COC Meeting 21st April 2005
Minutes
Present:
| Chairman: | Members: | Secretariat: |
| Professor P Blain CBE | Dr C Allen | Mr J Battershill (Scientific- DH) |
| Professor P Farmer | Ms F Pollitt (Scientific- DH) | |
| Professor D Forman | Mr D Benford (Scientific-FSA) | |
| Mrs Rosie Glazebrook | Mr K N Mistry (Administrative) | |
| Professor D Harrison | ||
| Ms D Howel |
||
| Dr B Miller | ||
| Professor D Phillips | ||
| Dr R Roberts | ||
| Professor D Shuker | ||
| Dr N Wallis | ||
| In Attendance: | |
| Dr P Edwards | (DH, item 8) |
| Dr K Fletcher | (DH Tox Unit) |
| Mr K Okona-Mensah | (DH Tox Unit) |
| Assessors: | Observers: |
| Dr R Fielder (HPA) | Dr K O'Leary (DH Tox Unit) |
| Ms A Gowers (EA) | Dr J Pritchard (HPA) |
| Dr P Howden (HSE) | Dr N Rajapakse (FSA) |
| Dr H Stemplewski (MHRA) | |
| Contents | Paragraph(s) | |
| Item 1: | Apologies/announcements | 1 |
| Item 2: | Minutes of meeting held on 18 November 2004 (CC/MIN/2004/3) |
5 |
| Item 3: | Matters arising not covered by later agenda items |
6 |
|
||
| Item 4: | Childhood cancer: | |
| 4.1 Expert opinions on trends in childhood cancer incidence (CC/05/7) |
10 | |
| 4.2 Paper by Knox on childhood cancers and atmospheric carcinogens (CC/05/3) | 12 | |
| 4.3 Review of the possible associations between childhood leukaemia and residence near sources of traffic exhaust and petrol fumes (CC/05/8) |
17 | |
| Item 5: | Carcinogenesis mode of action and human relevance framework (CC/05/2) |
25 |
| Item 6: | Joint COC/COM symposium (CC/05/1) | 28 |
| Item 7: | Single/short term exposure to carcinogens (CC/05/6) | 29 |
| Item 8: | Overview of nanomaterial toxicology (CC/05/5) | 32 |
| Item 9: | Draft annual report for 2004 (CC/05/4) |
36 |
| Item 10: | Papers for information: | |
| 10.1 Prostate cancer: evidence to the House of Commons (CC/05/9) | 37 | |
| Item 11: | Any other business | 38 |
| Item 12: | Date of next meeting | 40 |
ITEM 1: APOLOGIES FOR ABSENCE/ANNOUNCEMENTS
1. Apologies for absence were received from Professor A Boobis, Dr P Carthew, Dr S Kennedy and Professor P Vineis.
Announcements
2. The Chairman welcomed Mr K Okona-Mensah (DH Tox Unit), Dr K Fletcher (DH Tox Unit), Dr K O'Leary (DH Tox Unit), Dr J Pritchard (HPA), Dr N Rajapakse (FSA) and Dr P Edwards (DH, Item 8 only).
3. The Chairman noted that this was Professor Forman's last meeting and thanked him for his contribution to the work of the committee over the years. He noted that two new members had been appointed to fill the vacancy left by Professor Forman; these were Dr Brian Miller, Director of Research Operations and consultant statistician and epidemiologist with the Institute of Occupational Medicine, Edinburgh, and Professor Paolo Vineis, Chair in Environmental Epidemiology at Imperial College London. The Chairman welcomed Dr Miller to the meeting (Professor Vineis was unable to attend because of a previous arrangement).
