oral exposure to PAH mixtures Food Standards Agency,

Transcription

1 Health risk assessment for oral exposure to PAH mixtures Dr Stuart Creton, Food Standards Agency, London

2 Scope of presentation General approaches Opinion of the Scientific Committee on Food (2002) Opinion of the JECFA (2005) Further considerations

3 Risk assessment policy Based on opinions and approaches of independent scientific advisory committees UK Committee on Carcinogenicity of Chemicals in Food Consumer Products and the Environment (COC) Committee on Toxicity of Chemicals in Food Consumer Products and the Environment (COT) EU Scientific Committee on Food (SCF) until 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)

4 COC view on genotoxic carcinogens In the absence of mechanistic data to suggest a threshold for genotoxicity, COC recommends a non-threshold approach hfor risk assessment Exposure should be As Low As Reasonably Practicable (ALARP) Not helpful in the context of contaminated land

5 Opinion i of the Scientific Committee on Food on the risks to human health of Polycyclic Aromatic Hydrocarbons in food (4 Dec 2002)

6 Non-carcinogenic effects Liver, kidney, developmental and immunotoxicity Based on comparison of dietary intakes with NOAELs for various endpoints non- carcinogenic effects were not considered to be of concern

7 Genotoxicity and carcinogenicity 15 PAH clearly mutagenic/genotoxic, of which 14 also carcinogenic benz[a]anthracene benzo[a]pyrene benzo[b]fluo ranthe ne [benzo[ghi]peryle ne] benzo[j]fluoranthene benzo[k]fluoranthene chrysene cyclopenta[cd]pyrene dibenz[a,h]anthracene dibenzo[a,e]pyrene dibenzo[a,h]p yre ne dibenzo[a,i]p yre ne dibenzo[a,l]pyrene indeno[1,2,3 3-cd]pyrene 5-methylchrysene.

8 Carcinogenicity data Few studies involve oral administration Oral BaP produced tumours of the GI tract, liver, lungs and mammary glands in rats and mice Oral DBahP and BaA produced tumours of the 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)

9 Conclusion on results of Culp et al. Tumour sites following oral administration of coal tar mixtures lung, intestine, haemangiosarcomas, forestomach, liver Tumour sites following oral administration of BaP liver, forestomach, auditory canal potency of the coal tar mixes up to 5x that t expected from BaP content t

10 TEF approach for PAH mixtures Relies on dose addition, i.e. assumption of common mode of action Could not assume common mode of action for PAHs, based on different tumour sites for coal tar mixes cf BaP in Culp et al study applying TEF values (Larsen and Larsen, 1998) to Culp data underestimated potency of the coal tar mixes

11 SCF conclusion 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 varied by < 2 from that in food A conservative estimate implies that carcinogenic potency of total PAH in food would be 10 times higher than expected from BaP alone

12 64th JECFA, Feb 2005 General considerations: advice on compounds that are both genotoxic and carcinogenic Evaluations: acrylamide, ethylcarbamate, PAHs h h i bli i /2006/ df

13 Approaches considered by JECFA - 1 Dose-response analysis outside the observed dose range (low dose extrapolation) rejected on grounds similar to those of COC

14 Approaches considered by JECFA - 2 Linear extrapolation from a point of departure on the dose response curve calculate theoretical upper bound estimate of cancer risk actual risk could be anywhere between zero and the calculated estimate can be misinterpreted i t

15 Approaches considered by JECFA - 3 Margin of Exposure (MoE) ratio of a defined point on dose response curve to estimated human intake BMDL10 is preferred point of departure

16 BMDL and MoE BaP TBA Log-Logistic in Model rats with (Kroese 0.95 Confidence et Level al. 2001) log-logistic g model 1 Log-Logistic 0.8 BMD10- dose causing 10% increased incidence over control 0.6 CI for BMD Affected BMDL Fraction 0.2 BMD10 BMDL10- lower one-sided confidence limit of BMD10 Larger MoE = lower concern 0 BMDL BMD :58 01/ dose

17 JECFA evaluation of PAHs Agreed critical effect is carcinogenicity and cannot take threshold approach due to genotoxicity Human data occupational exposure, non-oral mixed exposures, confounders some observations consistent with animal studies, but do not provide dose-response data

18 Dose-response modelling Modelled data Range of BMD and BMDL values (mg of benzo[a]pyre ne/kg bw pe r day) Benzo[a]pyrene Coal tar mixture I Coal tar mixture II BMD BMDL BMD BMDL BMD BMDL Mouse forestomach Mouse lung * No observed increase in incidence of tumours Tumour-bearing mice * Rat liver Tumour-bearing rats Data from Culp et al., and Kroese et al., * Data combined as dose response curves did not differ significantly

19 Selection of BMDL Mixtures of PAH are present in food, Different PAH may act by different mechanisms, JECFA concluded that the data based on the total number of tumour-bearing mice treated with coal tar mixtures provided the most appropriate p basis for the evaluation. 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 was derived d for mixtures of PAH in food

20 Consideration of mixtures 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 approach BaP as marker of exposure and of the effects

21 PAH profiles in food relative to BaP JECFA concluded that BaP is a good marker for other genotoxic PAH, but does not correspond well with some of the lower molecular l weight, nongenotoxic compounds.

22 Comparison of PAH profiles in the coal tar mixtures with values in food a surrogate approach should be used., with benzo[a]pyrene being used as a marker of exposure to the genotoxic and carcinogenic i PAH, because this approach is based on data from a study of carcinogenicity with a relevant mixture of PAH administered by the oral route

23 Effects of non-genotoxic 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 oral administration However, tumour promotion is more likely to occur at higher doses than carcinogenicity arising from genotoxic effects

24 MoE for carcinogens in food - JECFA Carcinogen MoE at MoE at Conclusion average high level intake intake Acrylamide may indicate a human health concern Ethylcarbamate 20,000 of low concern exc alcohol Ethylcarbamate 3800 of concern inc. alcohol PAHs 25,000 10,000 of low concern

25 Further considerations New data on BaP profiles in EU food recently available Suitability of BaP as a marker in food to be reconsidered by EFSA

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