COC Meeting 18th November 1999 COC/MIN/99/3
Minutes
1. PRESENT
Chairman:
Professor P G Blain
Members:
Professor C Cooper
Professor P Farmer
Professor D Forman
Dr S J Kennedy
Ms M Langley
Professor J Parry
Professor I Purchase
Professor A G Renwick
Dr S Venitt
Professor G Williams Assessors:
Dr C Fisher (MAFF)
Dr A Smith (HSE)
Dr H Stemplewski (MCA)
Mr S Warren (PSD) Secretariat:
Dr R J Fielder (Scientific)
Mr J Battershill (Scientific/Minutes)
Mr M Al-Derzi (Minutes)
Mr K N Mistry (Administrative)
In Attendance:
All Meeting
Dr T Barlow (JFSSG/DH)
Professor A Boobis (ICSTM)
Dr S Gupta (DH)
Item 5
Dr S Khan (ICSTM )
Professor H Thomas (ICSTM)
Dr S Taylor-Robinson (ICSTM)
ITEM 1: APOLOGIES FOR ABSENCE
2. Apologies were received from Professors Chilvers, Dayan, Newbold, and, Mr A Browning (VMD).
Agenda
1. Apologies for absence 2-3
2. Minutes of meeting held 24 June 1999 4
3.
Matters arising not dealt with by other agenda items 5
4. Association between alcohol consumption and breast cancer
First draft statement 6-8
Proposal for investigation (Health Survey for England) 9-10
5. Trends in mortality from intrahepatic cholangiocarcinoma 11
6. Non-genotoxic carcinogens: identification and significance 12-16
7. Measurement of carcinogen DNA adducts using Accelerator
Mass Spectrometry 18-19
8. Papers for information 20-21
9. Any Other Business 22
10. Date of next meeting 23
Announcements
3 . Members were reminded of the need to declare all interests before the discussion of each item. Members were informed that the new procedures for greater openness of Committee business were being followed.
ITEM 2: MINUTES OF MEETING HELD ON 24 JUNE 1999 (CC/MIN/99/2)
4. The minutes were agreed subject to a number of minor editorial changes.
ITEM 3: MATTERS ARISING AND CONCLUSIONS FROM MEETING HELD 24 JUNE 1999.
5. The statements on organochlorine insecticides and breast cancer, MCPD and Ozone had been finalised during the summer and were now on the COC Website. The finalised statement on cancer incidence near to municipal incinerators would be placed on the COC Website at a time to coincide with the publication of the SAHSU report. A summary report of Dr Robinson's presentation on short-term carcinogenicity tests using transgenic animals had also been placed on the COC Website. A copy of this report and some of the data presented by Dr Robinson has been provided for Members information (CC/99/38 and addendum CC/99/32).
ITEM 4: ASSOCIATION BETWEEN ALCOHOL CONSUMPTION AND BREAST CANCER
4.1 First draft statement on evidence between consumption of alcoholic beverages and breast cancer (CC/99/34)
6. No interests were declared.
7. Members asked for a considerable number of changes to be made to the first draft statement. The most important were as follows:
Para 5 Clarify that reported relative risks for breast cancer are within the range where it is difficult to exclude bias and/or confounding as explanations for the observed results in epidemiological studies. Clarify that the difficulty in obtaining an accurate drinking history is an important reason for the observed variation in estimates of the consumption of alcohol and of relative risks for breast cancer at particular levels of drinking.
Para 8 Clarify the need for a full evaluation of the epidemiological data on alcohol and risk of breast cancer for potential confounding factors in addition to information on potential mechanisms.
Para 10 Reorder the objectives of the COC review as requested.
Para 13 Note that data from both cross sectional and intervention studies were available regarding the investigation of effects of alcohol consumption on oestrogen metabolism.
Para 17 Present the consideration of evidence according to Bradford-Hill criteria in a tabular form.
Para 20 Redraft conclusions to note clearly the nature and consistency of the evidence and magnitude of observed effect.
8. Members commented that new research reporting an increased risk of breast cancer in premenopausal women consuming 6.5 drinks/month was associated with alcohol dehydrogenase 3 (ADH3 (1-1)) genotype compared to other ADH 3 genotypes. No modifying effect of ADH3 genotype on relative risk of breast cancer was found in postmenopausal women. Members agreed that this new research should be noted in the statement and that any further information on the modifying effects of ADH3 genotype on the association between alcohol consumption and risk of breast cancer should be made available at the March 2000 meeting.
4.2 Proposal for investigation of stored serum samples obtained as part of the Health Survey for England (CC/99/40)
9. Members recalled the suggestion made at the June 1999 meeting that useful information on the effects of alcohol on oestrogen metabolism might be obtained from stored serum samples obtained as part of the Health Survey for England. Members thanked the team from Imperial College of Science and Technology for producing a draft research proposal at short notice. The proposed investigation consisted of a cross sectional investigation of serum samples taken for the 1998 Health Survey for England from premenopausal and postmenopausal women (divided into those who did or did not use Hormone Replacement Therapy) stratified by alcohol intake.
10. Members agreed that this was an important area of research. There were however, a number of aspects of the proposed investigation which needed further consideration. These include phase of menstrual cycle for premenopuasal women, detailed information on type of HRT prescribed for postmenopausal women, intake of phytoestrogens in the diet and details of analytical methods and appropriate limits of detection for oestrogen metabolites. Members agreed that a peer review from an endocrinologist with experience of this type of investigation would be valuable in planning any additional work.
ITEM 5: TRENDS IN MORTALITY FROM INTRAHEPATIC CHOLANGIOCARCINOMA (CC/99/35)
11. The minutes of this item will be published when the results of the research reviewed in CC/99/35 have been published.