4. Members were reminded of the need to declare any relevant interests before discussion of items.
ITEM 2: MINUTES OF THE MEETING OF 18 NOVEMBER 2004 (CC/MIN/2004/3)
5. The minutes were agreed subject to minor editorial changes.
ITEM 3: MATTERS ARISING NOT COVERED BY LATER AGENDA ITEMS
6. Alcohol consumption and breast cancer: the secretariat confirmed that the COC statement of breast cancer and alcohol had been published on the committee's website and reported that there had been no reaction from the press or public. The Imperial College meta-analysis had not yet been accepted for publication.
7. Prostate cancer: Professor Forman reported back on his appearance before the House of Commons Committee on Environment, Food and Rural Affairs. He explained that there had been considerable press interest in the sentence in the committee's statement on prostate cancer which stated that there was 'some evidence to suggest an association between ….exposure to pesticides and increased risk of prostate cancer.' Consequently, although the parliamentary committee is considering pesticide regulation, not health effects, it asked the COC and the Advisory Committee on Pesticides for formal statements. In his appearance he was asked to elaborate on the statement and answer questions. It was noted that DEFRA has put out a tender for a meta-analysis of prostate cancer and occupational exposure to herbicides.
8. Paragraph 21: the secretariat reported that the British Society of Toxicological Pathologists had made an offer to take responsibility for storage of the raw data arising from the BIBRA ED01 study on an indefinite basis.
9. Paragraph 24: Dr Wallis reminded the committee that she had withdrawn from discussion of this item at the last meeting because she was unsure as to whether her employer made tobacco smoking cessation products. She had since confirmed that this was the case and wished to declare an interest.
ITEM 4: CHILDHOOD CANCER
4.1 Expert opinions on trends in childhood cancer incidence (CC/05/7)
10. The secretariat reminded members that, at the last meeting, they had discussed an overview paper on childhood cancer which identified four tumour types which appeared to be increasing in incidence. These were acute lymphocytic leukaemia (ALL), germ cell tumours, CNS tumours and neuroblastomas. Therefore, it was proposed that the committee should consider whether there was evidence for chemical aetiologies for these cancer types. However, members had asked whether it was possible that all or part of the reported increased incidences, particularly of CNS tumours, was accounted for by better ascertainment and had requested expert advice on this issue. At the suggestion of members, expert advice had been sought from Dr Murphy of the UK Childhood Cancer Research Group (UKCCRG), Professor Craft and Dr Parker of the Newcastle Childhood Cancer Group and Dr Smith of the Western General Hospital, Edinburgh. Members discussed the advice received, which was presented in CC/05/7.
11. There was some discussion of the presentation of the UKCCRG data but, overall, it was considered that it presented a generalised and reasonable summary of the data which are currently available. Members noted that the increase in ALL was considered to be, at least in part, real although it was not clear that this was the case for the other tumour types. The consultees considered that there was little evidence for a chemical aetiology for these cancers.
Item 4.2 Paper by Knox on childhood cancers and atmospheric carcinogens
12. The secretariat explained that this paper had stimulated some press and parliamentary interest and DH had stated that the opinion of the COC would be sought on the methodology and conclusions.
13. The paper investigated the relation between major sources ('hotspots') of emissions of a range of pollutants ('emission hazards'), taken from Internet maps for 2001 compiled from the National Atmospheric Emissions Inventory (NAEI), and birth and death addresses of children dying from cancer between 1966 and 1980. The author had calculated the relative risk of a child being born close to, or distant from, the emission hazard among children who had moved more than 1 km between birth and death and who had one address within 1 km of the nearest hazard point and the other address more than 1 km away from the nearest hazard point. Outward/inward ratios substantially greater than 1 were taken to represent a cancer-initiating effect of the birth location (ie the hotspot for emissions of a certain pollutant). Using this methodology, the paper reported a positive association between deaths from cancer and hotspots for carbon dioxide, PM10, nitrogen oxides, carbon monoxide, all VOCs studied (including benzene), and dioxins. Attributable risks had been calculated for these pollutants.
14. The secretariat informed members that a number of criticisms could be made of the paper, including the fact that it used 1966-80 cancer mortality data but emissions data for 2001. NAEI had also pointed out that emission levels are not necessarily representative of ambient pollutant levels and hence, of exposure levels.
