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Minutes of the Meeting held 9th November 2000CC/MIN/2000/3 | ||||||||||
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Minutes of the meeting held at 10.30am on Thursday 9 November in room 103A, Skipton House, Department of Health, London SE1 6LH. 1. Present
ITEM 1: APOLOGIES FOR ABSENCE 2. Apologies were received from Professor D Forman, Dr A Smith (HSE), Mr A Browning (VMD) and Mr T Holmes (PSD). Announcements 3. The committee welcomed Dr Diane Benford (FSA) attending as secretary to COT and as part of the joint COC/COM secretariat. The Committee was informed of the appointment of Dr D Harper (Head of Profession for DH scientists) as Branch Head for Environment and Health. ITEM 2: MINUTES OF THE MEETING ON 17 JULY 2000 (CC/MIN/2000/2) 4. The minutes were agreed subject to minor editorial changes. ITEM 3: MATTERS ARISING 5. There were no matters arising, not considered as separate items during the meeting. ITEM 4: 3-MONOCHLOROPROPANE-1,2-DIOL CC/2000/19 6. Members heard that in 1999, on the basis of the available carcinogenicity studies with 3-MCPD and the lack of convincing in-vivo mutagenicity data, the COC concluded "that it would not be possible to draw conclusions about the significance of the observed carcinogenic effects of 3-MCPD and that it would be prudent to reduce exposure to as low a level as technologically feasible". 7. Members noted that following a recommendation from the COM, the Drinking Water Inspectorate (DWI) commissioned additional in-vivo mutagenicity studies with 3-MCPD. These new data (namely a rat liver UDS assay and a bone marrow micronucleus study in the rat) had recently been evaluated by COM at its October 2000 meeting. The COM considered that both studies had been carried out to an acceptable standard and concluded that in view of the negative results, 3-MCPD could now be considered as "having no significant gentoxic potential in-vivo." 8. Members were informed that the new data were likely to have implications for regulatory standards for 3-MCPD. The EC Scientific Committee for Food (SCF), who in 1997 re-affirmed its earlier 1994 view that 3-MCPD should be regarded as a genotoxic carcinogen, had been made aware of the new data and of COM's opinion. The new data were also due to be considered by the Joint Expert Committee on Food Additives (JECFA) at its meeting in June 2001. 9. The chairman noted that a review of the COC statement issued in 1999 was required to in order to accommodate the new advice from COM. Members were asked to consider a draft statement. 10. Members reviewed the available carcinogenicity data. The Committee noted that the available metabolism studies showed that the metabolite beta-chlorolactate was the predominant urinary metabolite in rats. Oxalic acid, derived from beta-chlorolactate was considered to be a probable cause of kidney cytotoxicity which might be associated with the observed renal tumours. However, members added that the metabolism data were old (1970s and 80s) and the possibility of tissue specific activation could not be discounted and that this needed to be acknowledged in the risk assessment and statement. With regard to the other tumours seen in rats (in the testes, mammary gland and preputial gland), members were informed that raised prolactin, luteinising and follicle stimulating hormones had been reported in rats given a single oral dose of 3-MCPD and it was considered possible that hormonal mechanisms were involved in the aetiology of these tumours. 11. The Committee agreed that according to current knowledge and practice, 3-MCPD could be considered as a non-genotoxic carcinogen and endorsed the COM advice. The Committee considered that uncertainties in the evaluation, particularly with respect to the limited metabolism data on 3-MCPD, needed to be noted in the risk assessment and statement. In addition it was noted that 3-MCPD contained a chiral carbon atom and hence stereoisomers might exist. This might be important in the risk assessment of 3-MCPD in food, where 3-MCPD is derived from the hydrolysis of proteins. 12. The Committee concluded that a no observed effect level (NOEL) of 1.1 mg/kg body weight/day could be identified for tumorigenicity from the currently available animal data. Members agreed that an uncertainty factor of 1000 (which reflected any remaining uncertainties in the data) could be used in assessment of human carcinogenicity risk. Members agreed the statement should be redrafted to present more information on the metabolism of 3-MCPD and on tumours seen in rats. It was agreed that the revised statement would be circulated by post and agreed by Chairman's action. ITEM 5: DEVELOPING STATEMENTS ON THE ROLE OF ENVIRONMENTAL CARCINOGENS IN RELATION OF SPECIFIC ORGANS (CC/2000/15) 13. The Committee was told that this paper sought to develop the idea discussed at the last meeting i.e. that the COC might produce authoritative statements about which human cancers are associated with environmental carcinogens. The paper outlined an approach to identify such chemicals and provided three prototype statements for the Committee to consider; on colorectal cancers, bronchial cancers, and cancers of the pancreas. The approach relied heavily on published IARC assessments of chemicals and on evidence obtained from human studies. At present, the statements contain only qualitative data but it was intended to incorporate data on potency and current exposures to the chemicals cited from the ranking exercise discussed in CC/2000/16, in due course. 