1409 1409 - Attorney General of Minnesota
Transcript of 1409 1409 - Attorney General of Minnesota
Fluomchemical Steeling Commillee Members
Jeff MandeL M.D., 333-8670 (220-3W-O5)
Papers/Dr. Gilliland
December 7, 1~ ¯
These are two additional papers that a~e being prepered by Dr. Gill=land_ They need ou~ inpul/appmval before being su~itted for publication.
The papers are negative for lhe.mos! part, We’re workirg with him regarding some of the wo~ding. We’re operaSng under the pre~nise Ihat these s0Hs of topics need 3M suppod.
Please send you~ ~,omments back !o me by the end of Ihe monlh so I can communJc~e with IDr_ Gitlilat~l.
JHM/vtk
CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO, 27-CV-10-28862
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Exhibit
1409 State of Minnesota v, 3M Co,,
Court File No, 27-CV-10-28862
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Peripheral Blood Lymph~T~e Coun¢ in Men Occupationally Exposed to
Perfluomoctanoic Acid
Prank D. GiRiland, M~D., Ph.D.
Jack S. Mandel PKD.
Affiliations: Division of Environmental and Occupational Health, School of
Public Health, University of Mirmesota, Minneapolis (F.D.G); and
Department o~ Internal Medicine, Occupational a~d ]~nvivonmei~tal Medic~e
Section, St_Paul Ramsey Medica~ Center, SuPaRI0 M~nnesota (F.D.G.)
Reprint requests should be addressed to F~-n~ir D. (~il!i!~d, Univers~W of
New Me~xic~ Sclmol of Me~e, New ~ T~or ~, ~ C~mi~ de
Salud ~, ~buque~ue, ~ 87131. Tetep~ (~5) 277-~41, F~
277-7041.
This study was supported in part by NIOSH Grant T150h07098-16 and 31v£
Medical Departmen~
Running title: Lymphocyte count and PFOA "
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ABSTRACT
Studies in Rhesus monkeys suggest thac perfluoroocta~oic acid (PFOA) has
immua0toxie effects on the coil-mediated immune system in pximates. The
predominant histopathological lesion in PFOA-treated monkeyswas diffuse
atrophy of lymph nodes and splenic germinal centers. Although PFOA
acmunts for the majority of fluorine presen~ in the serum of the general
population and in occupationally exposed worker~0 little information is
available concerning human responses to PFOA exposure. To as~ss whether
PFOA exposure is associated with effects on the human �~ll-mediated
immune system, we examined the cross-sectional associations between
peripheral bk~l lymphocyte courts and PFOA in 115 workers employed at- a
PFOA production planh Total serum fluorine was ur~ as a surrogate
measure for sex~.un PFOA levels. Peripheral blood lymphocyte cotmt was
sig~facanrly ass~L~e~_ with total serum JQ~oride level; however, the
magnitude and direction of the ~elationship was dependent on smoking,
alcohol use, and obesity status. For example, for nolI-smokers and moderate
drinkers, an ~ncrease of 10 ppm in/~! serum fluoride w~s associated with a
decrease in lymphocyte count of 1~40 ce)]s in non-obese (BM]=25 l~g/m2)
worker~ and by 925 cell in obese workers (BMI=35 kg/m2). ]’I~OA is
s~iated with alterations in peripheral blo~ lymphocyte numbers ha PFOA
pro~iuc~ion workers, suggesting ~hat cel].media~i immurd~y may be affected
~ PFOA.
WORDS perlluorooctanoic acid, epidemiology, immune toxicity,
CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO. 27-CV-10-28862
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Perfiuorooctanoie acid (PFOA) is widely used in industrial proce~3es and
consumer produet~ a~ a reset ofit~ unique chemleal properties and potent
surface activity (Ot~fith, 1980). Because PFOA has s long biological half-life,
small ~quent do~es can ac~lmulate to appreciable levels (Ube], 1980). As a
result, PFOA ha~ been found in the serum of all human population studied,
and accounl~ for the majority of fluorine pre~ent in the ~rum ofp~pul~i~n$
in industrialized countries1"7.