15. Members agreed with the criticisms highlighted in the secretariat's paper. Other problems identified were: the lack of controls; insufficient information in the Knox paper, especially on the statistical methods, including the method used to calculate the attributable risk; little consideration of confounding; and the failure to report the results for individual cancer types. Members were surprised by the large attributable risks for some contaminants and considered that they were unrealistic. It was also considered that the study could have been compromised by the large time span of the cancer mortality data because survival rates from some childhood cancers eg leukaemias, would have improved dramatically between 1953 and 1980. In conclusion, the committee concluded that, because of the flawed methodology and inadequate information provided, they were unable to draw any conclusions from the study.
16. It was noted that the UK Childhood Cancer Study had begun to report results. The secretariat was asked to contact the principal investigators at York and to ask if they would be able to provide a briefing for the committee at some point, particularly in relation to work on childhood cancer and industrial and/or traffic emissions.
Item 4.3: Review of the possible associations between childhood leukaemia and residence near sources of traffic exhaust and petrol fumes (CC/05/8)
17. The secretariat reminded members that, at the previous meeting, they had discussed a preliminary paper on childhood leukaemia and residence near to petrol stations, garages and road traffic exhaust fumes (CC/04/37) and had asked to see a full review of the relevant literature. This paper addressed that request.
18. CC/05/8 included a discussion of exposure issues. Exposures resulting from emissions arising from the evaporation of fuel (ie fuel vapour) contain carcinogenic compounds which differ in amount and type from those in vehicle exhaust. It was noted that petrol stations and garages are well noted for fuel vapour emissions but are unlikely to generate sufficient traffic to cause a substantial increase in pollutants from vehicle exhaust. Moreover, the results of a recent risk assessment by CONCAWE indicate that indoor exposures of children to evaporative emissions were of more concern than outdoor exposures. Benzene concentrations in homes with attached garages can be up to 2.5 times higher than the ambient air standard and it was suggested that the significance of this warrants further consideration.
19. The paper also included a review of 17 epidemiology studies on childhood cancer and residence near sources of traffic exhaust and petrol fumes. Nine of these specifically considered childhood leukaemia but only two examined the potential association with proximity to petrol stations and garages. Most examined the association with residential proximity to high traffic roads. In total, 10 studies reported positive findings, although these were generally based on much smaller sample sizes that those which reported a null association.
20. The secretariat informed members about two amendments to the paper:
In Annex 2, paragraph 9, the last sentence describes an additional study by the INSERM group and states that this will be completed by mid 2005. In fact, only the data collection will be completed by then. It is anticipated that the study will probably be completed by mid 2006.
The additional study is a new case control study and not a follow-up study as stated in the paper and in Annex 3.
21. It was noted that two of the more recent, larger studies were of better quality and hence the results were more convincing ie a study in Denmark by Raascho-Nielsen et al (2001) and one in California by Reynolds et al (2002). Both reported null results. The Danish study used a good method of exposure assessment. In comparison, the positive studies were of lesser quality and only that by Steffen et al (2004) had produced a substantive increased odds ratio. However, the view was also expressed that it would be imprudent to dismiss the 10 positive studies. In response to a suggestion from one member, the committee concluded that it would not be helpful to conduct a meta-analysis because of the different approaches they had used.
22. Members then commented on the study by Urayama et al (2004), which had compared the susceptibility of children with the variant CYP1A1m2 allele, and those with the homozygous wild type genotype, to traffic-related exposures. Members noted that the study was not in line with the COC criteria for the design of gene-environment studies because it lacked a prior hypothesis. A more rigorous study would have examined polymorphisms in all Phase I and II enzymes involved in the metabolism of compounds deriving from traffic.
23. In response to the questions posed in CC/05/8, it was agreed that:
1. The available evidence did not allow the committee to conclude that there is an association between childhood leukaemia and residence near sources of traffic exhaust and/or petrol fumes.
