COC meeting 7 March 2002
Minutes
| Chairman: | Members: | Secretariat: |
| Professor P G Blain | Professor C Cooper | Dr R Fielder (Scientific- DH) |
| Professor P Farmer | Mr J Battershill (Scientific- DH) | |
| Professor D Forman | Ms F Pollitt (Scientific-DH) | |
| Professor D Harrison | Dr D Benford (Scientific-FSA) | |
| Ms D Howel | Mr S Robjohns (Minutes) | |
| Dr S Kennedy | Mr K N Mistry (Administrative) | |
| Ms M Langley | ||
| Professor D Phillips | ||
| Professor A Renwick |
| In Attendance: | |
| Professor D Davis | (DH Tox Unit items 4,5 & 7) |
| Ms I Lindup | (DH Tox Unit item 5) |
| Dr D Clancy | (DH Tox Unit items 5 & 7) |
| Professor K Chipman | (Birmingham University item 6) |
| Dr A Mally | (Birmingham University item 6) |
| Professor H MØller | (Kings College: Advisor to COC) |
| Dr H Walton | (DH item 5) |
| Assessors: | |
| Dr H Stemplewski | (MCA) |
| Dr P Howden | (HSE) |
| Ms H Smethurst | (EA) |
| Contents | Paragraph(s) | |
| Item 1: | Apologies for absence | 2 |
| Item 2: | Minutes of meeting 11 November 02 (CC/MIN/01/2) | 7 |
| Item 3: | Matters arising | 8 |
| 3.1 Draft Statement on minimum duration of carcinogenicity Studies in rats (CC/02/02) | ||
| Item 4: | Genotype-Environment interactions effect on risk of cancer | 12 |
| Item 5: | Quantification of effects of carcinogenic air pollutants (CC/02/03) | 19 |
| Item 6: | Molecular markers of non-genotoxic carcinogens (a presentation on DH funded research into possible methods for identification of non-genotoxic carcinogens) | 25 |
| Item 7: | Revision of COC guidelines: Risk assessment of chemical carcinogens (CC/02/05) | 35 |
| Item 8: | Consideration of OST Code of Practice for Scientific Advisory Committees (CC/02/06) | 40 |
| Item 9: | Draft Annual Report for 2001 (CC/02/07) | 45 |
| Item 10: | Third draft OECD guidance notes for analysis and evaluation of Chronic toxicity and carcinogenicity studies (CC/02/08) | 46 |
| Item 11: | Glossary of terms used by COT/COM/COC (CC/02/09) | 49 |
| Item 12: | Any other business | 52 |
| Item 13: | Date of next meeting | 54 |
ITEM 1: APOLOGIES FOR ABSENCE
2. Apologies for absence were received from members Dr R Roberts, Professor G Williams, Professor D Shuker and assessors Mrs K Cameron (DEFRA), Mr A Browning (VMD) and Mr T Holmes.
Announcements
3. Members and the Secretariat congratulated the Chairman Professor Peter Blain on his award of a CBE. Dr Ruth Roberts was also congratulated on her Society of Toxicology Achievement Award for 2002, for her work on the molecular basis of carcinogen risk assessment. Dr Roberts is the first scientist outside of North America to have received this award.
4. The Chairman welcomed Professor Henrik MÆ ller as an adviser for a period of 2 meetings when Professor Forman will be unavailable (due to a 6-month sabbatical in Australia), and Professor D Davies Head of Department of Health Toxicology Unit at Imperial College (attending in place of Professor A Boobis).
5. The Chairman also welcomed Professor K Chipman and Dr A Mally from Birmingham University (attending for item 6), Ms I Lindup from DH Toxicology Unit at Imperial College (attending for item 5), Dr H Walton (DH, item 5) and Ms H Smethurst attending on a sabbatical to DH from the Environment Agency.
6. Members were reminded of the need to make any relevant declarations of interest before discussion of items.
ITEM 2: MINUTES OF THE MEETING ON 11 NOVEMBER 2001 (CC/MIN/2001/3)
7. The minutes were agreed subject to minor editorial changes.
ITEM 3: MATTERS ARISING
3.1 Draft Statement on minimum duration of carcinogenicity studies in rats (CC/02/02)
8. The Secretariat apologised for not sending this statement out earlier for comment. Members agreed the final statement.
