Minutes

1. Present

ITEM 1: APOLOGIES FOR ABSENCE/ANNOUNCEMENTS

2. Apologies were received from Mrs K Cameron (DEFRA) and Mr A Browning (VMD).

Announcements

3. Members were informed that this would be the last meeting of COC attended by Professor Parry as chairman of COM. The Chairman thanked Professor Parry on behalf of behalf of members and secretariat for his outstanding service to COM and COC over many years.

4. Members were reminded of the need to make any relevant declarations of interest before the discussion of items.

ITEM 2: MINUTES OF THE MEETING ON 22 MARCH 2001 (CC/MIN/2001/1)

5. The minutes were agreed subject to minor editorial changes.

ITEM 3: MATTERS ARISING

3.1 Joint meeting of COT/COC/COM

6. Members were informed that a date for this meeting had been set for the 8th October 2001. The meeting has two main objectives:

i) Closer working of the COT/COC/COM
ii) To provide advice to Government Departments and Regulatory Agencies on use of genomics/proteomics in toxicology and use of such data in risk assessment.

7. Members noted that a key part of the meeting would involve members from all three Committees participating in working groups. Members asked that a short presentation from each working group be given at the plenary session.

3.2 Chloropropanols

8. Members were informed that the statements by the COC and COM on dichloropropanols had been finalised and placed on the internet.

9. The FSA representative told the Committee that both the SCF and JECFA had recently set a Tolerable Daily Intake (TDI) for 3-monochloropropandiol (3-MCPD) of 2µg/kg bodyweight, based on a LOAEL for effects on the kidney and the application of an uncertainty factor of 500 (5 for extrapolation from a LOAEL to a NOAEL and gaps in the database, and 10 each for intra and inter species variability). JECFA had also concluded that 1,3-Dichloropropanol (1,3-DCP) should be regarded as a genotoxic carcinogen and that no TDI could be set for this chemical.

10. The FSA representative also reported the results of recently published surveys of 3-MCPD and 1,3-DCP in soy sauce and related foodstuffs containing acid hydrolysed vegetable protein. Twenty-two out of 100 samples of soy sauce contained levels of 3-MCPD above 0.5 mg/kg. Of the samples that contained 3-MCPD about two-thirds also contained quantifiable levels of 1,3-DCP (although always much lower than 3-MCPD). The highest level of 3-MCPD found was 93 mg/kg. The FSA had recommended that sale of all products containing levels of 3-MCPD above 0.5 mg/kg should cease and products be removed from shelves and had also advised consumers to avoid these products (as listed on the FSA website). The products of most concern were mainly specialist soy sauces imported from South East Asian countries such as Thailand. Main UK produced brands were not affected.

11. Members sought clarification on the levels of 3-MCPD and 1,3-DCP in other food products containing partially hydrolysed vegetable protein. In response the FSA confirmed that levels in products containing partially hydrolysed vegetable protein were 1000 times lower than in Soy sauce.

12. Members recalled that the DEFRA had funded the relevant in-vivo mutagenicity studies on 3-MCPD and asked that the FSA consider funding relevant in-vivo mutagenicity studies with 1,3-DCP.

ITEM 4: SECOND DRAFT STATEMENT ON DIOXINS (CC/01/12 and Addendum)

13. The Committee was reminded that the COT was undertaking a review of dioxins. The COC had been asked for up-to-date advice on the carcinogenicity of dioxins and, in particular, on the risk assessment of TCDD undertaken by the US EPA. The COC had considered the available information at its meeting on 22 March and had agreed to revise its 1998 opinion on dioxins in the light of new data published since then. A draft statement had been submitted to the COT on 1 May. The COT had asked the COC to further consider the potential implications of any polymorphisms of the Ah receptor (AhR ) and the Ah Receptor Nuclear Transfer Factor (ARNT) in risk assessment.

14. The Committee considered a recently published, 20 year mortality update of the Seveso cohort (Bertazzi PA et al 2001, American Journal of Epidemiology, 153, 1031-1044). Members noted that this cohort provided valuable information on the association between exposure to TCDD and cancer since the accident had resulted in exposure to TCDD alone and not to a mixture of dioxins, and the exposed group included both men and women. In addition, the follow-up and documentation of this study were excellent with over 99% of the cohort traced. The authors reported a 10% increase in risk of total cancer mortality in males but not in females. Among males, there was a 30% increase in mortality from respiratory cancer. There were also significant increases in risk of mortality from lymphohaematopoietic cancers in both sexes (males 70%, females 80%). The risk of Hodgkin's disease was elevated in the first 10 years of follow-up whilst risk of non-Hodgkin's lymphoma and myeloid leukaemia were increased after 15 years. Members noted that lymphohaematopoietic cancers had not been identified in the industrial cohorts and commented that it would be important to continue to monitor the literature for evidence of these particular cancers associated with exposure to dioxins.

