e r s o f t h e b o n e (100 c a n c e r s
p e r 10^ man r a d a l p h a (100 p e r 10^ man G y ) ) , l i v e r (100 c a n c e r s p e r 10^
man r a d a l p h a (100 p e r 10 " man G y ) ) , l u n g (1+00 c a n c e r s p e r 10^ man r a d
a l p h a (1+00 p e r 10 " man G y ) ) a n d g a s t r o i n t e s t i n a l t r a c t (1+00 c a s e s p e r
10^ man r a d a l p h a (1+00 p e r 10^ man G y ) ) . F o r s e r i o u s h e r e d i t a r y d i s e a s e s
a t o t a l o f 111+0 c a s e s p e r 10^ man r a d a l p h a (111+0 p e r 10^ man Gy) i s
p r e d i c t e d o v e r many g e n e r a t i o n s . T h e s e v a l u e s a r e b a s e d o n t h e u s e o f a
q u a l i t y f a c t o r o f 20 f o r a l p h a r a d i a t i o n .
To a s s e s s t h e b i o l o g i c a l c o n s e q u e n c e s o f i n t a k e s o f a c t i n i d e s t h e s e
r i s k c o e f f i c i e n t s m u s t b e w e i g h t e d b y t h e d o s e s a c c u m u l a t e d b y t h e
v a r i o u s t i s s u e s . F u r t h e r m o r e t h e r i s k c o e f f i c i e n t s f o r r a d i a t i o n i n d u c e d
c a n c e r s a r e b a s e d o n t h e a s s u m p t i o n t h a t t h e f u l l r i s k t o t h e t i s s u e s i s
e x p r e s s e d . B e c a u s e o f t h e l o n g l a t e n t p e r i o d f o r c a n c e r i n d u c t i o n t h i s
w i l l o n l y a p p l y t o d o s e s r e c e i v e d e a r l y i n l i f e . The g e n e t i c a l l y s i g n -
i f i c a n t d o s e i s t h a t a c c u m u l a t e d u p t o a g e a b o u t 30.
A P P E N D I X N o t e o n U n i t s
1 . The u n i t s m o s t f r e q u e n t l y u s e d i n t h e t e x t a r e :
U n i t o f a c t i v i t y : t h e c u r i e ^ i s t h a t q u a n t i t y o f r a d i o a c t i v e m a t e r i a l
g i v i n g 3*1 x 1 0 " ^ d i s i n t e g r a t i o n s p e r s e c o n d , a n d c o r r e s p o n d s t o t h e
a m o u n t o f r a d o n i n e q u i l i b r i u m w i t h l g o f r a d i u m . Some s u b - u n i t s a r e :
1 m i l l i c u r i e ( m C i ) = l c f ^ C i
1 m i c r o c u r i e ( | i C i ) = 10~^ C i
1 n a n o c u r i e ( n C i ) = 10~^ C i
—12 1 p i c o c u r i e ( p C i ) = 10*" C i
U n i t o f a b s o r b e d d o s e : t h e r a d , w h i c h c o r r e s p o n d s t o a n a b s o r b e d —2 —1
e n e r g y o f 10 j o u l e s p e r k i l o g r a m o f t i s s u e ( = 100 e r g . g ) .
U n i t o f d o s e e q u i v a l e n t : t h e r e m . The b i o l o g i c a l e f f e c t i v e n e s s o f
t h e a b s o r b e d d o s e d e p e n d s u p o n s u c h f a c t o r s a s t h e s p a t i a l d i s t r i b u t i o n
o f t h e d o s e a n d t h e l i n e a r e n e r g y t r a n s f e r o f t h e r a d i a t i o n . The rem
i s t h e p r o d u c t o f t h e a b s o r b e d d o s e m u l t i p l i e d b y o n e o r m o r e w e i g h t i n g
f a c t o r s w h i c h t a k e a c c o u n t o f t h e s e d i f f e r e n t i r r a d i a t i o n c o n d i t i o n s .
