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Present:
2. Apologies for absence were received from the members Professor D Harrison, Dr R Roberts, Dr N Wallis, and the assessors Dr H Stemplewski (MHRA), Mrs R Kearsley (VMD) and Mr R Alexander (NAW). Announcements 3. The Chairman welcomed two new lay members to the Committee, Dr Carolyn Allen and Mrs Rosie Glazebrook, and the new assessor Alison Gowers (Environment Agency). The Chairman also welcomed Dr Sarah Bull (DH Toxicology Unit), Dr Karin Fletcher (DH Tox Unit), Dr A Smith (HSE) and Paul Buckley (HSE). 4. The Chairman informed the Committee of changes to the secretariat that would take place after Dr Fielder's retirement on the 18 August 2004. The COC Secretary would be Frances Pollitt. Jon Battershill would become the Secretary for the COM and continue to undertake projects and papers for the COC. The Chairman on behalf of the COC thanked Dr Fielder for his highly valued contribution to the Committee over the years. 5. Members were reminded of the need to make any relevant declaration of interests before the discussion of items. ITEM 2: MINUTES OF THE MEETING OF 1 APRIL 2004 (CC/MIN/04/1) 6. The minutes were agreed subject to minor editorial changes. ITEM 3: MATTERS ARISING NOT COVERED BY LATER AGENDA ITEMS
7. The Committee was reminded that the Chairman had written on behalf of the COC on the 16 January 2004 to the UK Biobank project outlining members' comments following a presentation by Dr Peter Greenway (Assistant Director of research and Development Division, Department of Health) on the UK Biobank project at the November 2003 COC meeting. 8. Professor John Newton (Chief Executive of UK Biobank) had responded specifically on the comments raised by the COC on the development of a questionnaire (related to concerns over information on chemical exposure) and storage/analysis of samples in a letter dated 26 March 2004. Professor Newton expressed a willingness to consider advice on these aspects from the COC. Professor Forman agreed to take the lead for the COC on advising on the design of the Biobank questionnaire and Professor Shuker agreed to take the lead on advising on sample storage and biomarker evaluation. The Chairman would respond to Professor Newton.
9. The minutes of this item now published - see paragraphs 71 - 73.
10. The COC was informed that its statement on olfactory neuroblastoma had been published and that the Chief Medical Officer Sir Liam Donaldson had written to the HSE on the subject and had received a reply. The Chief Dental Officer Professor Raman Bedi and Sir Liam Donaldson had also written to the appropriate Dental associations/organisations.
11. The Committee heard that the COC and COM would adopt the procedures for open meetings already used by the COT from their next meetings onwards (ie from November 2004 for the COC).
12. Members were reminded that an updated COC statement on organochlorine insecticides and risk of breast cancer had been agreed at the April 2004 meeting. Members had asked for a summary analysis to be undertaken on three specific epidemiology studies on dieldrin. The Statistics Services of Imperial College had produced a report for the DH Toxicology Unit (CC/04/26). 13. A summary risk estimate for the association between dieldrin and breast cancer had been produced, but the author suggested that the data set was too heterogeneous for a meaningful summary. 14. The COC were content with the analysis by Imperial College and noted that it was helpful. Members agreed that at present there were limited data on dieldrin but that this was likely to increase with time and would be reviewed again by the Committee in due course. ITEM 4: PROSTATE CANCER 15. No interests were declared.
16. Members recalled that the overview paper produced by the DH Toxicology Unit (http://www.advisorybodies.doh.gov.uk/pdfs/annex1cc0335.pdf) had cited some evidence for an association between occupational exposure to PAHs and increased risk of prostate cancer. However the full papers had not been reviewed by COC and thus a further paper (Annex 1 to CC/04/12) had been prepared. The information had been subdivided into occupational categories. Some data on benzo(a)pyrene exposure in different occupational, and environmental settings were provided for members information. It was noted that there were a number of typographical errors in the presentation of the benzo(a)pyrene exposure data and recommended occupational exposure levels. Members agreed to pass on editorial comments to the DH Toxicology Unit. 17. The Committee noted that there were very limited exposure data pertaining to the individuals in the epidemiology studies evaluated in the DH Toxicology Unit report. Members felt that given the widely available approaches for estimating PAH exposure the paucity of exposure data in the published epidemiology studies was disappointing. It was noted that although the data were limited, there was no evidence to suggest higher risks occurred in occupational categories where, from published data, exposures would be anticipated to be relatively high (eg coke oven workers, truck drivers, and foundry workers) compared to other occupational categories or environmental exposures. Overall, the available studies do not provide convincing evidence that there is an increased risk of prostate cancer in those occupations with exposure to PAHs. 18. HSE commented on the need to apply the findings of the review to strategies for occupational exposure assessment of PAHs in the UK. Members considered that the available data did not support the need for enhanced monitoring of PAH exposure with respect to the evaluation of risk of prostate cancer. 19. The Chairman asked the Committee to consider the draft overall conclusion for inclusion in the statement which had been presented in the covering paper. Members agreed the text subject to a number of editorial changes and amendments. The draft conclusion would be included in the revised statement and circulated to members.
