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Present:
ITEM 1: APOLOGIES Announcements 2. The Chairman welcomed Mrs F Cleaver (FSA), Dr P Edwards (HPA), Dr S Dyer (DH), Mr M Hosford (EA), Mr D McElvenny (HSE), Ms C Mulholland (FSA), Dr V Navratnam (Home Office), Dr K O'Leary and Mr K Okona-Mensah (DH Tox Unit), Ms S Read (FSA), Mr S Samuels (PSD), Ms M Singh (FSA), Mr H Stemplewski (MHRA), Dr A Tedstone and Mr S Whelan (FSA), and Mrs J Cleverly who was shortly to join the HPA as the new administrative secretary. The Chairman thanked Mr Mistry for all his work for the committee over the years as administrative secretary. He also congratulated Dr Roberts on her appointment as professor. 3. Members were reminded of the need to declare any relevant interests before discussion of items. ITEM 2: MINUTES OF THE MEETING OF 2 March 2006 (CC/MIN/2006/1) 4. The minutes were agreed subject to minor editorial changes. Members agreed that comments from observers should be reported in brief and personal or emotive information were inappropriate. ITEM 3: MATTERS ARISING NOT COVERED BY LATER AGENDA ITEMS 3.1 Testicular Cancer (oral report) 5. At the March 2006 COC meeting, an overview paper of background information and risk factors for testicular cancer was discussed at the COC. The incidence of testicular cancer has been increasing steadily in Great Britain since 1975. One hypothesis that has been proposed involved dietary practices. In a number of papers an increased intake of milk and dairy products has been associated with increased testicular cancer risk. 6. At the March meeting, a committee member asked if there was any information on the current oestrogen content of milk and whether any changes had occurred in the oestrogen levels in milk since 1970. If so, was there any evidence of a correlation between the increasing incidence of testicular cancer and the oestrogen content in milk? 7. The DH Toxicology Unit had sought additional information. Data from the National Food Survey up to 2000 and the Expenditure and Food Survey published by the National Statistics Office in 2003 indicates that UK consumption of all cows' milk and cream has fallen by 33 per cent from 3.0 litres in 1975 to an average of 2.0 litres per person per week in 2002-03. 8. Information was obtained from the Milk Development Council (MDC) about whether there has been a change in the oestrogen content of cows' milk since the 1970s. Despite changes to farming practices that may have occurred, the MDC reported that the oestrogen content of milk has not changed since the 1970s. This was reiterated by Dr George Mann, Associate Professor at the Animal Physiology department at the School of Biosciences, University of Nottingham who had reported that the current oestrogen content in cows' milk was in the range 1-2 pg/ml and that the levels had not changed in the past thirty years. It was further noted that the bioavailability of oestrogens from cows' milk would be low (the bioavailability of oestradiol is less than 5%). 3.2 Ramazzini study on the carcinogenicity of aspartame - further information (CC/06/17) 9. Dr Carthew declared a personal, non-specific interest. 10. Aspartame is a widely used artificial sweetener which was initially approved in 1982 and has been reviewed on several occasions subsequently. In 2005, a carcinogenicity study published by the independent European Ramazzini Foundation of Oncology and Environmental Sciences (ERF) suggested that aspartame was associated with an increase in lymphomas and leukaemias, transitional cell carcinomas of the renal pelvis and ureter, malignant schwannomas of peripheral nerves and pre-neoplastic and neoplastic lesions of the olfactory epithelium. Overall, a significant increase in malignant tumour bearing animals of both sexes was reported. This was considered in detail in CC/06/6, discussed at the March meeting. 11. Following a request from the European Commission, the European Food Safety Authority (EFSA) asked its Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC) to review the findings of the study. As part of this process the Food Standards Agency sought the views of the COC at the March meeting on the quality of the study and the interpretation of the results. The preliminary views of the Committee were passed on to EFSA to assist in their consideration. 12. The Committee expressed a number of concerns about the design and conduct of the study and requested additional information in several areas. The request was forwarded via EFSA and a direct reply to EFSA had not been received from the Ramazzini Foundation. However, some new information was supplied to EFSA and this was included in CC/06/17. These new data included the individual animal pathology data and the report of the Working Group of pathologists from the US NTP. The EFSA opinion was also attached for information. Some additional details have been obtained from the published literature. Since the EFSA review had been completed it seemed unlikely that any more data would be forthcoming. 