3.2 ILSI/HESI research on Alternative Cancer Tests
9. Members were informed that COC and COM statements had been forwarded to the International Life Sciences Institute and Health and Environment Sciences Institute (ILSI/HESI). The Alternatives to Carcinogenicity (ACT) Steering Committee reviewed both statements at its meeting on the 10 January 2002. Technical comments by ILSI/HESI on the COC and COM statements had just been received by the DH Secretariat (6 March 2002) and were tabled for information.
10. The COC heard that there had been a suggestion that ILSI/HESI and COC/COM could submit their separate statements and commentaries on alternative cancer tests to Toxicologic Pathology.
11. Members agreed they would need to consider the ILSI/HESI response to the draft COC statement. Members were asked to forward any comments to the secretariat within 2 weeks.
ITEM 4: GENOTYPE-ENVIRONMENT INTERACTIONS (2ND DRAFT STATEMENT CC/02/1)
12. The Committee had considered a first draft statement at its November 2001 meeting. Members were generally content with the layout and approach taken. Reservations had been expressed at the November meeting regarding the assessment of significance to public health of genotype-environment interactions and the model calculations provided in the draft statement. The Committee agreed at its last meeting that a small subgroup should meet to clarify the approach to be taken in assessing the significance for public health and any further model calculations.
13. A subgroup meeting was held on 28th January 2002. Agreement was reached on a number of issues raised by the COC. The group felt that it was important to define types of interaction and scales of measurement before any model calculations were presented, for example on the identification of numbers required in case-control studies. The secretariat had prepared a 2nd draft statement for members to consider.
14. Members agreed that a clear definition was needed for the two types of gene-environment interactions namely additive and multiplicative in paragraph 8 of the 2nd draft statement. The Committee acknowledged that there were a number of different ways of examining the effects of interactions, but the COC was not expressing a preference for any particular method. It was noted that the selection of the example for model risk assessment calculations involved a voluntary exposure (GSTM1 and lung cancer in smokers) and was chosen because of availability of appropriate information for these calculations. The Committee was usually concerned with health risks from involuntary exposure to chemicals (eg. environmental chemicals), but the appropriate data for such a calculation was not available.
15. The Committee questioned the value of screening for susceptible genotypes. With respect to smoking it was considered that it would be beneficial not to smoke regardless of an individual genotype. Regarding other possible exposures, members agreed screening for susceptible genotypes was technologically feasible, but that such an approach would have little value in identifying those who would develop cancer. It was considered to be more beneficial to control exposure to carcinogens.
16. Members considered that there was unlikely to be a sharp distinction between high and low penetrant genes, and that it was more likely that there would be a continuum of degrees of penetrance. Members agreed that some gene-environmental interactions might be potentially important for both high and low penetrant genes.
17. Overall the Committee believed that a worthwhile document had been produced and agreed with its previous conclusions. However, it was noted that the possibility could not be excluded that significant genotype-environment interactions involved in chemically induced cancers would be discovered in the future. It was therefore important to keep this subject under review particularly in the light of developments of the genome project and other initiatives.
18. The statement and lay summary would be completed by postal circulation and Chairman's action.
ITEM 5: QUANTIFICATION OF EFFECTS OF CARCINOGENIC AIR POLLUTANTS (CC/02/3)
19. The non-cancer health effects of air pollutants are already being quantified for cost-benefit analysis using dose-response functions from epidemiological studies of environmental exposure to air pollutants. The Department of Health had been asked whether the benefits (ie reduction in cancer incidence), which could be attributed to lowering levels of carcinogenic air pollutants, could be quantified. Paper CC/02/03 examined this question using benzene and PAHs as illustrative examples. Simple linear extrapolation using WHO unit risk factors were used to highlight relevant issues for discussion. The Committee was asked for its views on possible approaches (eg risk estimation and relative ranking) to quantification of effects of carcinogenic air pollutants. This would also help inform a future paper by the DH Toxicology Unit at Imperial College on this topic.
20. Members considered it would be more useful to consider some of the general principles of Quantitative Risk Assessment first, as was being planned for the review of the COC Guidelines.