2. T h e s e u n i t s a r e b e i n g p r o g r e s s i v e l y r e p l a c e d b y t h e I n t e r n a t i o n a l
S y s t e m o f U n i t s ( S i )
U n i t o f a c t i v i t y : t h e B e c q u e r e l ( B q )
1 Bq = 1 d i s i n t e g r a t i o n p e r s e c o n d
U n i t o f a b s o r b e d d o s e : t h e G r a y ( G y ) _ 1
1 Gy = 1 j o u l e k g
U n i t o f d o s e e q u i v a l e n t : t h e S i e v e r t ( S v )
1 S v = 100 r em
187
188
The r e l a t i o n s h i p b e t w e e n t h e n e w S I u n i t s a n d t h e p r e v i o u s u n i t s a r e
s h o w n i n t h e t a b l e b e l o w :
Q u a n t i t y New n a m e d u n i t
a n d s y m b o l I n o t h e r S I u n i t s
O l d s p e c i a l u n i t a n d s y m b o l
C o n v e r s i o n f a c t o r
A b s o r b e d d o s e
g r a y ( G y ) J k g " 1 r a d ( r a d ) 1 Gy = 100 r a d
D o s e e q u i v a l e n t
s i e v e r t ( S v ) J k g " 1 r e m ( r e m ) 1 S v = 100 rem
A c t i v i t y b e c q u e r e l ( B q ) - 1
s c u r i e ( C i ) 1 B q * 2 . 7 x 1 0 " 1 1
C i
R E F E R E N C E S
Adams , N . ( 1 9 7 6 ) N a t i o n a l R a d i o l o g i c a l P r o t e c t i o n B o a r d , H a r w e l l . P e r s o n a l
c o m m u n i c a t i o n .
A d a m s , N . , ( 1 9 7 8 ) N a t i o n a l R a d i o l o g i c a l P r o t e c t i o n B o a r d , H a r w e l l .
P e r s o n a l c o m m u n i c a t i o n
A l b e r t , R. E . , B u r n s , F . J . a n d H e i m b a c h , R. D . ( 1 9 6 7 a ) The e f f e c t o f
p e n e t r a t i o n d e p t h o f e l e c t r o n r a d i a t i o n o n s k i n t u m o r f o r m a t i o n i n t h e
r a t . R a d i a t . R e s . , JO, 5 1 5 .
A l b e r t , R. E . , B u r n s , F . J . a n d H e i m b a c h , R. B . ( 1 9 6 7 b ) S k i n damage a n d
t u m o r f o r m a t i o n f r o m g r i d a n d s i e v e p a t t e r n s o f e l e c t r o n a n d b e t a
r a d i a t i o n i n t h e r a t . R a d i a t . R e s . , JO, 5 ^ 5 -
A l b e r t , R. E . , B u r n s , F . J . a n d H e i m b a c h , R. D . ( 1 9 6 7 c ) The a s s o c i a t i o n
b e t w e e n c h r o n i c r a d i a t i o n damage o n t h e h a i r f o l l i c l e s a n d t u m o r
f o r m a t i o n i n t h e r a t . R a d i a t . R e s . , JO, 5 9 0 .
A l b e r t , R. E . , A l p e n , E . L . , B a i r , W. J . , C a s a r e t t , G. W . , E p p , E . R . ,
G o l d m a n , M . , G r e g g , E . C . , L e w i s , E . B . , M c C l e l l a n , R. 0., R a d f o r d , E . P .
a n d H i l b e r g , A . W. ( 1 9 7 6 ) H e a l t h e f f e c t s o f a l p h a - e m i t t i n g p a r t i c l e s i n
t h e r e s p i r a t o r y t r a c t , r e p o r t o f Ad Hoc C o m m i t t e e o n "Hot p a r t i c l e s " ,
N a t i o n a l Academy o f S c i e n c e s , NRC, U . S . E . P . A . , EPA 5 2 0 / 4 - 7 6 - 0 1 3 «
A n d e r s o n , E . C. e t a l ( 1 9 7 4 a ) E f f e c t s o f i n t e r n a l r a d i a t i o n o n t h e l i v i n g
o r g a n i s m . A n n u a l r e p o r t o f t h e LASL H e a l t h D i v i s i o n , L A - 5 8 8 3 - P R , L o s
A l a m o s S c i e n t i f i c L a b o r a t o r y , p 2 .