13. Members were concerned that the only purity assessment of the test material used was qualitative and, therefore, inadequate. The stability of the test material in the diet had not been considered by the authors. The Committee agreed that such analyses would usually be standard procedure in a rodent carcinogenicity study. Given that the dietary dose levels were very high, the possibility that an impurity or degradation product was responsible for the observed pathology could not be excluded. 14. Members also noted the differences in interpretation between the NTP Pathology Working Group's peer review and the original histological diagnosis reported by the Ramazzini Foundation. The NTP Working Group had noted the poor animal health in the Ramazzini Foundation study. The Committee agree with the evaluation of the Ramazzini Foundation study of aspartame by the EFSA panel. 15. Overall, the COC was not convinced that any valid conclusions regarding the carcinogenicity of aspartame could be derived from the Ramazzini Foundation study in view of the inadequacies in design of the study and the use of rats with a high concurrent infection rate. In addition, the fact that animals were allowed to die naturally, and that groups fed with aspartame had a lower body weight and thus lived longer, also compromised the results. The COC noted that the EFSA had concluded that there was no reason for a review of the ADI for aspartame to be undertaken. ITEM 4: Folic acid fortification and carcinogenesis (CC/06/14) [closed session] 16. The minutes of this item will be published when the report of the Scientific Advisory Committee on Nutrition (SACN) on "Folate and disease prevention" is published. 17. Dr Carthew declared a personal, non-specific interest. 18. Folate is the generic term for a naturally occurring family of B-group vitamins comprising an aromatic pteridine ring linked to p-aminobenzoic acid and a glutamate residue. Folic acid (pteroylmonoglutamic acid) is the synthetic form commonly used in supplements and food fortification. 19. In 2000, the Committee on the Medical Aspects on Food and Nutrition Policy (COMA) concluded that the universal fortification of flour with folic acid would significantly reduce the number of conceptions and births affected by neural tube defects (NTDs). 20. In September 2003, the Scientific Advisory Committee on Nutrition (SACN) was asked to assess the evidence that had arisen since publication of the COMA report on folic acid. The SACN draft report on 'Folate and Disease Prevention' was published in November 2005. In its draft conclusions, SACN recommended mandatory fortification of flour to reduce NTD risk. SACN subsequently requested further time to reconsider its advice following some concerns about high intakes of folic acid and cancer risk. 21. SACN considered a wide range of evidence on folic acid and cancer risk and noted that most epidemiological studies have shown a protective effect of folate against tumours. However, it noted that, in some animal studies, folic acid consumption is associated with an increase in the incidence of tumours depending on the timing of the intervention. One controlled study in humans (abstract only), which has not yet been published in the peer reviewed literature, shows a significant increase in colorectal adenoma multiplicity following supplementation with folic acid (1mg/d). 22. SACN has asked the COC to review the data on folic acid and cancer risk and to give its opinion on whether dietary folic acid intake is associated with increased cancer risk. The data provided in CC/06/14 include animal studies, a review of epidemiological studies of folate intake and colorectal neoplastic risk, preliminary information from one recent unpublished controlled trial, and the abstract of another controlled trial. A paper on folic acid and breast cancer risk (Charles et al, 2004), two papers reporting trials which had examined folic acid supplementation on cardiovascular disease (CVD) outcomes but had also reported effects on cancer risk (HOPE 2 investigators, 2006; Bonaa et al, 2006) and an editorial commenting on the CVD prevention trials (Loscalzo, 2006), and a commentary on folate supplementation (Ulrich and Potter, 2006) were tabled. 23. Members were informed that the Recommended Nutrient Intake (RNI) for folate is 0.2 mg/day and that women who are planning a pregnancy are recommended to take an additional 0.4 mg/day until the 12th week of pregnancy. An additional dose of 5 mg/day is recommended for women at high risk of an NTD-affected pregnancy. 