20. Members recalled that HSE had asked the COC to review the available evidence regarding risk of prostate cancer within the rubber industry. The DH Toxicology Unit overview paper had cited the literature review paper published by HSE (Muir and Harris. HSE publications 1998). A further review had covered all available epidemiology studies. This had been forwarded to the British Rubber Manufacturers Association (BRMA). Comments from the BRMA were tabled for members' consideration. 21. The Chairman asked the Committee to consider the DH Toxicology Unit paper first and then to respond to the points raised by the BRMA. 22. The review presented an assessment of data from epidemiological studies from rubber manufacturing plants in different geographical locations and also considered the available information with regard to different job categories and chemical exposures within manufacturing plants. As a general comment members considered that the presentation of some of the results of the epidemiology studies needed additional clarification with regard to statistical significance. Members also agreed that a generic discussion regarding the presentation of epidemiology data should be included in the horizon scanning paper for the November meeting. Members agreed that overall the evidence was not convincing for an increased risk of prostate cancer in those working at rubber manufacturing plants. It was noted that there was some evidence from a limited number of studies that suggested a small increased risk of prostate cancer associated with certain job titles or areas of work. These included compounding and mixing, cement mixing, calendering and plystock handling. Members considered there was a lack of consistent evidence for any job title or group of titles and there was no evidence for a common exposure within these categories, but commented that the available evidence was limited. 23. Members also asked the secretariat that future reviews should include paragraph numbering and greater tabulation of data. 24. The Chair asked for comments on each paragraph of the BRMA comments. Members agreed the suggested factual editorial comments. The Committee considered that the final conclusion reached in the DH Toxicology Unit review was appropriate. 25. The Chairman asked the Committee to consider the draft overall conclusion for inclusion in the statement which had been presented in the covering paper. Members agreed the text subject to a number of editorial changes and amendments. The draft conclusion would be included in the revised statement and circulated to members.
26. Members were informed that the 2nd draft statement had been revised to take into account the editorial comments raised at the previous meeting. In addition some additional review material was available from the recently published Ontario College of Physicians review on pesticides. (The overall approach to considering this review was to be discussed under matters arising at this COC meeting). Members commented that some additional details on farm workers and exposure to pesticides as noted in the minutes of the April 2004 COC meeting needed to be included in the draft statement. One member expressed concern regarding the number of multiple comparisons undertaken by Alvanja MC (American Journal of Epidemiology, vol 157, 800-814, 2003) and the significance to be attributed to the conclusions reached in this paper. The Chairman asked the secretariat to consider the comments made by members and resubmit the draft statement to the November 2004 meeting. ITEM 5: OESOPHAGEAL CANCER: INITIAL OVERVIEW PAPER (CC/04/14) 27. The COC had asked for a review of oesophageal cancer during its discussion of the 2003 horizon scanning paper. The DH Toxicology Unit had drafted an overview paper (CC/04/14), which was intended as a guide to the COC on whether further more detailed work was required. 28. Oesophageal cancer is broadly classified into two histological types, squamous cell carcinoma (occurring mainly in the upper region of the oesophagus) and oesophageal adenocarcinoma (occurring mainly in the lower region of the oesophagus). 29. Members agreed that the incidence of oesophageal adenocarcinoma (EAC) was increasing whilst the incidence of squamous cell carcinoma (SCC) had essentially stabilised. 30. Tobacco smoking and alcohol consumption are considered to be the predominant risk factors for SCC with about 90% of cases being attributable to these factors. There was no convincing evidence for an association between alcohol consumption and EAC. Members were aware of some studies which documented results supporting an association between tobacco smoking and EAC but agreed the evidence was less convincing than for tobacco smoke and SCC. 31. Members agreed there was convincing evidence for an association between body mass index and gastro-oesophageal reflux disease (GERD) and EAC whilst the incidence of SCC did not appear to be affected by these two factors. 32. Members considered the evidence for particular chemical exposures and SCC and EAC. It was agreed that the limited evidence for an association between the rubber industry and an increased risk of oesophageal tumours was not convincing. In particular, it was noted that the available studies did not account for potential confounding by alcohol consumption or tobacco usage. Members commented that evidence for increased risk associated with occupational exposure to nitrosamines, PAHs, various dusts or other chemicals was limited. However many of these studies had not adjusted for confounding by alcohol consumption or tobacco usage and were therefore of limited value. 