15. Members considered the areas of discussion highlighted in CC/01/12 and suggested a number of amendments to the draft statement.

16. Ah receptor "knock-out" mice: Members confirmed that Ah receptor "knock-out" mice showed poor survival and tended to die at 2-3 months of age although the actual cause(s) of death were unclear. It would therefore not be feasible to carry out a carcinogenicity study with these mice. The draft statement was amended to reflect this.

17. Margin of safety: Members were asked whether they confirmed the statement made last March that there were 1 to 2 orders of magnitude between extrapolated body burdens in the cancer mortality studies of workers exposed to TCDD and other dioxins and background body-burdens. Data presented in the EPA risk assessment indicated that, whereas this might be true for the mean extrapolated peak body burden in each cohort, it did not take account of the range of peak body burdens within each cohort. Members also referred to information presented in a commentary by Smith and Lopipero on the recently published 20 year mortality study on the Seveso cohort (American Journal of Epidemiology, 153, 1045-1047). This indicated that back-calculated TCDD blood lipid concentrations (at the time of last exposure) were 1 order of magnitude lower in the Seveso cohort than in the major industrial cohorts, altough still one order of magnitude higher than the general population. Thus, using this parameter, background TCDD levels were 1 to 3 orders of magnitude lower than in the occupational cohorts. It was not clear whether body burdens or peak blood lipid concentrations was the most appropriate parameter to use for comparison purposes. Members asked that these issues be discussed in detail in the statement.

18. AhR/ARNT Polymorphisms: Members agreed changes to the statement to indicate that no conclusions could be drawn about the functional significance of polymorphisms of the AhR gene in humans in terms of risk of carcinogenicity.

19. The Committee agreed that a revised statement should be circulated by post and agreed through chairman's action.

ITEM 5: GENETIC SUSCEPTIBILLITY TO ENVIRONMENTAL CARCINOGENS: CRITERIA FOR CAUSALITY (CC/01/11)

20. During the discussion of CC/01/5 (A review of how gene-environment studies should be used in risk assessment process) at the March 2001 meeting, members asked for some additional work to be undertaken to develop a set of criteria for assessing whether a causal relationship existed between a particular gene-environment interaction in respect of the induction of a particular cancer.

21. The COC had used the criteria for causality developed by Sir Austin Bradford-Hill (Bradford-Hill, Annex 1) on a framework for considering the evidence for a causal relationship on number of occasions (specifically the assessment of passive smoking and the evaluation of alcohol and breast cancer). The Bradford-Hill criteria had been particularly useful in assessing associations where relative risks are low and has helped to focus the COC discussion on the critical data. Ideally, the development of a set of criteria for evaluating gene-environment studies in respect of cancer should provide a framework for assessing the critical data. The two papers cited by members as being relevant to this discussion were appended as Annexes 2 and 3.

22. The secretariat had attempted to develop a proposal for a new set of criteria based on an assumption that greater weight of evidence should be applied to the relevance of gene-environment interaction in respect of mechanism of cancer (i.e. biological plausibility) and the consistency of association in epidemiological studies. A set of deductive tests were developed for each of these criteria. This approach could be said to reflect the refutationist approach outlined in Annex 2.

23. Members disagreed with this proposal and considered that strength and consistency of association would be the most important factors to consider in evaluating the significance of any gene-environment interaction in the induction of a particular cancer. Members considered that data on biological plausibility would be important supporting information. It was noted, for example, that information on the function of the H-ras gene had only become available several years after it had been demonstrated that this gene was important in the aetiology of certain cancers. Members considered that applying deductive tests would limit flexibility in assessments. The secretariat was asked to provide a further paper and to include information on examples where possible.

24. Members also commented on general terminology and suggested that the phrase genotype-environment interaction was a more accurate description of the topic under consideration.