2. The significance of indoor exposures to gasoline vapour and/or benzene warrants further consideration.
3. Ideally, future studies should take into account a child's complete residential history, not just residence at diagnosis, but in practical terms this might not be possible.
4. There should be a separate analysis of the available data on exposure to vehicle exhaust and those on exposure to vehicle evaporative emissions.
5. Future studies should only perform analyses of leukaemia incidence on a subtype basis.
24. The secretariat was asked to prepare a draft statement for consideration at the next meeting.
ITEM 5: CARCINOGENESIS MODE OF ACTION AND HUMAN RELEVANCE FRAMEWORK (CC/05/2)
25. The COC considered the IPCS Mode of Action (MOA) and the ILSI Human Relevance Framework (HRF) during the 2004 horizon scanning exercise. Members commented that further consideration of some worked examples of evaluation using the IPCS MOA approach and the ILSI HRF would be valuable. A short paper had been prepared summarising the application of these two approaches using both some published evaluations and a number of examples of anonymised pesticide evaluations from PSD.
26. Members noted that the HRF approach extended the MOA approach by considering whether the key events in the MOA are plausible in humans, taking into account kinetic and dynamic factors. One member gave a brief presentation of the discussions by the ILSI subgroup of PPARα rodent liver cancer. Members noted the advantages of collaborative working in that it enabled a consensus view to be reached in this particular evaluation where there was both conflicting evidence and conflicting views in the published literature about mechanisms of carcinogenesis. One particular value of the HRF approach was that data were presented in a structured format which allowed data gaps to be readily identified. It was hoped that completion of the case studies would provide generic evaluations, limiting the need for duplication of effort.
27. Overall, the COC considered that the MOA and HRF approaches both provided a logical framework in which to set the information needed when assessing the relevance of chemical induced animal tumours to humans.
ITEM 6: JOINT COC/COM SYMPOSIUM (CC/05/1)
28. Members noted the proposed programme for the joint meeting with the COM, to be held on 9 June 2005. A short statement would be produced, in addition to a full report of the meeting which would be submitted for publication in a scientific journal.
ITEM 7: SINGLE/SHORT TERM EXPOSURE TO CARCINOGENS (CC/05/6)
29. During its 2004 horizon scanning review, the COC had agreed to undertake a further review of the potential risks associated with single or short term exposure to carcinogens. CC/05/6 had been drafted by the DH Toxicology Unit and provided some limited information on the epidemiology data relating to the short term exposure carcinogens identified in the paper by Calabrese EJ and Blain RB (Toxicological Sciences 50, 169-185, 1999).
30. Members noted that Calabrese and Blain had described the period of <1 year as being relevant to the identification of potential single /short-term exposure carcinogens but considered that there was no rationale for this criterion. It was considered that exposure to single doses of certain cytotoxic medicines or genotoxic carcinogens might be associated with an increased risk of cancer. One member noted that asbestos might also be associated with an increased risk following a single exposure. It was also possible that the persistence of carcinogens following a single exposure was also a potentially important factor in the assessment of risk associated with a single exposure. Beryllium was cited as an example of a carcinogen which persisted in the body. Members cautioned that care was needed when interpreting the data cited in the Calabrese and Blain paper. Thus, single parental exposure of experimental animals to chemicals in pellets might be associated with carcinogenicity in animals but such data were unlikely to be relevant to single exposures of humans to carcinogens. Members agreed that there was no evidence to support the view proposed by Calabrese and Blain that risks associated with single exposures to carcinogens varied with life stages. Written comments from one member supported these views and the need for a more detailed review of the information cited in the Calabrese and Blain database.
31. The secretariat indicated that it would discuss these matters with the DH Toxicology Unit and relevant Government Departments to formulate an appropriate strategy for a review.
