Minutes of the meeting held 24th June 1999 COC/MIN/99/2
Minutes of the meeting held at 10.30am on Thursday 24 June 1999 in Room 136/7B, Skipton House, Department of Health, London SE1 6LH.
1. PRESENT
Chairman: Professor P G Blain |
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Members: Professor CD Chilvers |
Assessors: Mr E Efa (PSD) |
Secretariat: Dr R J Fielder (Scientific) |
In Attendance: All meeting |
Item 6 |
Item 8 Professor D Davies (ICSTM) |
| Item 5.2 Dr H Walton (DH) |
ITEM 1: APOLOGIES FOR ABSENCE
2. Apologies were received from Professors Dayan, Newbold, Parry and Williams, Mr A Smith (HSE) and Mr S Warren (PSD, Mr Efa attending).
Announcements
3 . The Chairman welcomed Ms Langley to her first meeting as lay member of the COC. Members were reminded of the need to declare all interests before the discussion of each item. Members were informed that under the new procedures for greater openness of Committee business, agendas would be placed on the Internet site just before a meeting, minutes and conclusions approximately one month after a meeting. There will be case-by-case arrangements for items where there are issues of confidentiality.
Agenda
| Item | Content | Paragraph |
| 1 | Apologies for absence | 2-3 |
| 2 | Minutes of meeting held 18 March 1999 | 4-6 |
| 3 | Matters arising not dealt with by other agenda items | 7 |
| 4 | Conclusions from meeting held 18 March 1999 4.1 OC Insecticides and Breast Cancer 4.2 3-Monochloro propane,1,2-diol (in drinking water) |
8-18 9-10 11-14 |
| 5 | Conclusions held over from previous meetings. 5.1 Ozone 5.2 Cancer incidence near Municipal Incinerators |
15-18 |
6.1 Association between alcohol consumption and effects on oestrogen metabolism. 6.2 Proposal for meta-analysis 6.3 Association between alcohol and cancer of the
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20-24 25-27 28 |
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| 7 | IPCS framework for considering mode of action of chemical carcinogens | 29-30 |
| 8 | Presentation on validation of short-term carcinogenicity tests using transgenic animals. | 31 |
| 9 | Any Other Business | 32 |
| 10 | Papers for information: Royal Commission on Environmental Pollution - Setting Environmental Standards |
33-34 |
| 11 | Date of Next Meeting: 18 November 1999 | 35 |
TEM 2: MINUTES OF MEETING HELD ON 18 MARCH 1999 (CC/MIN/99/1)
4. The minutes were agreed subject to a number of minor editorial changes and the following changes;
Item 4.2 (Alcohol and breast cancer: CC/99/9) para 15 line 3
5. "might induce play a role in breast cancer..."
Item 5.1 (OC Insecticides and breast cancer: CC/99/6), page 6, para 17
6. "...where the authors had claimed that potential synergism of xenoestrogens had been inadequately studied were unfounded and agreed, although study designs and data analyses were not optimal to reveal slight interactions, any toxicologically significant synergistic interactions should have been identified in the available published experiments."
ITEM 3: MATTERS ARISING NOT CONSIDERED UNDER OTHER ITEMS.
7. There were no matters arising.
ITEM 4: CONCLUSIONS FROM MEETING HELD ON 18 MARCH 1999
8. A summary of the items to be considered was given in CC/99/19.
4.1 OC Insecticides and Breast Cancer (CC/99/20)
9. Members considered the fourth draft statement and agreed that there were a number of amendments and changes required;
i. Tabulation of data for concentrations of beta-HCH in human fat (table 3).
ii. Redraft of epidemiology to present results of additional 8 studies in a table.
iii. Revision of conclusions on individual chemicals in epidemiology section.
iv. Revision of overall conclusions to cite earlier parts of statement and to give rationale for conclusion reached for each of the chemicals considered.
v Tabulation of Annexed material on relative oestrogenic potency in the text of the statement as table 2.
vi. Revision of reference numbers.
10. Members considered the confidential summaries submitted by PSD of reproduction studies in rats and mice undertaken using lindane and agreed that there was no need for any additional testing (uterotrophic assay) for potential in-vivo oestrogenic activity. The Committee agreed that lindane should be regarded as not having any potential in-vivo oestrogenic activity. It was agreed that the revised statement would be circulated by post with final agreement through chairman's action.
