Health risk assessment forHealth risk assessment for oral exposure to PAH mixturesp

Dr Stuart CretonDr Stuart Creton, Food Standards Agency,

LondonLondon

Scope of presentationScope of presentation

• General approachesOpinion of the Scientific Committee on• Opinion of the Scientific Committee on Food (2002)

• Opinion of the JECFA (2005)• Further considerations• Further considerations

Risk assessment policyy• Based on opinions and approaches of

independent scientific advisory committeesindependent scientific advisory committees• UK

Committee on Carcinogenicity of Chemicals in Food– Committee on Carcinogenicity of Chemicals in Food Consumer Products and the Environment (COC)

– Committee on Toxicity of Chemicals in Food– Committee on Toxicity of Chemicals in Food Consumer Products and the Environment (COT)

• EUEU– Scientific Committee on Food (SCF) until 2002

European Food Safety Authority since 2002– European Food Safety Authority since 2002• WHO

J i t FAO/WHO E t C itt F d– Joint FAO/WHO Expert Committee on Food Additives and Contaminants (JECFA)

COC view on genotoxic gcarcinogens • In the absence of mechanistic data to

suggest a threshold for genotoxicitysuggest a threshold for genotoxicity, COC recommends a non-threshold

h f i k tapproach for risk assessment• Exposure should be As Low As p

Reasonably Practicable (ALARP)• Not helpful in the context of• Not helpful in the context of

contaminated land

O i i f th S i tifiOpinion of the Scientific Committee on Food onCommittee on Food on

the risks to human health of Polycyclic Aromatic Hydrocarbons in food

(4 Dec 2002)(4 Dec 2002)

http://ec.europa.eu/food/fs/sc/scf/out153_en.pdf

Non carcinogenic effectsNon-carcinogenic effects

• Liver, kidney, developmental and immunotoxicityimmunotoxicity

• Based on comparison of dietary intakes with NOAELs for various endpoints non-with NOAELs for various endpoints noncarcinogenic effects were not considered to be of concernconsidered to be of concern

Genotoxicity and carcinogenicity• 15 PAH clearly mutagenic/genotoxic of

Genotoxicity and carcinogenicity• 15 PAH clearly mutagenic/genotoxic, of

which 14 also carcinogenic

benz[a ]anthracene benzo[a]pyrenebenzo[b]fluoranthene [benzo[ghi]perylene]benzo[b]fluoranthene [benzo[ghi]perylene]benzo[j]fluoranthene benzo[k]fluoranthenechrysene cyclopenta[cd]pyrenedib [ h] th dib [ ]dibenz[a,h]anthracene dibenzo[a,e]pyrenedibenzo[a,h]pyrene dibenzo[a,i]pyrenedibenzo[a l]pyrene indeno[1 2 3-cd ]pyrenedibenzo[a,l]pyrene indeno[1,2,3 cd]pyrene5-methylchrysene.

Carcinogenicity dataCarcinogenicity data• Few studies involve oral administration• Oral BaP produced tumours of the GI

tract liver lungs and mammary glands intract, liver, lungs and mammary glands in rats and mice

• Oral DBahP and BaA produced tumours of the GI tract, lungs and liver in micethe GI tract, lungs and liver in mice

• Most recent studies– gavage study in rats (Kroese et al., 2001)– diet study in mice with BaP and coal tar

mixtures (Culp et al., 1998)

Conclusion on results of Culp pet al.

• Tumour sites following oral administration of coal tar mixturesof coal tar mixtures – lung, intestine, haemangiosarcomas,

f t h liforestomach, liver• Tumour sites following oral administration g

of BaP – liver forestomach auditory canalliver, forestomach, auditory canal

• potency of the coal tar mixes up to 5 th t t d f B P t t5x that expected from BaP content

TEF approach for PAH mixturesTEF approach for PAH mixturesR li d dditi i ti• Relies on dose addition, i.e. assumption of common mode of action

• Could not assume common mode of action for PAHs based onaction for PAHs, based on – different tumour sites for coal tar mixes cf

B P i C l t l t dBaP in Culp et al study– applying TEF values (Larsen and Larsen,

1998) to Culp data underestimated potency of the coal tar mixes

SCF conclusionSCF conclusionTEF h t it bl• TEF approach not suitable

• BAP could be used as a marker– PAH profiles in food varied by < 5

PAH profile in the Culp coal tar mixes– PAH profile in the Culp coal tar mixes varied by < 2 from that in food

• A conservative estimate implies that carcinogenic potency of total PAH in g p yfood would be 10 times higher than expected from BaP aloneexpected from BaP alone

64th JECFA Feb 200564th JECFA, Feb 2005

• General considerations: “advice on compounds that are both– advice on compounds that are both genotoxic and carcinogenic”

E l i• Evaluations: – acrylamide, y ,– ethylcarbamate,

PAHs– PAHs

h h libd h i / bli i /2006/9241660554 dfhttp:whqlibdoc.who.int/publications/2006/9241660554_eng.pdf

Approaches considered byApproaches considered by JECFA - 1JECFA 1

• Dose-response analysis outside theDose response analysis outside the observed dose range (low dose extrapolation)extrapolation)– rejected on grounds similar to those of