24. It was noted that in the US, where mandatory folic acid fortification was introduced in 1998, voluntary fortification of other foods continued to be permitted and blood analyte data indicated that current intakes of folic acid were higher than planned. FSA informed Members that mandatory fortification of flour with folic acid would be subject to tight controls. 25. In response to a query about whether data from the European Prospective Investigation of Cancer (EPIC) on cancer risk and folic acid consumption might be available in the near future, Members were informed by the SACN secretariat that this had not been indicated to them. 26. Members discussed the animal studies summarised in CC/06/14 and noted that the limitations of the experimental approaches had been identified in the papers. Members noted that the animal data suggested that timing of the folic acid administration could be an important factor in potential cancer risk since the data showed that high doses of folic acid may progress the development of pre-existing neoplasms. They commented that the data suggested a possible effect on inherited accelerated colorectal tumourigenesis in mice but not on sporadic colorectal tumourigenesis. It was noted that the dose levels used in several of the studies (e.g. Wargovitch et al, 1996; Reddy et al, 1996; Le Leu et al, 2000) were considerably higher than would be achieved in humans following fortification. A clear dose-response relationship was not apparent in the animal studies as one study (Wargovich et al, 1996) showed an increase in the development of aberrant crypt foci at the lower dose of folic acid but not at the higher dose. In addition, the body weight changes in some folic acid deficient groups (16-19% reduction) were a potential confounding factor for rodent tumourigenesis. Overall, the Committee agreed there were multiple plausible mechanisms, including epigenetic mechanisms, whereby folic acid may influence cancer risk. A Member commented that the animal data were equivocal and cautioned against over-interpretation of data from these studies. 27. With regard to the human studies, the Committee considered that these were well summarised in paragraph 12 of CC/06/14. Most epidemiological studies indicate a reduced risk of cancer with increased folic acid or folate intake. It was noted that, in many of the studies, the folic acid had been taken in multivitamins, and the presence of other micronutrients in the multivitamins was a complicating factor. However, Members agreed that preliminary results from one unpublished, randomised trial showed a significant increase in adenoma multiplicity in subjects with a recent history of colorectal adenomas who had been supplemented with folic acid (1 mg/day) for over 3 years. They also noted the results of the two studies of folic acid supplementation on CVD outcomes which showed non-significant associations between folic acid (in combination with either vitamin B12 or B12 and B6) and cancer. The Committee noted that the reported association by Charles et al (2004) between folate intake during pregnancy and breast cancer mortality was also not statistically significant and was based on small numbers. 28. The Committee noted that there may be susceptible subgroups in the population. It was not possible at this stage to identify these. Factors which might be relevant were age and the presence of pre-neoplastic conditions. 29. It was reported that the COM review of background variation in micronuclei in peripheral blood lymphocytes had indicated that there was good evidence from cross sectional and intervention studies to suggest that plasma or serum folate levels were negatively correlated with micronucleus formation (COM, 2006). In response, it was noted that whether or not risk is increased or reduced may depend on a balance between the thresholds for epigenetic promotional effects and reduction of DNA damage. 30. Members agreed with the comments made by Ulrich and Potter (2006) i.e. that it remains unclear whether the possible deleterious effects of high folic acid outweigh the known and potential health benefits and that this balance may differ across individuals and populations by genetic characteristics and by life stage. 31. In conclusion, a precautionary approach was recommended in considering mandatory fortification of flour with folic acid. ITEM 5: Age related differences in susceptibility to carcinogenesis (CC/06/8) 32. At last year's horizon scanning exercise, Members considered data from 2 publications by Hattis which developed the analyses in the EPA guidance on assessing susceptibility from early-life exposures to carcinogens. Members asked for a detailed consideration of the publications. 