ITEM 8: OVERVIEW OF NANOMATERIAL TOXICOLOGY (CC/05/5)
32. The risk assessment of nanomaterials has been identified by COT/COC/COM as an area of interest during horizon scanning discussions for 2004. The committees' interest in this area was prompted by the publication of the Royal Society review of nanotechnology. (http://www.nanotec.org.uk/). The documents appended to CC/05/5 were drafted to provide baseline toxicology information for all three committees. The secretariat stated that the objective was to collect initial views from the COC (21 April), COM (26 May) and COT (12 July) and to draft a short statement which would be published on the committees' websites. The COT/COC/COM review is limited to nanomaterial manufactured for nanotechnologies and excludes medicines and medical devices. Some information had been included on chemically defined ultrafine particles which have been studied by research groups interested in air pollution, in order to assist in potential hazard identification for nanoparticles, although the remit of the COT/COC/COM review does not extend to air pollution (a COMEAP responsibility). CC/05/5 was supported by the recently published HSE review on nanomaterials (Annex 1) and an update review prepared by the secretariat (Annex 2).
33. Members noted that no carcinogenicity data were available on nanomaterials. There had been some discussion at the recent Society of Toxicology meeting in the USA about the possibility that nanotubes had fibre properties similar to asbestos but no appropriate studies were available. It is noted that the physico-chemical properties of nanotubes met the conventional definition of a fibre (aspect ratio >3). Members agreed that particle size and surface chemistry were likely to determine the toxicological properties of nanomaterials. One important area of research described in the HSE hazard assessment document was the potential for systemic translocation of inhaled particles deposited in the lung. There was evidence from the reviewed studies for both rapid translocation and for negligible translocation. No overall conclusion could be reached in view of the limited amount of studies available (which used iridium or carbon particles) and there was a need for further studies.
34. Members noted the negative skin promotion assay in mice with a fullerene soot. It was noted that, in addition to the development of substituted fullerenes within the pharmaceutical industry, these chemicals were also environmental contaminants formed during incomplete combustion processes. Members were informed that current applications of nanomaterials were limited to cosmetics and pharmaceuticals but there was potential for use of novel nanoparticles such as nanotubes in electronics and precision engineering.
35. A joint statement from all three committees would be prepared.
ITEM 9: DRAFT ANNUAL REPORT FOR 2004
36. Members were asked to forward any comments on the draft to the secretariat by 6 May 2005.
ITEM 10: PAPERS FOR INFORMATION
37. Paper CC/05/9 was an extract from the report of the discussions of the House of Commons Environment, Food and Rural Affairs Committee.
ITEM 11: ANY OTHER BUSINESS
38. The secretariat informed members that a paper on proquinazid (a pesticide currently under regulatory review by the ACP) is to be discussed at the July 2005 meeting. The applicant is DuPont. Members were asked whether they had any interests to declare. None were declared.
39. The secretariat informed members that it expected to circulate shortly a draft opinion from the European Food Safety Authority's Scientific Committee on how to approach risk assessment for substances that are both genotoxic and carcinogenic, which proposed a margin of exposure approach. There will be a 6 week consultation period. Members would be asked to submit comments and the secretariat would prepare a response from the committee.
ITEM 12: DATE OF NEXT MEETING
40. 14 July 2005.
ACTIONS
| ITEM | ACTION | WHO |
| 4 | Contact PIs of UK Childhood Cancer Study and invite them to brief the committee on the study results Secretariat | Secretariat |
| 4.3 | Draft statement on review of the possible associations between childhood leukaemia and residence near sources of traffic exhaust and petrol fumes Secretariat/DH Tox Unit | Secretariat/DH Tox Unit |
| 4.3 | Write paper on indoor exposures to gasoline vapour and/or benzene and childhood leukaemia, if sufficient information available in scientific literature Secretariat | Secretariat |
| 7 | Reassess subject and draft further paper Secretariat | Secretariat |
| 8 | Prepare joint COC/COM/COT statement Secretariat | Secretariat |