Little i~ known abou~ the toxic potential of PFOA in human~; however,
studie~ have suggested that the celIomediated immu~e system may be a site
of tuxicity in primates. Rhesus monkeys treated with oral PFOA developed
histologle ehange~ in ~p~eeu and lymph nodes. The primary histopathologic
lesion was atrophy in lymph node and splezfic gex~ninal centers1. The immune
system o~rodent species bee not been rei~orted to undergo
histvpathologie changes in subacute and chronic feeding studies !. No data
available concerning immunotox~c~y in human~. Becatt~e PFOA ~s present in
the ~erum ofexpo~ed worker~ and in the general population ~-7, it is a matter
of concern whether the finding~ in monkeys indicate the potential rot human
immunotexicity. To assess whether PFOA could affect the cell-media~ed
immune system in humans, we studied the a~ciation of PFOA. as measured
by total serum fluorine, wi~h peripheral b~ lymphocyte count (PBL) in 115
occupationally exposed emp]oyee~ at_ a plant l:hat produces
B~L-kTERL-~L~ AArD ~THODS
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All current workers employed in PFOA production over the 5 previous years
and a sample of workers in jobs with no apparent PFOA e~posure for the
previous ~ years were invited to participate. Participants had vi£a!
paxameters measured in the.plant medical department by an occupational
health nurse, c~mpleted a medical history questionnaire, and underwent
venipunc~me. Blood was drawn foz assays ofperipheral lymphocyte count. A
fluorine-L,-ev 15 ml va~tainer was used to ~Hect blo~i for total serum
fluorine dete ~r~_ i~Ation. Total serum fluorine was used as the measure of
PFOA in this eccupatieual g~oup, Total sexttm fluorine was determined using
the sodium biphenyl extraction and atomic absorption spectrometry s,
RESULTS
Pax~icipant charac~ezistics are displayed in Table L Total serttm fluorine
values ranged f~m 0 and 26 ppm with a mean of 3.3 ppm. Twenty-three
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(20.0%) par~cipants bad ~erum values less than I ppm. 6 (5.2%} had values
between t0 and 15 ppm, and 5 (4.456) had values greater than 15 ppm_
Table 2 presents the o~rdation coefficients between PIlL and total serum
fluori~e, age, BMI, akohol use, and cigarette co~umption. Peripheral blood
lymphocyte count was significantly correlated with total ~erum fluorine
(r=.19, p=,04). The fin~] regression model for PBL, which adjusted for age,
BMI, cigarette use, and alcohol use. included data for Ill workers; 4 of the
115 workers had miss~g assay values and were excluded from the analysi~
(Table 3). Total serum fluorine was inversely associated with PBL; however,
the relationship was complex, with si~ut interactions bel~ween total
serum fluorine and BMI0 ~iRarette use, mud alcohol use. Table 4 illustrates
t~e rela~onship for a 10 ppm chan~e in total s~rum fluor~e for comb~uations
ofsmokingo alcohol consumption, and BMI st~tu~. In moderate ~h~;-ker~ (1o
3oz ~kohol per day), PBL decrea~d in the categar~es of ~moking an~ of
obesity; ~n light drinkers (<loz per day), PBL decre~d ~n non-obese smokers
only.
Discussion
Serum PFOA level is asaocia~ed with chan~es in the cell-mediat~ imm~me
~’stem, as e~denced by cha~ ~ PB~ ~we~r, t~ rela6o~ depen&
u~n smok~, alcohol use, ~d ob~i~. PFOA ~d ~ ~B ~ by
alte~ng the kn~ effec~ of smo~g, ~co~l ~ump~o~ and a~si~ on
pe~phe~ le~o~e ~ (~). No human sc~es oft~ eff~ oEPFOA on
~he ~mune sys~m a~ av~ble for ~mpa~n: howe~r, a study of th~
~up ofworke~ s~gesm ~hat PFOA may mo~ ~ ~pafic ~pon~ ro
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alcohol and obesity. Modulation of endobiotic and xenobiotic metabolism
could represen~ a common mechanism for ~he observed association o~ PFOA
with alterations in hepatic and immune response.
q’he relationship between the changes in PBoL in humans and the lymph node
and splenic germinal center atrophy observed in monkeys is not clear.