21. The COC had concerns over the uncertainties involved in extrapolating effects from occupational epidemiology data to much lower levels of air pollution. Members considered that exposure via air pollutants could be different to occupational exposure in a number of ways. Thus a comparison was being made between the cancer effect of occupational exposure at high levels and environmental exposures, which could vary between urban and rural areas and even within urban areas. A comparison was also being made between workers and the general population including the young and elderly and those who were ill. Toxicokinetics and metabolism could differ between high and low dose exposures. In addition, in the case of PAHs, consideration needed to be given to whether the size of particles to which the PAHs were attached differed when comparing occupational and environmental exposures, as this could influence the site of deposition in the respiratory tract and hence uptake. This would make any comparison difficult. The required extrapolation of around three orders of magnitude in exposure would introduce considerable uncertainty in estimates of risk. Members were concerned that presently it was not possible to determine whether a dose-response relationship would be linear over the entirety of its range.
22. The Committee was asked whether a recent study showing a correlation between particle levels in a city and rates of lung cancer would help in the interpretation of low dose risks of carcinogenic air pollutants. Members agreed that air pollution monitoring and cancer data could be helpful but this still involved difficulties as measures of exposure were crude (sometimes as little as 1 monitor per city) and did not take account of factors such as different exposures resulting from the time spent indoors or outdoors.
23. The Committee considered that all methods of ranking carcinogenic potency of air pollutants made large assumptions. There were some concerns whether relative ranking derived from epidemiological studies of occupational exposures were relevant to environmental exposure levels. It was also felt that there was a lot of potential confounding factors between and within cities, which might not all have been taken in to account. Members agreed that the development of biomarkers for exposure would be helpful, particularly comparative data on occupational and environmental exposure levels. Members also suggested that a review of available data on DNA adducts in humans, resulting from occupational and environmental chemical exposure, could help evaluate the assumption of a linear cancer dose-response relationship.
24. The quantification of effects of carcinogenic air pollutants could be developed in parallel with the review of the risk assessment of chemical carcinogens (see item 7) and would have to be revisited at a future meeting.
ITEM 6: MOLECULAR MARKERS OF NON-GENOTOXIC CARCINOGENS (a presentation on DH funded research into possible methods for identification on non-genotoxic carcinogens) (CC/02/04)
25. The purpose of this DH funded project was to investigate mechanism-based biomarkers for the detection of effects of chemicals with the potential to act as non-genotoxic carcinogens. The study outline had been presented and discussed with the COC at the 17 July 2000 meeting.
26. The agreed strategy incorporated the investigation of a variety of non-genotoxic carcinogens that operate through different mechanisms and on different target organs. Both target and non-target organ effects were assessed at two time-points, 3 and 28 days. Dose-response relationships were also assessed. The priority chemicals identified by the COC included TCDD, hexachlorobenzene, oestradiol and chloroform (top priority), alachlor, methapyrilene, pyrilamine, dichlorobenzene and paracetamol. Investigation of some interactions with an independent study on Wyeth 14,643 was also intended.
27. Professor Chipman and Dr Mally presented their results and conclusions to the Committee.
28. Compounds were administered by gavage at 3 dose levels to groups of 3 male rats. The quantitative assessment had been completed of non-gentoxic carcinogen effects on cell proliferation, cell death by apoptosis and expression of gap junction proteins (connexins) in the liver, kidney and thyroid.
29. Potential inhibition of gap junction intercellular communication (GJIC) via down-regulation of connexin plaques (assessed by microscopic evaluation of sections using immunological staining methods) was identified with the test chemical carcinogens and appeared to be target organ specific. For some compounds the effect seemed to be dose-dependent. There was no dose-dependent decrease in connexin placques in non-target organs. Reduced expression of connexin plaques occurred, in some instances, at dose levels below the apparent threshold for induction of cell proliferation and tumour development. However, the correlation between the degree of plaque loss and extent of impaired gap junction function remained to be determined. Additionally, disruption of gap junction intercellular communication could possibly have occurred due to a mechanism that did not alter the detection of plaques.
30. It has been proposed that inhibition of apoptosis by non-genotoxic carcinogens contributes to the cancer process by allowing cells to survive that would normally die. In these studies undertaken for DH, there was little evidence for suppression of the background level of apoptosis in target organs. However, this process may preferentially occur in "initiated" cells or cells with DNA damage and could still be a very important mechanism involved in cancer development. In contrast a recent paper on fumonisin B1 and the results of this study on methapyrilene suggested cell loss by apoptosis might, like necrosis, result in compensatory cell proliferation.