A n d e r s o n , E . C , H o l l a n d , L . M . , P r i n e , J . R. a n d R i c h m o n d , C . R. ( 1 9 7 4 " D )
Lung i r r a d i a t i o n w i t h s t a t i c p l u t o n i u m m i c r o s p h e r e s . I n : E x p e r i m e n t a l
l u n g c a n c e r , c a r c i n o g e n e s i s a n d b i o a s s a y s , I n t e r n a t i o n a l s y m p o s i u m ,
S e a t t l e - , 2 3 - 2 6 J u n e 1 9 7 4 , E . K a r b e , J . F . P a r k E d s , B e r l i n , S p r i n g e r -
V e r l a g , p 4 3 0 .
A n t o n c h e n k o , G. P . , K o s h u r n i k o v a , N . A. a n d L y u b c h a n s k i i , E . R. ( 1 9 ^ 9 )
M o r p h o l o g i c a l c h a n g e s i n t h e l u n g s o f r a t f o l l o w i n g i n h a l a t i o n o f l a r g e
d o s e s o f p l u t o n i u m - 2 3 9 c o m p o u n d s . R a d i o b i o l o g i y a £ , 7 5 .
A r c h e r , V . E . a n d L u n d i n , F . E . J r . ( 1 9 ^ 7 ) R a d i o g e n i c l u n g c a n c e r i n ^ a n .
e x p o s u r e - e f f e c t r e l a t i o n s h i p . E n v i r o n . R e s . , 1_, 3 7 0 .
A r c h e r , V . E . , J o s e p h , K . , W a g o n e r , S . D . , F r a n k , E . a n d L u n d i n , F . E . J r .
( 1 9 7 3 ) U r a n i u m m i n i n g a n d c i g a r e t t e s m o k i n g e f f e c t s o n man . J . O c c u p .
M e d . , l £ , 2 0 4
A r c h e r , V . E . , D e a n G i l l a m , J . a n d W a g o n e r , J . K. ( 1 9 7 6 ) R e s p i r a t o r y
d i s e a s e m o r t a l i t y among u r a n i u m m i n e r s . A n n a l s o f t h e New Y o r k A c a d .
S c i . , 2 7 1 , O c c u p a t i o n a l C a r c i n o g e n e s i s , V . S a f f i o t i a n d J . K. W a g o n e r
E d s , p 2 8 0 .
189
190
A r n o l d , J . S . ( 1 9 5 0 M e t a b o l i s m o f B o n e a s s t u d i e d b y r a d i o a u t o g r a p h i c
d i s t r i b u t i o n o f c a l c i u m , p l u t o n i u m a n d r a d i u m . Am. J . P h y s i o l . , 1 6 7 ,
7 6 5 .
A r n o l d , J . S . a n d J e e , W. S . S . ( 1 9 5 7 ) B o n e g r o w t h a n d o s t e o c l a s t i c
a c t i v i t y a s i n d i c a t e d b y r a d i o a u t o g r a p h i c d i s t r i b u t i o n o f p l u t o n i u m .
Amer . J . A n a t . 1 0 1 , 3 6 7 .
A r n o l d , J . S . a n d J e e , W. S . S . ( 1 9 6 2 ) P a t t e r n o f l o n g - t e r m s k e l e t a l
r e m o d e l l i n g r e v e a l e d b y r a d i o a u t o g r a p h i c d i s t r i b u t i o n o f p l u t o n i u m - 2 3 9
i n d o g s . H e a l t h P h y s . , Q, 7 0 5 -
A s t l e y , C. a n d S a n d e r s , C . L . ( 1 9 7 3 ) B i l i a r y e x c r e t i o n o f i n j e c t e d
p l u t o n i u m - 2 3 8 . B a t t e l l e P a c i f i c N o r t h w e s t L a b o r a t o r y . A n n u a l R e p o r t
f o r 1 9 7 2 . V o l u m e 1 . L i f e S c i e n c e s P a r t 1 . B i o l o g i c a l S c i e n c e s . BNWL
1 7 5 0 P T 1 p 3 5 .
A t h e r t o n , D . R . , L l o y d , R. L . , T a y l o r , G. N . , S t o v e r , B . J . a n d M a y s , C. W.
