The "Information Desk" Aim:

To answer questions of the authorities and Flemish official agencies on

-danger associated with a particular agent

- risk associated with a particular exposure

To provide authorities with up to date independent advice and insights concerning environmental (low dose) exposures and their biological and health effects.

In this presentation:

List of reports of the Information Desk

List of publications of the Information Desk

PCBs and dioxins in Belgian food: background concentrations, contamination episodes ,body burdens and sources of contamination

Importance of endogenous DNA damage and relative efficiency of exogenous DNA damage

Low dose effects of mutagenic agents: mechanisms involved in supralinear responses

Benzo(a)pyrene adducts and effects : dose-response and risk of cancer

Environmental exposures occur in doses below maximal induction of DNA repair: increased risk

Low dose effects of receptor binding epigenetic carcinogens

Biomarkers for genotoxicity are insufficiently sensitive for the evaluation of cancer risk from lifelong exposures starting in utero

Some potentially interesting data or conclusions concerning topics in answer to questions from authorities and to various suggestions

Reports from the “Information desk”Health effects of residing near landfillsBenzene: risk of cancer Long-term effects of pollution with fine particles (PM2,5) Acrylamide Health effects of sun creams Health effects of radiation from GSM’s and GSM-antenna’s High tension Cables Nitrates and nitrites Health effects of brominated flame retardants Acrylamide update Migration of Bisphenol A from packaging material to food Environmental medical risk analysis of Monomorium pharaonis (farao ant) Health effects of pesticides Transmission of human pathogens through aerosols from Water Purification InstallationsHealth effects of residing near an airport Health risks from the Marly fire Health effects of perfluoro octane sulfonate (PFOS) en perfluoro octanoic acid (PFOA) Criteria for the indoor environment Action plan drinking water norms Health effects of air-freshners Health effects of UMTS Action plan drinking water norms (cadmium, pesticides, tri- en tetrachloorethene). Stabilized hydrogen peroxide as desinfectant in swimming and whirlpools. Biomonitoring: DDE, HCB, PCB’s, PCDD’s en PCDF’s in cord blood and in adolescents. International data. Fytofarmaceutical substances used in the Flemish fruit cultivation:Short note in preparation of a biomonitoring study Epigenetic mechanisms in carcinogenesis: points of action of tumorpromotors and for chemoprevention Important receptor binding substances active at low doses

Publications of the “Information Desk”Mechanisms of Carcinogenesis. A short overview. N. van Larebeke In "Proceedings of the Technical Working Group on Environment and Health, "

Cancer as an Environmental Disease. P. Nicolopoulo-Stamati, L. Hens, C.V. Howard and N. van Larebeke (eds): Environmental Science and technology Library Vol 20, Kluwer Academic Publishers, Dordrecht/Boston/London.

Endogenous DNA damage in humans : a review of quantitative data. Rinne De Bont and Nik van Larebeke: Mutagenesis vol. 19 no. 3 pp. 169-185, May 2004.

A survey of 3 PCB and dioxin contamination episodes. From contamination of food items to body burdens." Rinne De Bont1, Marc Elskens2, Willy Baeyens2, Luc Hens3, Nik van Larebeke1 Reviews in Food and Nutrition Toxicity, Vol 2, p301-342.

“Hormesis”—An Inappropriate Extrapolation from the Specific to the Universal. DEBORAH AXELROD, MD, KATHY BURNS, PHD, DEVRA DAVIS, PHD, MPH, NICOLAS VON LAREBEKE, MD, MPH. INT J OCCUP ENVIRON HEALTH 2004;10:335–339

Omgevingsconcentraties van mutagene agentia als oorzaak van kanker: mechanistische inzichten. N. van Larebeke en R De Bont.Tijdschrift voor Geneeskunde, 62 (4) 319-329

Unrecognised / Potential Risk Factors for Childhood Cancer. N. van Larebeke, Linda Birnbaum , Marc Bracke , Marc Boogaerts , Devra Davis , David DeMarini , Jos Kleinjans , Marvin Legator , Greet Schoeters and Kirsi Vähäkangas In Proceedings of the "Technical Working Group on Environment and Health, ". INT J OCCUP ENVIRON HEALTH 2005;11:199–201