33. The Committee considered the available information on dietary nitrosamines in more detail. Nitrosamines were known to be oesophageal carcinogens in rodents and evidence suggesting similar metabolic pathways leading to activation was available for both rodents and humans. The metabolism and potential metabolic activation of nitrosamines in rats and monkeys were reported in the DH Toxicology Unit paper to be modified by ethanol. Nitrosamine exposure can occur through smoking and the diet and any effect on oesophageal cancer due to nitrosamines could potentially be influenced by alcohol. 34. There is some evidence from studies in China linking dietary nitrosamines and oesophageal cancer. However, no conclusions on the importance of nitrosamine exposure on oesophageal cancer in the UK could be drawn from these studies. 35. The Committee agreed with the overall conclusions in the DH paper, namely that lifestyle factors are likely to predominate in the aetiology of both types of oesophageal cancer. The available evidence did not clearly suggest any potential occupational or environmental exposure to chemicals that should be further considered at this point in time. 36. The Chairman asked members to consider what further review work should be undertaken. Members heard that research work originating from Professor Kenneth McColl and colleagues at the University of Glasgow (Iijima K et al Carcinogenesis. 2003 Dec;24(12):1951-60. Epub 2003 Sep 11) had demonstrated how saliva and gastric juice could aid a localised nitrosation in oesophageal epithelia and presumably Barrett's metaplasia. This provided some information for a potential role of nitrosamines in EAC. Members felt that a further review of the dose-response for alcohol and oesophageal cancer and a consideration of mechanism was warranted at this point in time. It was agreed the secretariat would add this to the Horizon scanning review to be presented at the November 2004 meeting. ITEM 6: DRAFT COC GUIDELINES: RESPONSE TO CONSULTATION (CC/04/15) 37. CC/04/15 presented an overview of the responses received to the consultation on the draft guidelines. It was noted that the document had been widely advertised in the FSA News Bulletin and a number of professional bodies had been contacted. However, comments had only been received from the Environment Agency, Toxicology and Advice Consulting, PSD, and from one private individual. 38. The Chair asked members to consider each set of comments separately. 39. Regarding comments from the Environment Agency, members agreed the term "Minimal Risk Level for Genotoxic Contaminants and Impurities" was more appropriate but asked the secretariat to ensure that the text of guidelines was explicit in defining the conditions under which this approach could be used. Members considered whether adopting a minimal risk level in the carcinogenic risk assessment of genotoxic contaminants and impurities could be interpreted by risk managers as fulfilling ALARP. It was noted that the draft guidelines clearly indicated that this approach was intended to be informative to risk managers, and that there was always the requirement to consider ALARP as well as the minimal risk level. There was no specific statement in the draft guidelines on what level of exposure would fulfil ALARP as this was outside the remit of the COC. 40. Members noted that the substantive comments from Toxicology and Advice Consulting (TAC) concerned the COM strategy for testing and evaluation of mutagens. TAC had suggested a risk assessment approach based on the application of uncertainty factors, which could be varied according to the evidence for mutagenicity. Members felt that the arguments advanced were not convincing. It was agreed that the COM should review the TAC proposal at its October 2004 meeting. Members agreed a number of minor editorial alterations suggested by the TAC response. 41. The Food Standards Agency made a number of editorial suggestions to paragraphs 65, 70 and 76 of the guidelines to aid distinction between risk assessment and risk management of genotoxic carcinogens. 42. Members were informed that PSD had asked for greater clarification regarding different approaches to potency ranking and the rationale for selecting T25 as the most appropriate method. Members agreed this would be valuable. HSE noted that there were uncertainties in the derivation and interpretation of T25 carcinogenicity potency estimates derived from animal studies with regard to the setting of concentration limits for carcinogens for classification purposes and suggested that reference to this should be made in the guidelines. Members agreed that this should be undertaken and suggested reference to the ECETOC publication (Technical report No 83, 2002) would be relevant. 43. Members also noted that some more recent references on the IPCS mode of action and the proposal from ILSI for a human relevancy framework (HRF) were available and should be cited in the guidelines. 