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Minutes of the meeting held at 10.30am on Thursday 23 March in Room 102/24A, Skipton House, Department of Health, London SE1 6LH. 1. PRESENT
ITEM 1: APOLOGIES FOR ABSENCE 2. Apologies were received from Professor Newbold, Professor J Parry, Mrs Cathy Cameron (DETR) and Dr H Stemplewski (MCA). Announcements 3. Professor A G Renwick was congratulated on being awarded an OBE and Miss F Pollitt (PH5 Environmental Chemicals Team) was welcomed as an observer. 4. Members were reminded of the need to declare all interests before the discussion of each item. Members were informed that the procedures for greater openness of Committee business were being followed. ITEM 2: MINUTES OF MEETING HELD ON 18 NOVEMBER 1999 (CC/MIN/99/3) 5. The minutes were agreed subject to a number of minor editorial changes. ITEM 3: MATTERS ARISING/CONCLUSIONS FROM 18 NOVEMBER 1999 (CC/2000/2) 3.1 Draft statement on increase in mortality rates from Intrahepatic cholangiocarcinoma (CC/2000/2) 6. The minutes and conclusions on this item will be made available when the research has been published. ITEM 4: SECOND DRAFT STATEMENT ALCOHOL AND BREAST CANCER: UPDATE FROM 1995 TO 1999 (CC/2000/4) 7. No interests were declared. 8. The Committee had considered a first draft statement at its November 1999 meeting. Members had asked for a number of amendments, in particular that the assessment of data should be tabulated using the Bradford-Hill criteria for causality. A second draft statement (Annex 1 to CC/2000/4) had been submitted for consideration. There were also two new epidemiology studies, a new study on the effects of alcohol on oestrogen metabolism and some additional information on proposals for further research. The chairman asked the Committee to first consider the new epidemiology studies. 9. Members agreed that the update of the Nurses Health II study (Garland M et al 1999, Cancer Epidemiology Biomarkers and Prevention, 8, 1071) had been well conducted but noted that alcohol intakes were relatively modest in this cohort. It was difficult to interpret the key findings of a statistically significant increase in breast cancer (RR = 1.72; 95% CI 1 01-2.91) in women consuming >6 drinks/week at ages 23-30y in comparison to other published studies. The Committee agreed that little weight could be placed on the results of a recent hospital based case-control study (Tavani A et al (1999) European Journal of Cancer, 35, 1361 - 1367). 10. Members considered that the results of the intervention trial of the acute effects of alcohol on oestrogen metabolism in premenopausal women provided novel results; namely increased oestradiol levels only in women given an alcoholic drink and who also were taking oral contraceptives (SarkolaT et al (1999) Alcohol Clinical Experimental Research, 23,976-982). The Committee agreed that this study should be cited in the statement, but considered that it was not possible to draw any conclusions on the mechanism of the increase in oestradiol levels in women drinking alcohol and also taking oral contraceptives. 11 The Committee recalled that it had considered whether any relevant information on the effects of alcohol on oestrogen metabolism could be derived from the Health Survey for England (HSE). However, it had become apparent that there was insufficient information available on the use of oral contraceptives and stage of menstrual cycle for premenopausal women, and on use of Hormone Replacement Therapy for postmenopausal women for any meaningful study to be undertaken using the HSE. The Committee acknowledged that undertaking either an observational or intervention study with sufficient power to detect an effect of drinking alcohol on oestrogen metabolism would be complicated and probably expensive. In the first instance, Members suggested that further consideration be given to whether appropriate investigations could be included in the proposed large prospective cohort to be established by the MRC/Wellcome Trust. Members agreed that the statement should make reference to the forthcomming results from the Oxford Collaborative Study on Hormones and Breast Cancer. 12 The Committee reviewed the second draft statement and agreed that the conclusions should be altered to clearly state that there was evidence for a plausible mechanism in both premenopausal and postmenopausal women. It was important to state that a key area for investigation in the proposed meta-analysis study would be an estimate of population attributable risk. Members reaffirmed that the COM should be asked to update its opinion of 1995 on the mutagenicity data on alcohol. It was agreed that the COC statement could be finalised by Chairman's action. ITEM 5. DISCUSSION PAPER ON LONGEVITY IN CARCINOGENICITY STUDIES: ANALYSIS OF A DATABASE PREPARED BY PESTICIDES SAFETY DIRECTORATE (PSD) (CC/2000/1) 13 The proper conduct of carcinogenicity studies is an important part in the evaluation and prediction of potential human carcinogens. Significant reductions in the number of animals surviving to termination have been widely reported in the scientific literature. This is a matter of concern since inadequate carcinogenicity studies could result in studies being rejected, and hence large numbers of animals being needlessly used, or in the failure to identify potential human carcinogens. For a negative result from a rat carcinogenicity bioassay to be considered acceptable, survival at 24 months should be 50% or greater in all groups (see OECD, EPA and EC guidelines). 