COC

Approaches considered byApproaches considered by JECFA - 2• Linear extrapolation from a point of p p

departure on the dose response curve – calculate theoretical upper bound estimate– calculate theoretical upper bound estimate

of cancer riskactual risk could be anywhere between– actual risk could be anywhere between zero and the calculated estimate

b i i t t d– can be misinterpreted

Approaches considered byApproaches considered by JECFA - 3JECFA 3

• Margin of Exposure (MoE)ratio of a defined point on dose response– ratio of a defined point on dose response curve to estimated human intakeBMDL10 i f d i f d– BMDL10 is preferred point of departure

BMDL and MoEBMDL and MoELog-Logistic Model with 0.95 Confidence LevelBaP – TBA in rats (Kroese et al. 2001) log-logistic model

1Log-Logistic

( ) g g

0.8 BMD10- dose causing 10% increased incidence over control

0 4

0.6

Affe

cted

CI for BMD

BMDL10BMDL10- lower one-sided confidence limit of BMD10

0.2

0.4

Frac

tion

BMD10

BMDL10 confidence limit of BMD10

Larger MoE = lower concern

0

0 5 10 15 20 25 30

BMDL BMD

dose08:58 01/24 2008

JECFA evaluation of PAHsJECFA evaluation of PAHs

• Agreed critical effect is carcinogenicity and cannot take threshold approachand cannot take threshold approach due to genotoxicity

• Human data– occupational exposure, non-oralp p ,– mixed exposures, confounders

some observations consistent with animal– some observations consistent with animal studies, but do not provide dose response datadose-response data

Dose-response modellingDose response modellingModelled data Range of BMD and BMDL values (mg of benzo[a]pyrene/kg bw per day)

Benzo[a]pyrene Coal tar mixture I Coal tar mixture II

BMD BMDL BMD BMDL BMD BMDL

Mouse 0 40 0 92 0 31 0 74 0 21 0 40 0 16 0 31 0 37 0 59 0 27 0 45Mouseforestomach

0.40–0.92 0.31–0.74 0.21–0.40 0.16–0.31 0.37–0.59 0.27–0.45

Mouse lung * No observed increase inincidence of tumours

0.14–0.26 0.11–0.20 0.14–0.26 0.11–0.20incidence of tumours

Tumour-bearingmice *

— — 0.13–0.29 0.10–0.23 0.13–0.29 0.10–0.23

Rat liver 3.4–4.0 2.9–3.4 — — — —Tumour-bearingrats

1.2–2.0 1.0–1.7 — — — —rats

Data from Culp et al., and Kroese et al.,

* Data combined as dose response curves did not differ significantly

Selection of BMDLSelection of BMDL• Mixtures of PAH are present in food• Mixtures of PAH are present in food, • Different PAH may act by different mechanisms, • JECFA concluded that the data based on the total• JECFA concluded that the data based on the total

number of tumour-bearing mice treated with coal tar mixtures provided the most appropriate basis for the p pp pevaluation.

• BMDL values ranged from 0.10 to 0.23 mg BaP/kg bw per day.

• JECFA used the more conservative lower end of this range for its evaluation.

• BMDL equivalent to 0.1 mg BaP/kg bw per day d i d f i t f PAH i f dwas derived for mixtures of PAH in food

Consideration of mixturesConsideration of mixtures• TEF approach• TEF approach

– TEFs that have been proposed for PAH were derived from studies involving parenteral administration or in-vitro approaches and no data on oral administration were available that were suitable for this purpose

• Surrogate approachg pp– BaP as marker of exposure and of

the effectsthe effects

PAH profiles in food relative to BaPPAH profiles in food relative to BaP

• JECFA concluded that BaP is a good marker for other genotoxic PAH butmarker for other genotoxic PAH, but does not correspond well with some of th l l l i htthe lower molecular weight, non-genotoxic compounds.

Comparison of PAH profiles in the p pcoal tar mixtures with values in food

• “a surrogate approach should be used with benzo[a]pyrene being used……., with benzo[a]pyrene being used

as a marker of exposure to the t i d i i PAHgenotoxic and carcinogenic PAH,

because this approach is based on data from a study of carcinogenicity with a relevant mixture of PAH administered by the oral route

Effects of non genotoxic PAHEffects of non-genotoxic PAHB P i t d k f f th PAH• BaP is not a good marker for some of the PAH of lower relative molecular mass,

• Some of these PAH are tumour promoters when administered by the dermal route

• further information needed to establish whether these substances may act as promoters after y poral administration

• However, tumour promotion is more likely toHowever, tumour promotion is more likely to occur at higher doses than carcinogenicity arising from genotoxic effectsarising from genotoxic effects

MoE for carcinogens in food -gJECFA

Carcinogen MoE ataverage

MoE athigh level

Conclusion

intake intakeAcrylamide 300 75 “may indicate a human

health concern”health concernEthylcarbamateexc alcohol

20,000 “of low concern”

Ethylcarbamate 3800 “of concern”Ethylcarbamateinc. alcohol

3800 “of concern”

PAHs 25,000 10,000 “of low concern”

Further considerationsFurther considerations

• New data on BaP profiles in EU food• New data on BaP profiles in EU food recently available

• Suitability of BaP as a marker in food to be reconsidered by EFSAbe reconsidered by EFSA

CommentComment

• There are limitations to all approaches Pragmatic decisions are necessary to• Pragmatic decisions are necessary to manage risks to public health