PCBs AND PCDD/FS IN FISH AND FISH PRODUCTS AND THEIR IMPACT ON THE HUMAN BODY BURDEN IN BELGIUM. W. Baeyens1, M. Leermakers1, M. Elskens1, N. Van Larebeke2, R. De Bont2, H. Vanderperren3, A. Fontaine3, J-M Degroodt4, L. Goeyens1,4, V. Hanot4, I. Windal4. Accepted for publication, A R C H I V E S O F Environmental Contamination a n d Toxicology  Adducts, SCE’s and Mutations following Benzo(a)pyrene Exposure: a Review of quantitative Data followed by some Considerations regarding Risk. Rinne De Bont, Nik van Larebeke . Accepted for publication in "Chromosomal Alterations: Importance in Human Health", edited by Gunter Obe and Vijayalaxmi (Springer Verlag).

PCB’s and dioxins: background concentrations in Belgian FoodA study based on measurements obtained from the Federal Agency for the Safety of the Food Chain and

on biomonitoring by the Flemish Center of Expertise on Environment and Health

Background concentrations measured in 2001

Crisis-related PCB concentrations May-August 1999

PCB and dioxin intake

Calculated and measured PCB and dioxin body burdens for female adolescents and adult women.

High PCB concentrations in Belgian meat stem for a large part from recycling of fat in animal feed

Measured PCB body burdens in Belgian women before and after the contamination crisis early in 1999.

    PCBs

    Concentration (ng/g fat)

Maximum level (ng/g fat)

Percent of samples (ng/g fat)

  N AM±SD GM ≥200 ≥1,000

Beef 312 34.2 ± 6.2 33.3 71.0 None None

Cow’s milk

190 29.5 ± 11.3 25.1 35.0 None None

Poultry 302 35.0 ± 0.5 35.0 35.0 None None

Eggs 345 32.8 ± 8.1 30.8 80.0 None None

Pork 295 35.2 ± 3.5 35.0 81.0 None None

Fat (unspec)

45 35.0 ± 0.0 35.0 35.0 None None

Animal feed

8,692 35.3 ± 10.1 34.8 586.0 0.05 None

Animal feed

308 39.3 ± 23.3 36.9 304.0 0.3 None

Other prod.

9 35.0 ± 0.0 35.0 35.0 None None

Sheep 5 21.8 ± 12.2 19.2 35.0 None None

Ostrich 4 32.7 ± 4.5 32.5 35.0 None None

Horse 5 91.6 ± 162.6 31.7 382.0 20 None

Rabbit 5 35.0 ± 0.0 35.0 35.0 None None

Baby food

15 35.0 ± 0.0 35.0 35.0 None None

Non-crisis-related PCB concentrations 2001

Dioxins

N Concentration(pg TEQ/g fat)

N Maximum level (pg/g fat)

Percent of samples (pg/g fat)

AM±SD GM ≥ 2 ≥ 5

9 2.9 ± 2.5 1.9 17 8.3 66.7 5.6

             

6 2.6 ± 1.3 2.4 8 13.7 87.5 

25.0

             

40 1.5 ± 4.7 0.5 50 29.6 4.0 4.0

Beef

Milk

Poultry

Eggs

Pork

Non-crisis-related dioxin concentrations september-december 1999

  PCBs

N Concentration (ng/g fat) N Maximum level

(ng/g fat)

Percent of samples (ng/g fat)

AM±SD GM ≥200 ≥1,000

Beef 224 61.0 ± 103.6 37.8 373 2,170.0 7.2 1.1

Cow’s milk 356 39.7 ± 43.7 28.7 721 336.0 0.6 None

Poultry 328 421.3 ± 2,084.8 59.6 1,403 56,856.0 10.8 3.0

Eggs 45 135.5 ± 270.9 56.1 290 46,000.0 17.9 5.5

Pork 3,081 383.8 ± 1,063.3 100.9 4,998 39,700.0 30.6 11.4

Animal fatunspecified

329 48.0 ± 36.1 37.2 768 4,092.0 0.9 0.5

Fat unspecified

240 98.7 ± 168.0 59.4 423 3,080.0 7.6 1.7

Animal feed

181 994.5 ± 9,447.9 38.8 615 336,000.0 12.2 3.6

Other foodproducts

402 36.8 ± 26.7 32.4 1,096 464.0 0.5 None

Waste oils 248 1,716.2 ± 16,672.9 101.6 274 245,992.0 5.5 4.0

Butter 46 41.6 ± 22.0 37.4 47 157.5 None None

Animal feed

92 80.3 ± 101.3 52.0 615 1,262.0 2.9 0.4

Crisis-related PCB concentrations May-August 1999

Beef

Cow’s milk

Poultry

Eggs

Pork

Animal fat unspec

Fat unspec

Animal feed

Other food products

Waste oil

Crisis-related dioxin concentrations May-August 1999

N Concentration(pg TEQ/g fat)