14. Members had a number of reservations and concerns about this exercise and about the statements as currently drafted: 15. It was not clear who the target audience was for the statements nor what the main purpose of the exercise was meant to be. 16. The IARC database only included chemicals on which there were sufficient data to make an assessment. Including only IARC Groups 1 and 2 chemicals in the statements failed to indicate that there were many other chemicals which might had a role in human cancer. It also gave undue emphasis to some chemicals which have undergone IARC assessments but may not, in fact, have a major role in human cancer e.g. the food mutagens IQ, MeIQ, MeIQx and PhIP, cited in the draft statement on colorectal cancer. 17. Information for the public on chemicals and cancer should include more details about the complexity of tumour types, discuss more fully the epidemiology and aetiology of each cancer, and give higher priority to the known causes of that cancer. Members agreed that this would not be an easy task. Although this would take the project beyond the remit of the COC, this was considered to be inevitable if a balanced view was to be conveyed. 18. It was suggested that the Committee could present the known causes of cancer in a particular organ in a pictorial from (e.g. a pie chart), the chart for each organ also indicating the percentage of cases of unknown cause. This might enable any newly discovered cause to be put in context and could be useful in demonstrating to the public that different cancers have different causes. However, some members thought that there was insufficient information to attempt a quantitative exercise of this type. 19. In summary, there was a need to redefine the aims of this exercise, the audience and the methodology to be used. In the context of informing the public about environmental chemicals and cancer, it might be better to adopt a more targeted approach which addressed commonly expressed concerns. ITEM 6: DISCUSSION PAPER: RANKING OF ENVIRONMENTAL CARCINOGENS (CC/2000/16) 20. The Committee was informed that the paper presented a discussion of possible approaches that utilise information on carcinogenic potency and exposure in ranking of carcinogens. A suggested proposal for an overall ranking of environmental carcinogens is outlined which uses scoring for potency, level of exposure and proportion of population exposed. Key objectives of the proposal were that it should be; pragmatic, relevant, and comprehensive. The proposal outlined in this paper is solely concerned with IARC group 1 (definite) and 2A (probable) carcinogens since these are likely to be of highest hazard to humans. 21. Members cautioned against the development of ranking schemes giving a single numerical value of ranking which might give an unduly simplistic assessment. The Committee considered that it would be difficult to define environmental exposure categories as much data from epidemiological investigations of cancer was derived from occupational exposures. Moroever actual exposure and population exposed resulting from environmental dispersion of chemicals would vary with time. Members agreed that there was some value in the suggested work on carcinogen potency and agreed a comparison of the methods reviewed and in particular an updated COC view of the T25 would be valuable. ITEM 7: REVIEW OF RISK PROCEDURES USED BY GOVERNMENT ADVISORY COMMITTEES DEALING WITH FOOD SAFETY (CC/2000/21) 22. Members considered a report on the review of risk procedures used by the Government's advisory committees dealing with food safety, written by a group led by Sir Robert May. 23. Members agreed that the role of COC predominantly concerned hazard identification and risk assessment but not risk management. There was inadequate expertise on the Committee to advise in risk management. The Committee agreed that it should focus its work on scientific considerations and it was not the role of the Committee to consider policy options. Members heard that the COT might be asked to provide a risk assessment including on options for risk management. ITEM 8: CONSULTATION DOCUMENT ON A CODE OF PRACTICE FOR SCIENTIFIC ADVISORY COMMITTEES (CC/2000/22) 24. The committee considered a consultation document drafted by the Office of Science and Technology on a code of practice for Scientific Advisory Committees. Members agreed that it was important to demonstrate transparency of Committee procedures and work. Members felt that the current arrangements for openness (publication of agenda, minutes, statements) were adequate. The Committee discussed the holding of open meetings. Some members felt that there would be no impact on Committee work whereas others felt that the role of specialist advisory Committees was to produce advice which could be subject to public scrutiny. It was agreed that any further proposals for greater openness needed careful planning in consultation with members and would place additional resource requirements on the secretariat. ITEM 9: CONSIDERATION OF LONGEVITY IN CARCINOGENICITY BIOASSAYS: FDA COMMENTS (CC/2000/18) 25. The COC reviewed the data on survival from 26 carcinogenicity studies held by the Pesticide Safety Directorate at its November 1999 meeting. A statement was published on the COC Internet site after the March 2000 meeting. A copy of the COC statement and supporting paper were forwarded to the US FDA. Dr Leaky from FDA had responded. Members considered that it was inappropriate to recommend single housing of animals. The Committee felt that environmental enrichment of group housed animals reduced infighting and stress. It was agreed to review the revised FDA points to Consider Document when this became available. ITEM 10: COC CONSIDERATION OF ASSOCIATION BETWEEN ALCOHOL AND BREAST CANCER: SCOPING STUDY TO INVESTIGATE THE ASSOCIATION BETWEEN ALCOHOL AND OESTROGEN METABOLISM (CC/2000/18) 26. The Chairman thanked Dr T Key (ICRF Oxford) for agreeing to present a resume of the report prepared for the COC. He thanked Professor H Jacobs (Emeritus Professor of Reproductive Endocrinology, University College Medical School, London) for reviewing the report. 27. Members recalled that in the 1999 statement, the COC had agreed that there was an association between drinking alcohol and breast cancer, but the magnitude of the association was in the region (RR 1-3) which might be explained by confounding factors. The COC had recommended that a systematic review (meta-analysis) of the published epidemiology studies be undertaken in order to assist in evaluating causality. This study had been funded by the Department of Health but was not due to report for 18 months. The committee had also considered it plausible that alcohol induced increases in serum oestrogens (in particular oestradiol) might explain the association between drinking alcohol and breast cancer. One study had shown that alcohol induced significant increases in serum oestradiol in women taking oral oestradiol as HRT. The Committee had recommended that further research on the effects of alcohol and oestrogen metabolism, in particular information on the threshold was desirable. 28. Dr Key gave an overview of the report prepared for the Committee. He noted that the pooled analysis of prospective studies and the available meta-analyses of epidemiological studies suggest an increase in risk of breast cancer of 1.1 for a daily consumption of one unit of alcohol (8g ethanol), although there was considerable variance between individual investigations. He also reported that recent (and as yet unpublished) results from the Oxford Endogenous Hormones and Breast Cancer Collaborative Group showed an increase in risk of breast cancer of 1.6 for a doubling in serum oestradiol concentration. Dr Key noted that the data were relatively crude but could be used to estimate the numbers of individuals that would be required in investigations of the effect of alcohol consumption on oestrogen metabolism. He observed that comparatively few studies had investigated the effects of alcohol on plasma oestrogen concentrations. Of most importance was the study by Reichman M. E. et al (JNCI, 85,722-727,1993) which had been considered in the COC statement. The Ginsburg (JAMA 276, 1747-1751, 1996) study of women taking HRT was also of particular interest as it demonstrated a significant but relatively short-lived increase in serum oestradiol following consumption of alcohol in women taking oral oestradiol as HRT. Dr Key emphasised the particular problem of timing blood sampling following ingestion of alcohol. Dr Key considered that on balance serum oestradiol and sex hormone binding globulin (SHBG) were the most appropriate oestrogen measurements. Dr Key noted that he had been asked to consider the design of a study that could investigate the effects of alcohol on endogenous hormones in pre-menopausal and post-menopausal women and effects of exogenous hormones (i.e. oral contraceptives and