ITEM 6: INCREASE IN MORTALITY RATES FROM INTRAHEPATIC CHOLANGIOCARCINOMA (CC/01/16; CC/01/20)

25. At the November 1999 meeting, the Committee had heard a presentation from Professor H Thomas' group at Imperial College School of Medicine in which they reported a marked increase in mortality rates from intrahepatic cholangiocarcinoma (IHCC) in England and Wales from 1968 to 1996. A draft paper from the group postulated that this might be due to environmental chemical contaminants and, therefore, the COC had been asked for advice. The COC concluded that the recorded increase in mortality from IHCC might be due to changes in diagnostic standards over time and recommended further investigations before a definite conclusion could be reached. A draft statement was prepared, summarising the Committee's advice, for publication when the researchers' paper was published in the scientific literature. The paper by Professor Thomas' group had now been published (Taylor-Robinson et al (2001) in Gut, volume 6, pp 816-820.). As it differed from the 1999 draft, it was being brought to the Committee in case members wished to reconsider their previous advice. It was noted that a recent abstract presented at a scientific meeting in Atlanta reported a similar increase in IHCC incidence and mortality in the US from 1979 to 1998.

26. The Committee was also told that, shortly before the meeting, the secretariat had been informed that a figure in the publication by Taylor-Robinson et al reporting age-specific mortality rates of IHCC (Figure 2) had been found by the authors to be incorrect and a revised figure was to be published. A copy of the revised figure was tabled.

27. The revised figure indicated that the steepest rise in mortality rate for IHCC had occurred in the older age groups, especially the 75+ age group. The Committee considered that this could reflect improved diagnosis consistent with changes in clinical practice whereby older patients were now more fully investigated than in the past. Members noted that one of the axes on the figure had changed and asked the secretariat to write to the authors about this and about their current interpretation of the data in view of the revised figure. Members commented that they still considered that changes in diagnostic practice, particularly better diagnostic imaging, could account for the recorded increase in mortality from IHCC. Nevertheless, the data indicated that this cancer was more common than previously thought and it was therefore important to investigate its aetiology. The Committee did not consider that it would be useful to conduct epidemiological studies to determine whether there is any geographical clustering of cases around the UK as, if such clusters were found, it would probably not be possible to determine the cause.

ITEM 7: ILSI/HESI RESEARCH PROGRAMME ON ALTERNATIVES TO CANCER MODELS (CC/01/13)

28. Minutes will be published when statement is finalised.

ITEM 8: RANKING OF CARCINOGENS; COMPARISON OF METHODS USING SOME AIR POLLUTANTS (CC/01/17)

29. The draft paper attempted to consider two objectives. The first objective was to consider if there was comparability of ranking methods with respect to air pollutants and whether it was possible to derive broad categories for these chemicals. The second objective was to further consider the performance of the T25 as a method for ranking carcinogenic potency. Part of the consideration of the latter objective would involve comparing the performance of T25 with the TD50. There is a need for a pragmatic method for ranking the potency of carcinogens based on animal data for use in the identification of carcinogens present in chemicals (as impurities) and in mixtures at low levels as part of the classification and labelling procedure. [The COC has previously advised that the TD50 should only be used for genotoxic carcinogens.]

30. The current paper presented an analysis of the rank orders of potency for seven carcinogens; arsenic, benzene, 1,3-butadiene, benzo[a]pyrene (taken as representative of polycyclic aromatic hydrocarbons), cadmium, nickel and ozone, using a range of measures; ED10, inhalation unit risk estimate, NEHEL, TD50 and T25. Members agreed that the exercise had provided some useful information on the derivation of different indices of potency but it would be necessary to undertake a further evaluation of a greater number of compounds in order to draw any conclusions regarding a comparison of these methods. It was not possible to draw any conclusions with regard to the air pollutants examined as relevant potency estimates were not available for all of the chemicals under consideration. The information presented in the paper highlighted the need to evaluate the usefulness of proposed potency estimates based on animal data by comparing them with estimates based on appropriate human data.

31. Members noted that an ECETOC document on the use of T25 in chemical regulation was due to be published in the near future and that it would be useful for the COC to provide further advice on the T25 particularly as some EU Member States had suggested it could be used to assist in the identification and labelling of carcinogenic substances present at low levels in products. The Committee agreed to discuss the use of the T25 at the November 2001 meeting.

ITEM 9: PAPER FOR INFORMATION

32. Members were informed of correspondence on organochlorine insecticides (CC/01/18) and the COC reply to Hoyer et al which has been published in the Lancet. Members were also made aware of a paper on spatial variation and temporal trends of testicular cancer in Great Britain (CC/01/19).

ITEM 10: ANY OTHER BUSINESS

33. There was no other business.

ITEM 11: DATE OF NEXT MEETING

34. 22 November 2001.

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