33. The COC discussed the EPA guidance in 2003. Using the limited number of studies (some quite old) which have compared tumour incidence after dosing with a chemical at different life stages, the EPA has developed adjustment factors in its quantitative estimates of lifetime cancer risk for genotoxic chemicals of 10 for exposures from birth to 2 years of age, and 3 for exposures from 2 to 15 years of age. No factors were recommended for non-genotoxic chemicals due to insufficient information or analyses. 34. The papers by Hattis et al (2004, 2005) present a new analysis of the experimental data using statistical and modelling techniques. For the genotoxic chemicals, Hattis calculates that the sensitivity in the in utero, birth-weaning, and weaning-60 day periods in the test animals is 8.4, 24 and 3.7 times greater than with adult only dosing. For the non-genotoxic chemicals, there was no increased sensitivity in the in utero and weaning-60 day periods and only 3-fold higher sensitivity in the birth-weaning period. 35. In the second paper (Hattis et al, 2005), Hattis tries to draw implications from the derived sensitivities of rodents at different life stages for assessing human risks at different life stages. Appreciable uncertainties were identified, particularly in the mapping of rodent exposure periods to human equivalents. Hattis had made a comparison based on weight-related estimates of relative age in rodents and humans. The main conclusion from the paper was that most of the total lifetime risk of cancer from continuous exposure to genotoxic carcinogens arises from exposures received before adulthood. 36. Members queried whether the default assumption used by Hattis, that juvenile rodents and humans would always be at a higher risk of cancer following exposure to genotoxic carcinogens than adults, would always be appropriate. It was considered that this was theoretically possible for direct acting genotoxic carcinogens but not for those requiring metabolic activation. In addition, for non-genotoxic carcinogens, it was likely that the accumulation of mutations with age could influence the subsequent response to tumour promoting agents. Although several studies have been published containing data on the effect of age at starting smoking on the risk of tobacco-induced cancer, it is difficult to disentangle the effect of age at start from the effect of duration. 37. Members considered that there was insufficient evidence at this stage to adopt adjustment factors for genotoxic carcinogens for different life stages. Members did not support the conclusion that most of the lifetime risk associated with genotoxic carcinogens arose from pre-adult exposure. Asked to consider the method used in Hattis et al (2005) to produce estimates of comparable life stages in mice, rats and humans, Members commented that it was important, in neonatal models, to consider comparability in stages of embryogenesis. They considered that there was no need for additional work on this subject at present. 38. Members agreed to continue to keep this subject under review. Members heard that a large EU funded study of genotoxicity in newborn infants was being initiated which might provide useful information in the future. ITEM 6: 'Creative Accounting' - report by People for the Ethical Treatment of Animals (PETA) [closed session] (CC/06/12) 39. The Home Office had asked the COC for advice on this report, which proposes that the costs of carcinogenicity studies, in terms of animals and money, vastly exceed their benefits and that project licences should no longer be issued for these studies. It cites lack of repeatability and lack of relevance to human cancer risk e.g. a high level of false negative results. Some of the recent papers referred to in the report were provided in CC/06/12 for Members' information. Following a question from the Chair, the Home Office confirmed that it wished to have the Committee's views on aspects relating to the scientific validity of carcinogenicity studies. 40. Members agreed with elements of the PETA report. They commented that rodent carcinogenicity studies could over-predict the number of carcinogens. However, it was important to note that the studies were part of a weight of evidence approach to carcinogen risk assessment and that there were no viable alternatives to in vivo models for carcinogenicity. Members did not agree with the assertion that approximately two-thirds of chemicals listed by IARC as known human carcinogens showed no carcinogenic effects when tested in rodents, nor with the implication that there was no value in the IARC classifications of "not classifiable" or "possibly carcinogenic". The Committee considered that the IARC Group 1 (carcinogenic to humans) and Group 2A (probably carcinogenic to humans) agents were predominantly identified in long-term rodent carcinogenicity studies of chemicals. 