44. The Chairman informed members that the secretariat had suggested a number of amendments to the draft submitted which were given in Annex 2 to CC/04/15. He asked the secretariat to prepare a final draft for circulation to members and assessors. The finalised guidelines would be agreed through Chairman's action and would be available in electronic and printed formats. ITEM 7: MALACHITE GREEN/LEUCOMALACHITE GREEN (CC/04/18) 45. No interests were declared. 46. Malachite green (MG) is a cationic triphenylmethane dyestuff that has been used as a fungicide in freshwater fisheries. Its use in fish for human consumption was banned in the EU in June 2002 but residues continue to be found in fish. 47. The COM have advised on the mutagenicity of MG and lipophilic metabolite leumalachite green LMG in 1999. On the basis of limited information the COM recommended that both compounds should be regarded as in-vivo mutagens. 48. The NTP have now published the results of carcinogenicity bioassays in rats and mice using both MG and LMG, together with significantly more mutagenicity data on these compounds. The COM reviewed the new mutagenicity data at their meeting in May 2004. Overall, the COM confirmed that MG should be regarded as an in-vivo mutagen in rats and mice in view of DNA adduct formation in the liver of rats and mice. LMG should also be regarded as an in-vivo mutagen due to the induction of mutations in the liver DNA in female mice. 49. The COC were now being asked to advise on the results obtained in the NTP carcinogenicity bioassays, and whether MG and LMG should be regarded as genotoxic carcinogens. 50. It was noted that MG had been investigated in female rats and female mice. The use of female only was questioned, but it was noted that the rationale for this was the greater toxicity of the compound in female animals. Members felt that the study had been adequately carried out, and agreed with the conclusions as endorsed by the NTP peer review panel. There was no evidence of carcinogenicity in the female mice and no clear evidence in female rats. There was equivocal evidence in the rat based on an increase in thyroid gland tumours (adenoma or carcinoma combined), hepatocellular adenomas and mammary gland carcinomas, but this was not convincing for a carcinogenic effect. 51. In the female mouse treated with LMG there was evidence of liver carcinogenicity based on an increase in hepatocellular adenoma or carcinoma (combined). There was no clear evidence of carcinogenicity in the rat. There was equivocal evidence of carcinogenicity in male rats based on an increase in interstitial cell adenoma of the testes and the occurrence of thyroid gland follicular cell adenoma or carcinoma (combined). There was also equivocal evidence in female rats based on an increase in the incidence of hepatocellular adenoma or carcinoma (combined). 52. In general, members felt that the only data that indicated concern was the increase in hepatocellular adenoma or carcinoma by LMG in the female mice. LMG induced liver cancer in female mice. 53. Members discussed the potential mechanisms for the induction of the liver tumours in the female mice. 54. In answer to a query it was explained that the COM view that the in-vitro data provided evidence of mutagenic potential with MG and LMG was based on consideration of the weight of evidence, including the fact that the compounds have structural alerts for DNA reactivity. With regard to the in-vivo data it was accepted that there were some inconsistencies, and that only a low level of DNA binding had been observed. However, the DNA binding seen in the liver with MG and the CII mutations seen with LMG in female mice was felt sufficient to conclude that both compounds should be considered as in-vivo mutagens. 55. It was also mentioned that there was no evidence from organ weight changes or liver histopathology to support a non-genotoxic mechanism for the liver tumours. There was discussion as to whether the 28 day NTP repeated dose study with LMG in female mice had given any evidence with regard to liver enzyme induction or liver damage. [This was checked after the meeting and it was confirmed that this was not the case. No induction of liver damage was seen at doses comparable to those used in the bioassay, and the only effect seen at a much higher dose (1,160 ppm in the diet) was a small increase in relative liver weight. No parameters of liver enzyme induction were measured. This study did not help in providing any evidence of liver damage]. 56. In general members felt that the overall tumour profile seen in the carcinogenicity bioassays with MG and LMG was not that which would be expected from a genotoxic carcinogen. The only clear evidence of carcinogenicity was with LMG in female mice due to an increase of liver adenoma or carcinoma (actually mainly due to adenoma). The inconsistency of the data between MG and LMG was surprising. A small increase in the number of tumours in the liver of LMG treated mice suggested that LMG was a carcinogen of low potency. Members also noted that there was no evidence for a non-genotoxic mechanism in the liver and that no threshold for carcinogenicity could be assumed. 57. The COC agreed that on the available data, and considering the advice from the COM, it was not possible to discount a genotoxic mechanism for the induction of liver tumours by LMG in female mice. Members considered that LMG was at most a very weak genotoxic carcinogen. ITEM 8: DRAFT STATEMENT ON 1,3-DICHLOROPROPANOL AND 2,3-DICHLOROPROPANOL (CC/04/16) 58. No interests were declared. 