31. Professor Chipman considered that a unifying feature specific for association with target organ carcinogenicity was a combination of connexin plaque modulation and cell proliferation. But limonene was an exception to this, where in the kidney, connexin loss was not observed at the time points investigated. Professor Chipman stated that connexin loss appears as a requisite provided it is associated with cell proliferation. These combined markers might serve as an alert for a non-genotoxic carcinogen, for which a NOEL could be determined from short-term studies.
32. Members considered that the work undertaken by Professor Chipman and colleagues for DH had been excellently planned and executed. Members were concerned however that the proposed strategy for a non-genotoxic cacinogen alert might be a screen for cytotoxicity. Professor Chipman felt that a combination of cell proliferation, connexin plaque expression and histology could aid in the differentiation between non-genotoxic carcinogens and cytotoxicity. [Post meeting note: Some additional histological information from the DH sponsored work has become available to support this view]. A number of areas for possible future work were identified Professor Chipman, and these were considered by the COC.
33. The COC considered that it was not possible to define a single predictive test for non-genotoxic carcinogenesis. It was agreed that this work by Professor Chapman was valuable, but there was a need to establish the significance of down regulation of connexins and plaque levels to the carcinogenic process. Members considered that were considerable technical difficulties in assessing apoptosis and felt there was a need for basic research on marker reproducibility before the use of apoptosis could be taken further.
34. The Committee concluded that a battery of tests for detection of non-genotoxic carcinogens was desirable, but the prospect of developing such an effective test system would take considerable time.
ITEM 7: REVISION OF COC GUIDELINES: RISK ASSESSMENT OF CHEMICAL CARCINOGENS (CC/02/5)
35. At the last COC meeting (November 2001) it was agreed that it would be timely for the Committee to update its advice in the 1991 COC guidelines, in the section on risk assessment of chemical carcinogens. It was noted that the COM had recently completed a review of its strategy for the testing and evaluation of mutagens, and its assessment of in-vivo mutagens (genotoxic carcinogens). Both documents were now available on the COM website. The secretariat was working with the DH Toxicology Unit at Imperial College, and it was hoped that a comprehensive paper covering approaches to risk assessment of chemical carcinogens would be available for the 27th June 2002 COC meeting.
36. The Committee was asked to give some initial consideration to a key aspect of the risk assessment of genotoxic carcinogens, namely the identification of minimum risk levels. There is considerable pressure to produce numerical advice on specific chemicals in this regard, rather than a generic statement that exposures should be reduced to as low as reasonably practical, although ALARP would still apply. It was explained that any such pragmatic values would only be used in areas where some exposure to genotoxic carcinogens is largely unavoidable due to contamination. There was no intention to apply any derived 'minimal risk values' to intentional exposures (i.e. residues in food or consumer products).
37. Paper CC/02/5 presented two examples where the Department of Health had to provide advice on minimum risk levels, and could be used to consider possible approaches to risk assessment. The COT provided urgent advice in 2000 on the toxicity of HCBD relating to public health concerns from environmental contamination. Low levels were detected in the indoor air of some houses close to a chemical waste dump. For this genotoxic carcinogen, the COT agreed a minimum risk level of 0.6ppb based on non-cancer effects. This was 10,000 fold below the LOAEL for tumourigenesis (kidney in rat), and therefore represented a minimal risk level. Another example related to the derivation of Index Doses for specific soil contaminants including genotoxic carcinogens, where a TDI would be inappropriate. The approach has been to define a minimum risk level from authoritative reviews. Index Doses can be based on nationally (mainly UK or US agencies) or internationally derived (eg WHO, JECFA, SCF) exposure standards. Expert judgement is required to identify a value that can be considered as representing a minimum risk to humans. An Index Dose for arsenic was provided as an example.
38. Members commented that the International Life Science Institute (ILSI), Health and Environmental Sciences Institute (HESI) were to convene a meeting to consider whether the 'threshold of concern' approach (used by the USA Food & Drug Administration) could be adapted to mutagens and genotoxic carcinogens. It was agreed that any papers from this meeting could serve to assist in the COC's discussion of its revised guidelines.
39. The committee agreed that the paper by the DH Toxicology Unit on risk assessment of chemical carcinogens should include the approaches used by other countries in this regard.
ITEM 8: CONSIDERATION OF OST CODE OF PRACTICE FOR SCIENTIFIC ADVISORY COMMITTEES (CC/02/06)
40. A copy of the new "Code of Practice" for Scientific Advisory Committees published by the Office of Science and Technology (OST) on 19th December 2001 was provided to members for information and comment.