( 1 9 6 8 ) D i s t r i b u t i o n o f a m e r i c i u m - 2 l + 1 i n t h e b e a g l e . R e s e a r c h i n
R a d i o b i o l o g y . A n n u a l R e p o r t o f t h e I n t e r n a l I r r a d i a t i o n P r o g r a m ,
U n i v e r s i t y o f U t a h , C 0 0 - 1 1 9 - 2 3 9 , P 1 1 7 .
A t h e r t o n , D . R . , S t e v e n s , W. a n d B r u e n g e r , F . W. ( 1 9 7 3 ) E a r l y r e t e n t i o n
a n d d i s t r i b u t i o n o f c u r i u m i n s o f t t i s s u e s a n d b l o o d o f t h e b e a g l e .
I n : R e s e a r c h i n R a d i o b i o l o g y . A n n u a l R e p o r t o f t h e I n t e r n a l I r r a d i a t i o n
P r o g r a m , U n i v e r s i t y o f U t a h , C 0 0 - 1 1 9 - 2 1 + 8 , p 1 7 8 .
B a i r , ¥ . J . a n d W i l l a r d , D . H . ( 1 9 ^ 2 ) P l u t o n i u m i n h a l a t i o n s t u d i e s : I V .
M o r t a l i t y i n d o g s a f t e r i n h a l a t i o n o f p l u t o n i u m - 2 3 9 d i o x i d e . R a d i a t .
R e s . , 1 6 , 8 1 1 .
B a i r , W. J . , W i g g i n s , A . D . a n d T e m p l e , L . A. ( 1 9 6 2 ) The e f f e c t o f i n h a l e d
p l u t o n i u m - 2 3 9 d i o x i d e o n t h e l i f e s p a n o f m i c e . H e a l t h P h y s . , 8 , 6 5 9 -
B a i r , W. J . , T o m b r o p o u l o s , E . G. a n d P a r k , J . F . ( 1 9 6 3 ) D i s t r i b u t i o n a n d
r e m o v a l o f t r a n s u r a n i c e l e m e n t s a n d c e r i u m d e p o s i t e d b y t h e i n h a l a t i o n
r o u t e . I n : P r o c . Symp. D i a g n o s i s a n d T r e a t m e n t o f R a d i o a c t i v e P o i s o n i n g
V i e n n a 1 9 6 2 . V i e n n a IAEA, p 3 1 9 -
B a i r , W. J . , P a r k , J . F . a n d C l a r k e , W. J . ( 1 9 6 6 ) L o n g - t e r m s t u d y o f
i n h a l e d p l u t o n i u m i n d o g s . T e c h n . r e p o r t n o . A E W L - T R - 6 5 - 2 1 1 + .
B a i r , W. J . , B a l l o u , J . E . , P a r k , J . F . a n d S a n d e r s , C . L . ( 1 9 7 3 ) P l u t o n i u m
i n s o f t t i s s u e s w i t h e m p h a s i s o n t h e r e s p i r a t o r y t r a c t . I n : U r a n i u m ,
p l u t o n i u m , t r a n s p l u t o n i c e l e m e n t s , H . C . H o d g e , J . N . S t a n n a r d ,
J . B . H u r s h E d s . , S p r i n g e r - V e r l a g , B e r l i n , p 5 0 3 -
B a i r , W. J . ( 1 9 7 1 + a ) T o x i c o l o g y o f p l u t o n i u m . A d v a n . R a d i a t . B i o l . , 1±, 2 5 5 *
191
B a i r , W. J . ( l 9 7 U b ) The b i o l o g i c a l e f f e c t s o f t r a n s u r a n i u m e l e m e n t s i n
e x p e r i m e n t a l a n i m a l s . I n : P l u t o n i u m a n d o t h e r t r a n s u r a n i u m e l e m e n t s :
s o u r c e s , e n v i r o n m e n t a l d i s t r i b u t i o n a n d b i o m e d i c a l e f f e c t s . WASH 1 3 5 9 ,
HSAEC.
B a i r , W. J . a n d T h o m p s o n , R. C. ( 1 9 7 U ) P l u t o n i u m : B i o m e d i c a l R e s e a r c h .
S c i e n c e , 1 8 3 , 7 1 5 .
B a i r , W. J . , R i c h m o n d , C. R. a n d W a c h h o l z , B . W. ( 1 9 7 U ) A r a d i o b i o l o g i c a l
a s s e s s m e n t o f t h e s p a t i a l d i s t r i b u t i o n o f r a d i a t i o n d o s e f r o m i n h a l e d
p l u t o n i u m . W A S H - 1 3 2 0 , USAEC.