59. Members agreed the draft statement subject to a number of editorial amendments. Members considered that the reference to bacterial formation of epichlorhydrin in the oral mucosa needed to be reduced in the statement, as there was no evidence to support this hypothesis. The COC reaffirmed its previous conclusion that further data on the mechanism of the tumours in the rat tongue in the chronic drinking water study with 1,3-DCP were required. It was concluded that until such data were available, it was not possible to exclude the possibility of a genotoxic mechanism for the induction of the tumours of the rat tongue by 1,3-DCP. ITEM 9: HSE CARCINOGENS PRIORITY SUB-PROGRAMME (CC/04/23) 61. The objectives for the COC presentation were to inform members and assessors of the principles of the HSE plan, to place this information into context regarding other initiatives on chemicals, and to provide information on possible future consultation with experts. 62. A Health & Safety Hazards strategic programme was one of five recently initiated as part of a HSE's commitment to address government targets on improving occupational health and safety. HSE were to direct resources on priority areas of occupational health where there was a potential to reduce occupational morbidity and mortality. The H&S Hazards programme is to include sub-programmes on musculo-skeletal disorders, stress, trips/slips, work transport, falls, noise and chemicals. 63. Within the chemicals programme there would be specific programmes aimed at reducing the risks of skin disease, respiratory disease and cancer caused by occupational exposures. On carcinogens, HSE would first be undertaking an evidence gathering and prioritisation exercise (up to around mid 2006), and this would be followed by projects aimed at reducing cancer risks in the workplace. The evidence gathering would include two workshops to revisit the Doll and Peto data on attributable risks (J National Cancer Institute. 1981 Jun; 66(6):1191-308). The programme is being given a high priority status in HSE and will be resourced with a multidisciplinary group of policy staff, scientists, occupational physicians and hygienists. 64. Members welcomed the inclusion of chemical carcinogens as a priority area and queried whether endocrine disruption would be considered further. HSE noted that the predominant area of interest for endocrine disruption had to date concerned low-level exposure to mixtures of chemical in the environment. HSE's principle focus was on occupational exposures to chemicals and thus this area had not been included in the chemicals programme. Members queried how chemicals would be prioritised for consideration. HSE replied that criteria were to be developed and commented that that prioritisation of carcinogens would include, among other factors, consideration of hazard classification (weight and strength of evidence) and potency ranking. It was likely that the COC would be consulted on this aspect. Another activity within the programme that the COC might be asked to comment on was the development of appropriate proxy-measures of carcinogenic risk. 65. The Chairman thanked HSE for providing the paper for members consideration. ITEM 10: PAPERS FOR INFORMATION 66. The following were provided for information:
67. Members noted the contents of these papers.
ITEM 11: ANY OTHER BUSINESS
68. Members heard that the ACP secretariat had asked for advice from COC epidemiologists on the evaluation of this report. The secretariat had forwarded the report to COC epidemiologists along with a brief overview paper. Some initial comments have been received. The secretariat had also been asked to undertake some cross checking of epidemiology studies for results not included in the Ontario College report. 69. The Committee agreed that the secretariat should prepare a letter detailing members' comments and circulate to COC epidemiologists for any further comments or clarification. The letter would be cleared by the Chairman. ITEM 12: DATE OF NEXT MEETING 70. 18 November 2004. ************************* 71. The COC was informed that the revised systematic review on alcohol and breast cancer by Imperial College now included information from a further 21,000 cases (ie information from January 1999 up to 31 December 2003). The results of the updated systematic review were included in a revised statement and a revised non-technical summary. The overall estimates for relative risk, dose-response relationship and the population attributable risk had been slightly modified. The data suggested a population attributable risk in the UK of 6% (95% CI 3.2-8.8%). 72. Members generally agreed the accuracy of the statement but had a number of editorial and presentational suggestions. The secretariat would contact the relevant members after the meeting for their comments on the revised statement and non-technical summary. 73. The Committee was informed that the revised Imperial College systematic
review had been submitted to a further journal. There was some concern
over the delay regarding publication. Members were aware that the recent
publication of the Oxford Collaborative group study might impede the publication
of the Imperial College report. Some members felt the COC statement should
be published as it stood. It was agreed that the secretariat would seek
a meeting with the authors if acceptance for publication was not forthcoming
over the next two months.
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