4.2 3-Monochloro propane,1,2-diol (in drinking water) (CC/99/21)
11. No interests were declared.
12. Members noted the COM had concluded that it would be prudent to assume that 3-MCPD was an in-vivo mutagen. The COM had recommended that further negative results in an in-vivo mutagenicity test in a second tissue namely rat liver UDS were required in order to provide adequate reassurance that the activity seen in-vitro is not expressed in-vivo.
13. Members discussed the draft conclusions as set out in paragraph 6 of CC/99/21 and agreed that the tumourigenic response seen in rats given 3-MCPD in the drinking water did not appear to be consistent with genotoxic carcinogens. Thus statistically significant increases in tumours seen at the high dose level in males (in the testes, mammary gland and preputial gland) consisted of benign tumours under conditions where the Maximum Tolerated Dose level was exceeded and were possibly due to gross disturbances of physiology. Members agreed that the proposed non-genotoxic mechanisms advanced were plausible, but there was no compound specific data to support any of the contentions suggested. Members noted the comparison of the different approaches to statistical evaluation of the data from this study (which had been tabulated in CC/99/21 addendum) and agreed that the conclusions should note this information.
14. Overall the committee agreed that it was not possible to draw a definite conclusion regarding the significance of the observed carcinogenic effects of 3-MCPD in the rat. However, in view of the COM conclusions and need to further investigate the potential for in-vivo mutagenic activity, it would be prudent to reduce exposures to as low as technologically practicable.
ITEM 5: CONCLUSIONS HELD OVER FROM PREVIOUS MEETINGS.
15. A summary of the items to be considered was given in CC/99/19.
5.1 Ozone
16. Members heard that the COM had finalised its conclusions on ozone following consideration of a generic paper from ICSTM on the significance of mutational signatures in tumours isolated from animals exposed to putative carcinogens. The COM had concluded that the mutational signature data on ozone provided some evidence for in-vivo mutagenic activity. The COC was asked to consider the revised conclusions as set out in paragraph 8 of CC/99/22.
17. Members considered that para 8 iii should be redrafted to clearly indicate that significant increases in lung tumours in the 2 year inhalation study only occurred in the female mice at the top dose level and in the presence of chronic irritation. Members considered that further additional work to confirm the A-T transversions in mouse lung would provide important additional information. The Committee agreed that overall; the present data were inadequate to draw any conclusions regarding potential carcinogenicity of ozone to humans. The Committee agreed that revisions to the conclusions could be agreed by Chairman's action.
5.2 Cancer incidence near Municipal Incinerators
18. The minutes and COC statement on this item will be made available upon acceptance of the paper written by SAHSU for publication.
6. ALCOHOL AND BREAST CANCER
19. No interests were declared.
6.1 Association between alcohol consumption and effects on oestrogen metabolism (CC/99/24).
20. Members recalled that the Committee had asked for the data on potential effects of alcohol on oestrogens to be retabulated to report on individual metabolites in the pathway and a further paper had now been provided by ICSTM (Annex 1 to CC/99/24). Members had also agreed that the available evidence should be considered by an endocrinologist for a view specifically on what effects alcohol might have on the metabolism of oestrogens in premenopausal and post menopausal women. The Chairman welcomed Professor H Jacobs who had provided an expert endocrinological view on the studies of the effect of alcohol, which was appended as Annex 2 to CC/99/24.
21. Professor Jacobs stated that the classical approach to evaluating whether there was an endocrine mechanism involved in the association between alcohol and increased risk of breast cancer was to look for evidence that alcohol was associated with both elevated hormone levels and for receptor involvement in the carcinogenic process. He considered that, whilst there were limitations to the recent publication by Enger et al (British Journal of Cancer (1999), 79, 1308-1314.), these data provided some evidence that alcohol consumption preferentially increased the risk of ER+/PR+ breast cancer in postmenopausal women, which was consistent with a receptor-mediated effect. There was convincing evidence that alcohol raised blood concentrations of oestrogen (particularly of oestradiol) in both premenopausal and postmenopausal women, but it was important to consider what effects might occur in different tissues.