41. Members commented that it was important to understand the genesis of NTP studies before criticising them and noted that they were not designed for the purposes of quantitative risk assessment. The NTP programme had produced a wealth of information. They considered that criticism was better directed at laboratories which do not carry out good quality carcinogenicity studies or effort should be made to ensure that all studies were conducted to agreed guidelines. 42. Members were advised that the report had quoted selectively from the OECD Guidance Document on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment (OECD, 2005). This document applied to new test methods and revisions of existing methods and was derived from criteria for validation of alternatives to animal tests. Members commented that OECD guidelines include tests that have not been through a formal validation process but which have been used for long periods and so gained acceptance in the scientific community. 43. Members were informed that the OECD intended to review the 1981 guidelines for chronic toxicity, carcinogenicity and the combined guideline for chronic toxicity/carcinogenicity and were invited to provide views or relevant documents. Animal welfare was a key consideration in guideline development and OECD guidance document on humane endpoints for experimental animals was published in 2000. 44. The Committee noted that high dose levels were used in long term rodent carcinogenicity studies to keep the numbers of animals required to detect a 5-10% increase in tumour incidence to a minimum of 50 animals/dose group. They noted the correlation between carcinogenic potency in long-term rodent carcinogenicity studies and toxicity (i.e. those chemicals with a low LD50 or low Maximum Tolerated Dose were likely to show carcinogenic effects in the target organ) but also noted that not all toxic chemicals tested in the NTP programme were carcinogenic in rodents. 42. Members noted that carcinogenicity studies were not used in the simplistic manner implied by the report. They were peer-reviewed and all data used in the overall evaluation. The COC concluded that, at present, there are no viable alternatives to in vivo models of carcinogenicity and that it was likely that long-term rodent studies would be needed for the identification of potential human carcinogens for the foreseeable future. However, it was important that all studies are conducted to internationally agreed guidelines. 43. The Committee decided that it would be valuable to draft a statement, in a similar style to the PETA report, describing the value of animal carcinogenicity studies. ITEM 7: Initial discussion on comparative risk assessment (CC/06/13) 50. Members heard that a discussion paper had been seen by the COM in May 2006 and comments on the three approaches outlined in the paper had been provided. These were the Calman Risk Scale, Paling Perspective Scale, and Dr Frank Duckworth's Riskometer. The DH Toxicology Unit and the secretariat had subsequently identified a CRA approach developed by the National Radiation Protection Board (NRPB) (part of the HPA) for radiation and this had been appended. . 51. The Chairman noted that it was a useful exercise for the COC to consider its approach to communication of carcinogenic risk. The COC had previously considered that comparing risks of environmental carcinogenesis to smoking tobacco was unlikely to be helpful for a variety of reasons including the comparison of involuntary exposure to chemicals to voluntary activities such as smoking, and the fact that some individuals had a perceived risk of smoking which was far lower than the actual risk. He asked for members' comments on the proposals outlined by the DH Toxicology Unit and secretariat. Members were also asked to endorse the COM proposal for a presentation from a risk communication professional 52. Members noted that the primary role of COC/COM was to provide advice to government departments and regulatory agencies which were responsible for risk management and risk communication. However, it was agreed that a wider understanding of the low risks associated with exposure to environmental carcinogens was desirable. Members agreed with the COM proposal that current approaches to drafting statements needed to be improved with non executive summaries developed for all statements. Members considered that COC/COM documents should provide more information on the reasons for undertaking reviews. 