B a i r , W. J . ( 1 9 7 6 ) R e c e n t a n i m a l s t u d i e s o n t h e d e p o s i t i o n , r e t e n t i o n a n d
t r a n s l o c a t i o n o f p l u t o n i u m a n d o t h e r t r a n s u r a n i c c o m p o u n d s . I n : P r o c .
S e m i n a r , D i a g n o s i s a n d T r e a t m e n t o f I n c o r p o r a t e d R a d i o n u c l i d e s . V i e n n a ,
1 9 7 5 , V i e n n a IAEA, p 5 1 .
B a i r , W. J . a n d T h o m a s , J . M. ( 1 9 7 6 ) P r e d i c t i o n o f t h e h e a l t h e f f e c t s o f
i n h a l e d t r a n s u r a n i u m e l e m e n t s f r o m e x p e r i m e n t a l a n i m a l d a t a . I n : P r o c . i
Symp. T r a n s u r a n i u m n u c l i d e s i n t h e E n v i r o n m e n t , S a n F r a n c i s c o , 1 9 7 5 -
V i e n n a IAEA, p 5 6 9 -
B a l l o u , J . E . ( 1 9 5 8 ) E f f e c t s o f a g e a n d mode o f i n g e s t i o n o n a b s o r p t i o n
o f p l u t o n i u m . P r o c . S o c . E x p . B i o l . M e d . , 28» 7 2 6 .
B a l l o u , J . E . a n d B u s c h , R . H . ( 1 9 7 2 ) A c u t e t o x i c i t y o f DTPA a d m i n i s t e r e d
i n t r a t r a c h e a l l y . B a t t e l l e P a c i f i c N o r t h w e s t L a b o r a t o r y . A n n u a l R e p o r t
f o r 1 9 7 1 . V o l u m e 1 . L i f e S c i e n c e s P a r t 1 , B i o l o g i c a l S c i e n c e s . BNWL
1 6 5 0 ( P t 1 ) p 1 6 U .
B a l l o u , J . E . a n d H e s s , J . 0 . ( 1 9 7 2 ) B i l i a r y p l u t o n i u m e x c r e t i o n i n t h e
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I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 5 9 ) R e p o r t o f
C o m m i t t e e I I o n P e r m i s s i b l e B o s e f o r I n t e r n a l R a d i a t i o n , ICRP
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o f ICRP. ICRP, P u b l i c a t i o n 8, P e r g a m o n P r e s s , O x f o r d .
I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 6 6 c ) R e c o m m e n d a -
t i o n s o f t h e I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n .
ICRP P u b l i c a t i o n 9 , P e r g a m o n P r e s s , O x f o r d .
I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 6 8 ) A r e v i e w o f
t h e r a d i o s e n s i t i v i t y o f t h e t i s s u e s i n b o n e . ICRP P u b l i c a t i o n 1 1 ,
P e r g a m o n P r e s s , O x f o r d .
I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 ^ 9 ) T a s k Group
o f C o m m i t t e e 1 o f t h e I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n
R a d i o s e n s i t i v i t y a n d s p a t i a l d i s t r i b u t i o n o f d o s e . ICRP P u b l i c a t i o n 1l+,
P e r g a m o n P r e s s , O x f o r d .
I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 7 2 a ) The RBE
f o r H i g h - L E T R a d i a t i o n s w i t h R e s p e c t t o M u t a g e n e i s . ICRP P u b l i c a t i o n
18 , P e r g a m o n P r e s s , O x f o r d .
I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 7 2 b ) M e t a b o l i s m o f
Compounds o f P l u t o n i u m a n d O t h e r A c t i n i d e s . ICRP P u b l i c a t i o n 19,
P e r g a m o n P r e s s , O x f o r d .
I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 7 5 ) R e p o r t o f t h e
T a s k Group o f C o m m i t t e e I I o n R e f e r e n c e Man. ICRP P u b l i c a t i o n 23,
P e r g a m o n P r e s s , O x f o r d .
2 0 2
I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 7 7 ) R e c o m m e n d a t i o n s
o f t h e I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n . ICRP
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