N Maximum level

(pg/g fat)

Percent of samples (pg/g fat)

AM±SD GM ≥ 2 ≥ 5

8 5.6 ± 2.1 5.3 71 19.5 94.1 47.1

11 2.8 ± 1.1 2.6 72 27.8 47.2 2.8

2 14.9 ± 1.3 14.9 39 2,613.4 64.7 38.2

4 2.4 ± 1.4 2.2 41 713.1 68.3 36.6

118 2.1 ± 2.9 1.2 184 62.8 32.1 10.3

             

2 9.4 ± 12.6 3.1 11 45.1 90.9 

90.9

10 144.6 ± 91.1 114.7 13 6,144.0 100 100

             

5 519.8 ± 1,041.4 73.9 5 2,379.4 100 100

Food product

Adolescents Adults

PCB intake (ng/kg/day)

Dioxin intake (pg TEQ/kg/day)

PCB intake (ng/kg/day) Dioxin intake (pg TEQ/kg/day)

Chicken 1.790 0.070 2.104 0.082

Pork 7.951 0.298 7.070 0.265

Beef 2.994 0.243 2.296 0.186

Egg 1.900 0.106 1.375 0.077

Milk 6.519 0.498 5.791 0.442

Fish 4.456 0.310 6.553 0.455

Vegetables 7.964 0.070 7.533 0.059

Sheep 0.258 0.008 0.150 0.005

Horse 0.367 0.029 0.165 0.013

Total 34.200 1.631 33.038 1.584

PCB and dioxin intake adolescents (14-18 years) and adults (non-crisis related values of the year 1999 (September-December)

Table 14. Calculated and measured PCB and dioxin body burdens for female adolescents and adult women.

  BODY BURDEN

  Calculated Measured

PCB (g/kg bw)

Dioxins (ng TEQ/kg bw)

PCB (g/kg bw) Dioxins (ng TEQ/kg bw)

Female adolescents

75.48 3.67 57.12 8.82

Female adults 146.95 7.07 121.63 14.66

bw body weight

High PCB concentrations in Belgian meat stem for a large part from recycling of fat in animal feed

From grain in animal feed

From fish flour in animal feed

Observed Non-crisis-related

2001 (AM±SD)

Pork 15.4 1.1 35.2 ± 3.5

Chicken 14.0 6.2 35.0 ± 0.5

PCB concentrations (7 marker) in ng/g fat in meat

Based on Schepens et al., 2001

  PCB 138 (ng/g fat)

PCB 153 (ng/g fat)

PCB 180 (ng/g fat)

1996-1998 106 infertile women (aged 24-42)(mean age 31.9)a

69.9 94.5 72.0

Second half on 1999120 girls (mean age 17.4)b

75.9 101.6 55.5

Second half of 1999197 women aged 50-65 (mean age 58.5)b

125.4 171.1 123.1

Body burden increase in 1999, after correction for agec, as percent of the body burden found during 1996-1998 in infertile women

33.6 33.5 10.2

Measured PCB body burdens in Belgian women before and after the contamination crisis early in 1999.

Most DNA damage is endogenous

- Oxidative processes: between 0.07 and 145.25 8-oxo-dG adducts/106 bases. 15 studies on 17 above 1 adduct/ 106 bases

-Lipid peroxidation: up to 0.9 M1G adducts /106 bases

-Genotoxic substances derived from DNA oxidation: base propenals

-Endogenous oestrogens

-Endogenous alkylating agents: up to 2.27 7-alkylguanine adducts /106 bases and 4.24 O4- ethylthymine adducts /106 bases

-DNA hydrolysis leading to abasic sites: of the order of 8 to 9 /106 bases

-Hydrolytic deamination

- Carbonyl stress (e.g. methylglyoxal from glucose metabolism)