41. Many of the issues were considered at the last (November 2001) COC meeting when the Committee reviewed the Government's response to the BSE enquiry. Members agreed that most of the COC procedures conform to the new code of practice and where this is not the case steps are being taken to comply.
42. The Committee noted that substantantive background papers would be published (excluding those containing commercial in-confidence data). Due to the highly technical nature of the work it would be difficult for papers to be truly comprehensible to the non-specialist, but it was hoped that the 'what's new section' of the COM website and lay summaries would help in this regard.
43. It was agreed that an opening paragraph in papers could summarise the public health issue in lay terms. Additionally, overview lay summaries should accompany some statements and a glossary of technical terms could help with public understanding. The COC would also contribute to a joint COT/COC/COM glossary (see item 11).
44. With respect to dealing with dissenting views members agreed that it should be made clear in the minutes and statements when decisions were not unanimous.
ITEM 9: DRAFT ANNUAL REPORT FOR 2001 (CC/02/07)
45. The draft Annual Report had been drawn up from previously agreed minutes and statements. Members were requested to send any written comments to the Secretariat.
ITEM 10: THIRD DRAFT OECD GUIDANCE NOTES FOR ANALYSIS AND EVALUATION OF CHRONIC CARCINOGENICITY STUDIES (CC/02/09)
46. The OECD guidance notes have been drafted primarily for use by regulatory authorities in the assessment of carcinogenicity studies. It is likely that any major issues will have to be dealt with in a subsequent revision of the document, whilst editorial changes may be taken into consideration in the current document.
47. The Committee was informed that some reference to mutagenicity data in the weight of evidence section of the document would seem to be appropriate. Member's attention was also drawn to the section on post mortem observations (para 1551-163 pp37-40) and to the assessment of "flawed" studies (para 208).
48. Members were asked to send any comments to the secretariat by 14 March. These would be passed on to the Authors (Chemical Review and International harmonisation Section, Chemicals and Non-prescription Medicines Branch, Therapeutic Goods Administration, Dept of Health and Ageing, Australia).
ITEM 11: GLOSSARY OF TERMS USED BY THE COT/COC/COM (MUT/02/09)
49. In recent COT discussions, Members had stressed the importance of using agreed terminology and definitions. Previous COT/COM/COC annual reports have included a glossary, which has been compiled by the Secretariats on an ad hoc basis, and COT/COM have agreed that it is appropriate to review these definitions. Paper CC/02/09 contains definitions derived from a number of sources:
- Previous COT/COM/COC annual reports
- COC guidelines
- Glossary compiled for the recent Joint COT/COM/COC Symposium on Genomics and Proteomics
- Additional terms taken from the IUPAC Glossary for Chemists of Terms used in Toxicology or revisions as proposed by the Secretariat.
50. Comments from the COT have been incorporated. Members were informed that the COT had provided alternative epidemiological terms, and questioned the inclusion of the Bradford Hill criteria, which gave the impression of a "check-list" approach. The COT also questioned the respective use of the terms "tumour" and "neoplasm".
51. The COC agreed to send any written comments.
ITEM 12: ANY OTHER BUSINESS
52. The COC was told that the ACP had referred malathion to the COM/COC for advice. The manufacturer is Cheminova Agro A/S. Pesticide approval holders are PetLife International Ltd, and United Phosphorous. Human Medicine Licences are held by EC De Witt and Co Ltd, Seton Poducts Ltd and Ultra Chemicals Ltd.
53. Members were asked to consider any declarations they might make on this chemical. A review paper is expected for the 27 June 2002 meeting.
The following papers were provided for information:
Coughlin S et Al American Journal Of Epidemiology, Vol 16 (2), 91-98, 1999. (CC/02/10).
Jarup L et al. Cancer risks in populations near landfill sites in Great Britain. (CC/02/11).
ITEM 13: DATE OF NEXT MEETING
54. 27 June 2002
ACTIONS
| ITEM | ACTION | WHO |
| 4. Gene-Environment Interactions | Draft statement to be circulated and agreed by chairman's action | Secretariat |
| 7. Revision of COC Guidelines | Draft Paper | DH Toxicology Unit |
| 9. Draft Annual Report for 2001 | Draft Annual Report | Secretariat |