HRT). He felt the most pragmatic approach would be to study these groups separately, as it was most likely that a different mechanism of alcohol interaction pertained to endogenous or exogenous hormones. Using the assumption that any study needed to detect either a 10% or 20% increase in plasma oestradiol, it had been possible to calculate the size of study groups for an intervention study in pre-menopausal women. Dr Key noted that quality of any study would be improved by examining daily doses over periods of up to 3 months (i.e. at least two menstrual cycles) in pre-menopausal women and up to 1 month in post-menopausal women, with multiple blood sampling in each woman. Dr Key commented that such a study design raised issues concerning recruitment, compliance and ethics of administering daily doses of alcohol at levels near to the safe drinking limit (of 2-3 units/day). The alternative approach would be to design a cross-sectional study or access stored samples available for analyses. One advantage of such an intervention study was that associations between other factors (such as diet and physical activity) that could have an effect on oestradiol levels, could be investigated. 29. The Chairman thanked Dr Key and asked Members if they had any comments on the paper before considering the research approaches outlined in the paper. Members observed the need for good quality analytical procedures. It was noted that some laboratories had reported high variations between duplicate samples. Members agreed that analytical methods would have to be validated. 30. Members heard from Professor Jacobs that the predominant form of oestrogen varied in women taking oral contraceptives and those on HRT depending on form of medicine used, and in the case of HRT, the route of administration (i.e. dermal or oral). The primary determinant of SHBG in women was body weight, which needed to be considered in any study. Professor Jacobs suggested that a study to repeat and further investigate the findings reported by Ginsburg et al (1996) on the effects of alcohol on serum oestradiol in women taking oral HRT was particularly important as these observations were quite marked and had never been followed up in the published literature. It was possible that the effects of alcohol were mediated through an effect on the splanchic metabolism of oestradiol derived from HRT. 31. Members noted the practical, technical and ethical issues reported by Dr Key and also commented that costs of such a study were likely to be very high, particularly if it were important to detect a 10% increase in serum oestradiol levels. Members agreed that the most pragmatic approach would be to examine the effects of single doses of alcohol under laboratory conditions. It would be possible to design preliminary investigations to examine the dose-response relationship between alcohol and serum oestradiol levels. It would also be possible to investigate oestradiol following use of oral contraceptives or HRT in individuals consuming single doses of alcohol, and examine the absorption of oestradiol from HRT in these individuals. 32. Members discussed a recent paper (Liehr JG, Endocrine Reviews 21, 40-54, 2000) in which it was suggested that one metabolite of oestradiol (4-hydroxoestradiol) could be further activated to reactive semiquinone/quinone intermediates. Members agreed that there was no in-vivo mutagenicity evidence to support this hypothesis. IARC stated in volume 72 of its monographs on the evaluation of carcinogenic risk to humans that most if not all the genetic effects associated with oral contraceptives (and most oestrogens) can be explained by oestrogen and progesten receptor mechanisms. IARC had also noted a minor pathway of oestrogen metabolism to catechol intermediates with significant potential for forming reactive intermediates and damage to DNA. Members also commented on the potential of oestradiol to induce aneuploidy in-vitro, which had recently been demonstrated, and suggested further research might provide evidence for a mutagenic effect. However members agreed that on balance the most important research should focus on investigating the effects of alcohol on oestrogen levels. 33. Some Members were concerned that the complexity of the research needed and the difficulty in obtaining the critical results to impact on the evaluation of the association between alcohol and breast cancer might limit the value of such research. The Committee agreed that a preliminary study focused on single doses of alcohol on oestrogen metabolism and interaction with HRT would be of most value. ITEM 11: ANY OTHER BUSINESS 34. There were no other items of business. The secretariat thanked members for their work during the year. ITEM 12: DATE OF NEXT MEETING: 35. 22 March 2001 ACTIONS
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