ITEM 6: NON-GENOTOXIC CARCINOGENS: IDENTIFICATION AND SIGNIFICANCE (CC/99/36)
12. It has been estimated that approximately 50% of all chemicals tested in animal carcinogenicity bioassays induce an increase in tumours in at least one tissue. Some of these animal carcinogens induce tumours via a direct interaction of the chemical or its metabolites with DNA; these are referred to as genotoxic carcinogens. It is prudent to assume that for these carcinogens there is no threshold dose below which no carcinogenic effect would be expected to occur and that they are therefore of particular concern to public health. The remainder of the animal carcinogens act through non-genotoxic mechanisms, for which a threshold may operate. Non-genotoxic carcinogens tend to be tissue and/or species specific. In some cases these are not relevant to human health. At present there are no short-term tests that can be used to identify such compounds and long term bioassays in animals are necessary. The development of rapid methods for the identification of chemicals that induce cancer by non-genotoxic mechanisms that are relevant to humans had been identified by the COC as a priority area for research in 1996
13. The DH Toxicology unit has drafted a discussion paper (Annex A to CC/99/36). They considered information available on the known human carcinogens as evaluated by the WHO International Agency for Research on Cancer (IARC) to identify non-genotoxic carcinogens and information on mechanisms of carcinogencity which were relevant to humans. The aim of the work had been to review experimental approaches which could be used to identify non-genotoxic mechanisms of carcinogenicity and to select the most appropriate short-term testing approaches which could be considered for further research. One important outcome of this work was to exclude rodent-specific carcinogenic mechanisms, such as chemically induced deposition of alpha2µ globulin in the kidneys of male rats, which are thought to be unimportant with respect to hazard identification for humans.
14. Members noted that mutations are found in all chemically induced cancers. Members agreed that the most important non-genotoxic mechanisms could be placed into one of four groups, (i) persistent cytotoxicity accompanied by proliferative regeneration, (ii) chronic inflammation accompanied by the production of reactive oxygen species, (iii) hormomimetic activity and (iv) ligand binding with xenobiotic induction receptors. Members considered that increased cellular proliferation was of particular significance.
15. The Committee considered the approaches suggested by the DH Toxicology Unit and agreed that it was not practical to design a test to detect all non-geonotoxic carcinogens. However, by focussing on a number of relevant mechanisms it should be possible to identify key toxicological responses in sub-acute studies which might provide an indication of carcinogenic activity. It was very important in designing a research programme to select appropriate reference compounds and to include as wide a range of mechanisms and target organs as was practicable to study. Members considered the IARC list of group 1 carcinogens as a useful start but felt that consideration ought to be given to chemicals listed as IIA by IARC and under the EU Dangerous Substances Directive (EEC/67/548) as category 1 and 2 carcinogens.
16. Members considered that future consideration of the application of gene arrays and approaches to transcription profiling would become important in studies of non-genotoxic carcinogenesis but at present there was little experience in the use of such methods. Members agreed there was little evidence to support the development of (in-vitro) methods such as cell transformation assays, or the use of the currently available transgenic animal models (such as the Tg.AC mouse). It was possible that appropriate transgenic animal models for certain classes of non-genotoxic carcinogens could be developed in the future.
17. The Chairman thanked the DH Toxicology Unit for their discussion paper.
ITEM 7: MEASUREMENT OF CARCINOGEN DNA AND PROTEIN ADDUCTS USING ACCELERATOR MASS SPECTROMETRY (AMS)
Project report of MAFF sponsored research. (CC/99/37)
18. The project report summarised DNA/protein adduct data from rodents and volunteers exposed to a number of carcinogens found in food (aflatoxin (AFB1), heterocyclic amines (MeIQx and PhIP) and polycyclic aromatic hydrocarbons (BaP)). Members agreed that the authors had demonstrated that AMS could, with appropriate sample work-up procedures, be a highly sensitive technique for detecting low levels of DNA adducts. However no definite conclusions could be drawn from the data provided by the authors on interspecies comparisons between rat and humans for MeIQx DNA adducts, or on the rank order in the rat of DNA adducts following dosing of the various carcinogens studied.
19. Members considered that there was a number of published papers on AMS which would be of value in drawing conclusions on the usefulness of this method for measuring DNA adducts and its potential application to the investigation of chemical carcinogenesis in animals and humans. The Committee agreed to review these papers at the March meeting. Members noted the one additional paper which had been tabled (Mani C et al, Toxicology and Applied Pharmacology,1999, 159, 83-90) and agreed that the approach used by these authors to measure total (i.e. area under curve ) DNA adducts in bone marrow of various strains of mice and rats dosed with 14C-benzene was acceptable. However it was not possible, as suggested by these latter authors, for any conclusions to be drawn regarding risk of cancer from the DNA adduct data.
ITEM 8. PAPERS FOR INFORMATION:
20. Summary of HESI/ILSI presentation on use
of transgenic animals in carcinogenicity testing CC/99/38
21. Additional data from HESI/ILSI CC/99/32 (addendum)
ITEM 9. ANY OTHER BUSINESS
22. There were no other items of business.
ITEM 10. DATE OF NEXT MEETING: 23 MARCH 2000
23. The Secretariat wished members a happy Christmas and best wishes for the new millennium.
ACTIONS
Item Action By Whom
Item 4
Alcohol and Breast Cancer Redraft statement, circulate
Investigate HSE as a source for further research Secretariat
Item 5
Intrahepatic cholangiocarcinoma Draft statement, circulate Secretariat
Item 6
Non genotoxic carcinogens Initiate DH research
Consider selection of chemicals Secretariat
Item 7
AMS Prepare further paper Secretariat