This damage is repaired swiftly and efficiently mostly by Base Exision Repair (BER), MGMT (O6-methylguanine DNAmethyltransferase) and MMR (mismatch repair)

Exogenous DNA damage : - Larger adducts removed preferentially by nucleotide excision repair (NER ), more complex and slower

- Double strand breaks repaired by homologous recombination and mainly by error-prone non-homologous end-joining

8-oxo-7,8-dihydro-2’-deoxyguanosine

Human brain (nDNA) 2.39-5.17

MalondialdehydeM1G (lipid peroxidation)

Human Breast 0.30

7-methylguanine Human Pancreas 0.40-1.39

Sum of 9 important endogenous

adducts

Human peripheral blood cells 4.97-69.05

Benzo(a)pyreendiolepoxide Cervix Niet rooksters

Cervix rooksters

0,019

0,035

Sum of 9 important endogenous

adducts

In vivo Rat organs including liver

Spontaneous liver tumor incidence is 1-2%

2.18-137.3

Aflatoxine Rat environmental exposure

Dose for 50 % liver tumorincidence

0,00091

0,85

Adducts/106 nucleotides

Exogenous adducts are often more efficient in the induction of mutations and cancer than endogenous adducts

Initiation of carcinogenesis: mainly from endogenous mutations.

Initiation < often mutation in repair mechanism for exogenous damage (mutation in repair for endogenous damage often lethal)

Initiated cells often more susceptible to exogenous agents

Mutational spectra in the HPRT gene of normal lymphocytes from different human populations: similar, < endogenous mechanisms of mutagenesis

Mutation spectra of the p53 anti oncogene in cells from different types of cancers (e.g. lung vs brain): substantial differences, < different exogenous agents

Additional mutations often from exogenous agents

Following mechanisms can lead to a relatively higher mutagenic efficiency of low dose exposures

1. Adaptation: Intense exposure induces DNA repair mechanisms. This results in less and other types of mutations. A very low dose, or a low dose spread over a large time interval, hits the cells while these repair mechanisms are not fully induced.

2. Bystander effect:cells that are not hit by an agent also can show effects. Proven for ionising radiation and gene therapy

3. Induced genetic instability. A form of induced genetic instability has been described that acts as an on/off phenomenon in which the genetic instability does not increase with the dose of the inducing agent. It acts as if a program for genetic instability is expressed. Probably a critical treshold value exists.It is not known when this phenomenon occurs

Benzo(a)pyrene: dose-effect relation

Supralinear exposure effect curves were found for:

BaP adducts in human cells exposed in vitro (11 studies totalling 23 measured adduct levels):mean adduct level < 5 µM: 2.47/106 nucl per µM

>= 5 µM: 0.104/ 106 nucl per µM p= 0.0054 ( in anova with confounders)

BaP adducts in animal cells exposed in vitro (6 studies totalling 11 measured adduct levels) : mean adduct level < 5 µM: 1.46/106 nucl per µM

>= 5 µM: 0.11/ 106 nucl per µM

Sister chromatid exchanges in human cells in vitro (5 studies) and in animal cells in vitro (3 studies) totalling 24 meas.:mean amount of SCEs in human cells: < 5 µM:1.48per cell per µM

>=5 µM: 0.18 per cell per µM p= 0.046 for the entire dataset mean amount of SCEs in animal cells: < 5 µM:13.32 per cell per µM anova with confounders

>=5 µM: 0.97 per cell per µM

Mutations in vitro in chinese hamster ovary cellsmean mutation frequency in HGPRT or XPRT gene: < 5 µM:4.30 per 105 per µM

>=5 µM: 0.88 per 105 per µM

Infralinear exposure effect curve found for:

Adduct formation in vitro following BPDE exposure (5 studes) showed a nonsignificant infralinearexposure effect curve

BaP adducts in human tissues following BaP exposure in vitro: doses < 5μM (left), doses ≥ 5 μM (right).