14 The discussion paper prepared by the secretariat and PSD was concerned primarily with the analysis of a database of 26 carcinogenicity studies considered by an Interdepartmental Secretariat during the period 1993-1998. A number of these studies had been reviewed by the Advisory Committee on Pesticides. A brief consideration of the use of dietary or caloric restriction in carcinogenicity bioassays was included in the paper. 15 The results of the analyses showed that acceptable survival occurred in only 17% of the studies where Sprague-Dawley rats were used. A further analysis of 6 studies where Sprague-Dawley rats had been used found that unexplained deaths occurred in about 2-4% of animals; there was however, no evidence that such deaths occurred more often in studies where survival was unacceptable. 16 Members agreed that the results obtained from the PSD rat carcinogenicity database were consistent with the experience of contract laboratories undertaking tests on pharmaceuticals. This was that inadequate survival occurred frequently in control Charles-River Sprague-Dawley rats, whereas survival in other strains such as the Harland Sprague-Dawley and Wistar was generally adequate. 17 The Committee agreed that the results raised a number of wider issues regarding carcinogenicity bioassays. Members were aware of the proposal from the Food and Drug Administration (FDA) in the USA to improve survival in carcinogenicity studies by restricting the intake of food or calories. It was noted that dietary restriction usually required the single housing of animals, a practice not adopted in the UK on animal welfare grounds. The Committee reaffirmed its earlier advice that the decision to apply dietary restriction in carcinogenicity bioassays must rest with the individual toxicologist. 18 The Committee considered the evaluation of early deaths from the six carcinogenicity studies which had been undertaken jointly by the secretariat and PSD. Members noted that the results suggested that early unexplained deaths were comparatively rare in Sprague-Dawley studies both with and without acceptable survival in control animals. The Committee agreed that the number of bioassays analysed was insufficient to draw any definite conclusions. Additionally, it was not possible to clearly state that standards of histopathological evaluation were equivalent between the six studies that had been performed in different laboratories. 19 The Committee considered that the revised conclusions could be agreed through chairman's action. ITEM 6: USE OF AMS IN INVESTIGATING CHEMICAL CARCINOGENICITY (CC/2000/3) 20 Accelerator Mass Spectrometry is a sensitive technique for measuring very low levels of radiolabelled chemicals (particularly 14C-) at around 10-21 to 10-18 mole. It is thus more sensitive than other currently available techniques for investigating chemical carcinogens and the formation of adducts with DNA. There are currently relatively few laboratories that have facilities to use AMS. However, the use of this technique is likely to increase and it is therefore important to review the applicability of this method to the assessment of chemical induced carcinogenesis. 21 The Committee considered some research using Accelerator Mass Spectrometry, which had been commissioned under the MAFF Risk Assessment Programme at the November 1999 meeting. Members asked for a more detailed consideration of the uses of AMS in the investigation of chemical carcinogenicity. The COM had considered these data at its October 1999 meeting and had made a number of preliminary comments on the results of DNA adducts measurements reported in this work. 22 The current paper presented an overview of the method, and of advances being made to reduce the size and cost of equipment needed to undertake AMS analyses, and the potential development of post-labelling methods for use with AMS. 23 Members agreed that AMS had also made a significant contribution to investigations into the quantification of DNA/protein adducts in tissues in both animals and humans over a wide dose range, i.e. from high dose levels used in long-term animal bioassays to the low dose levels that may encountered via the diet or through environmental exposure. Thus AMS studies in animals allow for a more informed assessment of the relevance of animal carcinogenicity data to human hazard assessment; i.e. investigations into the mechanism of carcinogenicity in laboratory animals and assessment of relevance to humans. The measurement of DNA adducts in-vivo using AMS has been mentioned in the draft revised COM testing strategy as one possible approach to DNA adduct measurements in in vivo assays. 24 Members agreed that evidence for the formation of DNA adducts provided by AMS needed careful interpretation to exclude non-specific binding, and that the nature of any DNA binding would have to be determined. It was not always possible to infer genotoxicity from AMS data without using other data indicating genotoxicity e.g. from short-term tests. However, negative results using AMS, such as with ortho-phenyl phenol in tumourigenic target tissue (i.e. the bladder), gave good evidence that the chemical was inducing tumours in rodents via a non-genotoxic mechanism. 25 The Committee agreed that a short statement could be drafted highlighting the examples considered. The statement could be cleared through Chairman's action. ITEM 7: PAPERS FOR INFORMATION: 26 7.1 Exposure to Environmental tobacco smoke and evidence for genetic susceptibility to lung cancer. CC/2000/5 7.2 Additional papers on alcohol and breast cancer CC/2000/6 ITEM 8: ANY OTHER BUSINESS 27 On behalf of the Department of Health, CMO and the Secretariat, Dr Fielder thanked Members for their hard work and their willingness to be contacted between meetings. ITEM 9. DATE OF NEXT MEETING: 17 July 2000 ACTIONS
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