Clothes in PBL may be unrelated to ger_m~al ~nter atrophy. Alterna~icely,
small changes m PBL could reflect larger ¢~__~n~e~ in T cell subset~ In
addition, the modi~ation of the relationship between smoking and PBL by
PFOA could be the ~es~lt of changes in the number of particular T
subset~. Furthermore, PI~)A may be associated with eh~nge~ in
function beyond simple changes in eell number. Cytokine
important in immtme f~m~ion and mu~d be all~l by PFOA exposure ~. The
response to ~u~i~en binding depends upon rearrangement of membrane
pmtein~. Changes in the membrane physical characteristics prod~i by the
potent surfactan~ action of PFOA could alter ~rnm~ r~b-pon~eso
Interpretation of the finding~ requires careful consideration of the study
limitations. Given the occupational study .setting. the voluntary
participation, and the requirements foz blood sample collection, the overall
participation was unexpectedly, high. and non-response bias is likely to be
small Workers not included may have had a different response pattern than
those who were included. Migration our of the high exposure ~obs is ~ml~kely
to be the result of subdinic~! changes in PBL counts. The vast majority of
workers who had sight exposure over the previous 5 years would be
included in the s~udy ~ample as the ~urn-over rate in plant emplo.vees was h)w
{3% per year) and the study included all current employees with appropriate
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job histories_ Selection bias is not a likelx explanation for the findings in this
study.
Inflammatory and infectious processes, which are major determinants of PBLo
were not assessed in ~his study. Because the~e is no evidence that these
precedes are related to tot~ serum fluorine or serum PFOA, they are
unlikely to confound the estimated ~elationships.
The cha,~ges in PBL count~ a~sociar~-d with PFOA expe~ur~ p~.sent a complex
picture. Alcohol use, cigarette use, and BMI modified the association of cell
count with PFOA. The magnitude of these association~ is not cllnle~lly
significant from an infectious disease perspective: however, ~udgment as to
the clinic~ relevance of such changes mus~ av~it further stedy. More
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remrarch is needed in the area ofPFOA immunotoxicity. The findings ofthe
pre~ent study need to be confirmed. Changes in T cell subsets could be
confirmed by immunophenotyping lymphocyr.es using well eetabli~hed flow
~;~metry metho~ls 2s. ~. In acldition, the standard Immunotoxicologic
assessment defined by the National Toxicnl~gy Program ~e ne~s to be
conducted Rsr PFOA.
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BMI tk~/mS) z6.~ zs.s.40.5
per day 8 ~uces per d~y 20 17.4
pe~ day 0 non-re~
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TABLE2 P~arson �orrelztion coeE~ients between to~l serum fluoride, bo~ly ~ass index (HMI). dai~y akoho! use, d~ily tobacco co~suml~tion, and
peripheral blood lymphocyt~ count
Total Age BMI Alcohol Tobacco
~pm)
LYMPHOCYTF.S .19 p=o04 p=.O02
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TABLE 3 Linoar multivariate ~egr~ssion mod~l of fac~rs predicting the lymphocy~ count among 111 workers.
2205.6 6tL1 .0005 Total ~1~or~ (ppm) ~
-526,6 222.7 .07~
-977.1 35~.7 .007 low X Fl~odae
189.0 52.3 .00~5
247.9 103.9 Cilg~u-ettegday
""~’~- 34.0
~..s .o~ ~ ~)
1.58 19.8
7.t5 4.1
R2= .~
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Table 4 Change in lymphocyte count for 10 ppm increase in total serum fluorine
oz. alcohol/day
Non-smoker Smoker (20 oig~/day)
BM125 mg/Kg2 +7~0 -406
BM135 mg/Kg2 .+965 +306
1-3 oz. of aIcohoYday
Non-smoker Smoker {20 cigs/day}
BM125 mg/Kg2 -1~10 -9.300
BM136 mgiKg~ -924 - 1585
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