Slope of the curve: 1.68 Slope of the curve: 0.105

Exposure in coke ovens in terms of BaP

Bap adducts per 106 nucleotides in white blood cells

(Based on 5 studies on coke oven or related industries)

Life time Cancer risk only due to

1 µg/m3 BaP (70 year lifetime exposure)

(Based on BaP unit risk OEHHA 1994)

Life time Lung Cancer risk from Coke oven emissions with 1 µg/m3 BaP (70 year lifetime exposure)

Based on all 22 coke oven, gas works and aluminium production studies

Based on 7 coke oven, gas works and aluminium production studies with exposures <=20 µg BaP/ m3

years

Armstrong et al. 2004

Meta-analysis

Life time Lung & genito-urinary Cancer risk (Costantino et al. 1995) from Coke oven emissions with 1 µg/m3 BaP (70 year lifetime exposure)

Based on all 22 coke oven, gas works and aluminium production studies

Based on 7 coke oven, gas works and aluminium production studies with exposures <=20 µg BaP/ m3 years

Armstrong et al. 2004

Meta-analysis

1 µg/m3 0.418 1.1 to 3.3 /1000

39/1000

200/1000

48/1000

245/1000

Cancer risk associated with BaP adducts in peripheral blood cells derived from exposure through inhalation

Environmental exposures do not reach the treshhold level for maximal induction of DNA repair and have consequently a higher efficiency in the induction of biological and health

effects than high experimental or occupational exposures

Critical dose for induction of adaptive repair by exogenous mutagenic agents: order of 1 mGy

Induction of adaptive response takes in the order of 1 hour

Duration of adaptive response: order of 40 hours

Exposure to 1mGy/40 hours during 70 years equals 15,3 Gy

1Gy (acute) causes 11% lethal cancers (UNSCEAR, 2000) , and a cancer incidence of about 22%. Chronic exposure might lead to only 50% of the above mentioned risk .

15,3 m Gy in chronic exposure causes of the order of 15,3 x 11%= 168 % cancer incidence in 70 years

The observed cumulative cancer incidence rate at age 70 is of the order of 30%

Consequently total current environmental and other external exposures are well below the level required for maximal induction of DNA repair and so have a higher efficiency per unit of dose than high experimental or occupational exposures on which norms are based.

Receptor binding exogenous ligands often show supralinear dose-effect curves and can have non-monotonous effects and effects that are substantially different from the

endogenous ligands

Saturation of the receptor leads to supralinear dose-effect curves

Binding of a ligand leads to changes in conformation of the receptor. Xeno-estrogens do not necessarily have the same effects , in qualitative terms, as endogenous estrogens.

0

20

40

60

80

100

0 0,1 0,2 0,3 0,4 0,5

Concentratie (nM) lineaire schaal

Bez

etti

ng

(%

van

max

imu

m)

Kd = 0,1 nM

4 x Kd

Fout door lineaireextrapolatie

Concentratie (nM) lineaire schaal

Bez

ettin

g (%

van

max

imum

)

0

20

40

60

80

100

0 1 2 3 4 5

Fout door lineaireextrapolatie

Concentratie, lineaire schaal

Res

pons

(%

van

max

imum

)

After Welshons et al., 2003

Biomarkers for genotoxicity have an acceptable sensitivity for exposures occuring during adult life but are insufficiently sensitive for the evaluation of cancer risk from lifelong

exposures starting in utero

10

20

30

40

50

Num

ber

of c

onse

cutiv

e ce

ll di

v isi

ons

Birth 20 40 80

Age from conception

Stem cel

Peripheral cells

0

2

4

6

8

10

12

Mu

tan

t fr

eq

ue

ncy p

er

millio

n c

ells

0 5 10 15 20 25 30 35 40 45 50

number of consecutive stemm cell divisions

peripheral cells w hen exposed from age 30 to 40

peripheral cells control

stemm cells w hen exposed from age 30 to 40

stemm cells control

Age from conceptionBirth 20 40 80

Exposure from age 30 to age 40An exposure increasing the mutation rate by 10%will result in an attributable risk percent of cancer amounting to 7,15% and in an increase of 4,9% in the observable mutant frequency in peripheral Cells.Ratio=7.15% / 4.9%=1.46

0

2

4

6

8

10

12

0 5 10 15 20 25 30 35 40 45 50

Number of consecutive stemm cell divisions

peripheral cells w hen lifelong exposed

peripheral cells control

stemm cells w hen lifelong exposed

stemm cells control

Age from conception

Birth 20 40 80

Mu

tan

t fr

eq

ue

ncy

pe

r m

illio

n c

ells

Lifelong exposure starting In uteroAn exposure increasing the mutation rate by 10%will result in an attributable risk percent of cancer amounting to 43,5% and in an increase of 10% in the observable mutant frequency in peripheral cells.Ratio=43,5%/10%=4,35