53. The secretariat noted that the COM had also advised against comparing actuarially derived and dose-response estimated risks or comparing voluntary and involuntary activities. The 'Risk It' game developed by NRPB essentially mixed all types of scenarios and approaches to risk estimation but had produced a comparison tool of potential use to the general public. Members noted the approach used for radiation but considered that it would not be possible to develop such an approach for chemicals as selection of exposure scenarios would be very difficult. Members also considered that the 'Risk It' game did not consider the impact of benefit in the comparative evaluations. It was suggested that a more suitable approach might be to compare closely connected risks e.g. those of natural toxins and synthetic pesticide residues in or on the same foodstuff. 54. The Committee agreed that a potential area which could be developed
to expand the communication of the risks of unavoidable exposure to carcinogens
was the 'Margin of Exposure' (MOE) approach being developed by EFSA, and
ILSI. This approach was essentially consistent with the Maximum Risk Level
approach outlined in the current COC guidance. It had been used by JECFA
for risk ranking purposes and, therefore, might also be extended for CRA. 56. The Committee considered the available information from the scales outlined in the draft discussion paper. Members considered that a lifetime risk e.g. loss of life expectancy, was more preferable to annual rates. Some comparisons e.g. slipping in the bath, were inappropriate to use as comparisons with the risks of exposure to carcinogens. 57. Members agreed that a presentation would be useful. The secretariat agreed to develop thinking on MOE and the overall approach used by COC/COM, and then approach appropriate individuals to identify a speaker for the 16 November meeting. One member suggested a possible contact source for speakers. Members asked the secretariat to consider carefully the audience in any further paper for the COC. ITEM 8: 'Tissue Organ Field Theory' of carcinogenesis (CC/06/10) 58. A paper by Newby and Howard (2006) claimed that it is feasible that chemical environmental contaminants could be major factors in cancer aetiology. After some press and parliamentary interest, the secretariat gave an undertaking to Ministers that the COC would consider the paper at this meeting. The draft discussion paper focussed on the wider aspects of the tissue organisation field theory of carcinogenesis (TOFT), referred to in the Newby and Howard paper. In summary, the TOFT assumes that proliferation is the default state of cells. Sporadic cancers arise when pathogens or carcinogens disrupt the biological interactions between different cell layers. The mutations present in neoplastic cells are considered to be incidental, not causal. 59. Members commented that the paper by Newby and Howard was not a systematic or reasoned review of the literature. 60. Members discussed the TOFT in detail and consider there were some interesting ideas. They commented that the MNU model was odd in that there was evidence that the ras mutation was not caused by MNU but was present in cells already and that MNU propagated clonal expansion of these cells. 61. Members noted that cell cycle activity requires not just mitogenic stimuli but also survival signals, only a proportion of cells in any cancer are truly stem cells that can contribute to a new colony of cells and that tumour suppressor gene inactivation is necessary but not sufficient to cause cancer. They noted that there is a growing literature on the importance of epithelial-mesenchymal transformation and mesenchymal-epithelial transformation in tumourigenesis. Before encoding mutations, epigenetic changes must occur and there is growing evidence for this from studies of chromatin structure to epigenetic silencing of genes by methylation. 62. Overall, Members agreed that the paper reported interesting ideas but that there were insufficient data to support the hypothesis. ITEM 9: PAPERS FOR INFORMATION 9.1 HSE Disease Reduction Programme: update on project on chemical carcinogens (CC/06/15) 9.2 Revised procedure for holding committee meetings in open session (CC/06/9) 63. The Chairman noted this had also been agreed by COT and COM. 9.3 Key et al (2006). Meta-analysis of studies of alcohol and breast cancer with consideration of the methodological issues. Cancer Causes Control 17: 759-770. (CC/06/16) ITEM 10: ANY OTHER BUSINESS 64. The committee was informed that the Government response to the RCEP report (Crop Spraying and the Health of Residents and Bystanders) will be issued on 20 July 2006. ITEM 11: DATE OF NEXT MEETING 16 November 2006
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