10

20

30

4

0

50

Nu

mb e

r o

f co n

s ec u

tive

ce

ll d

i vis

ion

s

Birth 20 40 80

Age from conception

Stem cel

Peripheral cellsFig. 1

Fig. 2

Fig. 3

Correspondence:Prof. Dr. N. van LarebekeStudy Centre for Carcinogenesis and Primary Prevention of Cancer,Ghent UniversityUniversitary Hospital 3K3, De Pintelaan 185B 9000 Gent, BelgiumTel. 32.(0)2.380.14.10Fax 32 (0)2 381 16 45GSM Mobile telephone 32.(0)475.44.99.55e-mail: nicolas.vanlarebeke@ugent.be

Air-freshners

Following substances were found in some air-freshners: Benzene, formaldehyde, styrene, acetaldehyde, toluene, chlorobenzene, naphthalene, glycolethers, ftalates, artificial musks,paradichlorobenzene, benzylacetate, benzylalcohol, dipropyleen glycol, terpenes.

Combined use of ozone generators and air-freshners leads to an increase in the number and concentration of fine particles

Exposure to air-freshners induced airway irritation and changes in behaviour in mice

Dipropylene glycol was found (National Toxicology Program, 2004) to cause nephropathy, liver toxicity and decreased body weight in rats

Use of air-freshners was associated with diarea and ear-ache in infants and with headache and depression in mothers

It was concluded that the use of air-freshners is contraindicated.

Benzene

Mutagenic metabolites and oxidative stress. Has radiomimetic properties epigenetic action: receptor mediated disruption of stem cell differentiation in bone marrow towards myeloid precursors

Metabolites hydroquinone and fenol might inhibit GJIC and act as tumorpromotors

In experimental animals benzene causes cancers in many organs, suggesting

There are at least 9 publications in the literature in which benzene was associated with cancers other than hematopoietic in humans

It seems likely that benzene is recognized as causing mainly or only hematopoietic malignancies, because of its relative importance as a hematopoietic carcinogen , and because of the fact that its effect on other tissues is masked by a high background of other carcinogenic influences on these tissues. Formerly, ionising radiation was considered to be mainly a hematopoietic carcinogen.

Probably benzene causes many different types of cancer in humans, as does ionising radiation.

Benzene risk estimations from the American Petroleum Institute and even those of EPA (2,2 to 7,7 deaths from hematopoietic malignancies/milion for life time exposure to 1 µg/m3) probably suffer from substantial underestimation.Our best estimate was 12,3.

Some reasonable worst case estimates (of the order of 50 deaths from hematopoietic malignancies/milion for life time exposure to 1 µg/m3) were presented.

Gap Junction Intercellular Communication (GJIC)

Important in growth, differentiation, development, homeostasis and carcinogenesis

Tumor-promotion: reversible inhibition of GJIC might contribute to selective expansion of initiated cells

Most tumorpromotors inhibit GJIC.

Tests for detection of tumorpromoting activity might be usefull (as are tests for mutagenic activity)

Simple tests based on GJIC could be used to detect tumorpromoting activity in environmental samples

In collaboration with Dr. Trosko we propose the use of such tests to the Flemish authorities

GSM and UMTS

Typical GSM (data 1999): a SAR= 1.6 W/KG in the brain

Antenna’s: generally a much lower exposure (8 seconds of GSM = 24 h at 100 m of a typical antenna)

Biological effects at SAR=4W/kg

In vitro effects on gene expression at exposures not far above those occuring in GSM users

Epidemiological studies: unlikely to have sufficient sensitivity and sufficient discerning power.

More experimental work, in vitro and on animals, recommended. Interactions with at least some important exposures occurring in real life should be included.

High Tension CablesELF magnetic fields above 0.4 Tesla might increase risk of cancer. Indoor magnetic fields above 0.2 Tesla almost always due to outdoor sources. Epidemiological studies: often association between 50 Hz-elektromagnetic fields and leukemia in children and chronic lymfoid leukemia in occupationaaly exposed adults adults. Further experimental research is indicated