22. The mechanism of action could potentially involve effects on oestrogen production or clearance. Investigating effects on production would be complicated in that glandular secretion (ovarian) predominated in premenopausal women whilst extra-glandular production and in particular conversion of oestrone to oestradiol in fat occurred in postmenopausal women. Other potential sites for an effect of alcohol included hepatic aromatisation, hydrolysis of oestrone sulphate in splanchnic circulation, or an effect on enterohepatic recirculation of oestrogens. He noted the evidence for an effect on clearance of oestrogens was limited to one study which had found that alcohol could reduce the clearance of oestradiol Ginsburg et al Fertil, Steril (1995), 63, 1227-1230. The evidence for a related reduction in sex hormone binding globulin, which was consistent with higher bioavailability of oestradiol, in relation to alcohol consumption might have been due to confounding by obesity. Professor Jacobs considered that the study by Ginsburg et al (JAMA, (1996), 276, 1747-1751) where raised blood levels of oestradiol was found in women given a single dose of oestrogen and alcohol but not in women given alcohol alone could be due to alcohol induced increased absorption of oestradiol from the gut. The lack of an effect on blood oestradiol levels in women given alcohol alone in this intervention study did not imply that alcohol was without an effect in women who did not use HRT as the important parameter to investigate in these women would be the conversion of oestrone to oestradiol which was likely to occur over a different time scale.
23. Overall, Professor Jacobs concluded that there was sufficient evidence from the available studies in humans to conclude that alcohol can elevate blood concentrations of oestrogens (particularly oestradiol) and the data concerning oestrogen receptor status in breast cancer suggested a plausible link between alcohol and an increased risk of breast cancer.
24. Members discussed the issues raised by Professor Jacobs and the information summarised in CC/99/24. It was agreed that there were a number of factors, which could explain the inconsistencies between some of the studies of alcohol effects on oestrogens. These included the use of single blood samples, the time-interval between blood sampling with reference to consumption of alcohol and the potential for inaccuracy in quantifying the intake of and patterns of alcohol consumption. Members noted that the evidence from the Enger paper for a greater increase in relative risk of breast cancer in women consuming alcohol who were also receiving HRT was limited but was consistent with the hypothesis that the mode of action of alcohol in post menopausal women was their increasing oestrogen levels. The mode of alcohol induced oestrogenic action in premenopausal women was very unclear and one speculation was that it might involve a central effect on the hypothalamic-pituitary axis. The Committee concurred with the conclusion suggested by Professor Jacobs and agreed that any further epidemiological work should consider a number of subgroups, i.e. premenopausal women who either used or did not use oral contraceptives and postmenopausal women who either had or had not undertaken HRT. The Committee agreed that there was insufficient data available to describe a threshold of action for alcohol induced elevation in oestrogens.
6.2 Proposal for meta-analysis (CC/99/25)
25 The Chairman welcomed Professors Elliott and Thompson and asked them to provide an overview of the proposed meta-analysis study. Members were told that the investigation of whether the observed association between alcohol and increased risk of breast cancer was causal would be complex as reported relative risks were generally under 3 and it was particularly difficult to control for the effects of bias and confounding in this instance. The proposed meta-analysis to be undertaken at Imperial College of Science Technology and Medicine would include a detailed quality assessment of papers, assessment of bias and exclusion of papers where selection of other biases are operating, confounding, and a statistical evaluation for potential heterogeneity, an evaluation of dose-response and careful interpretation of the data. The Committee was informed that the analysis would be based on published literature, as it would be impracticable to extract all primary data and undertake appropriate analyses within the time available for this study (ca 18 months). Professor Elliott noted the comments of the referees (in particular the need to undertake an assessment of attributable risk for the U.K population) and agreed that any suggestions would be taken into account in the study design.
26. The Committee endorsed the proposal. Members were told that the study would be initiated upon the appointment of a suitable experienced research officer to the ICSTM team. A management board would be convened to monitor the study and that the secretariat would attend as observers and to provide progress reports for the COC.
27. The Committee agreed that a draft statement summarising the current status of the COC evaluation of the association between breast cancer and consumption of alcohol should be drafted for the November meeting.
6.3 Association between alcohol and cancer of the endometrium (CC/99/25)
28. Members heard that there was no evidence from the published epidemiological studies to support an association between alcohol consumption and cancer of the endometrium. Members also noted Professor Jacobs' comment that the uterus in premenopausal women was protected from the effects of oestrogens during the luteal phase of menses by secretion of progesterone from the corpus luteum. In post menopausal women progesterone was included in HRT. Thus on endocrine grounds, an association between consumption of alcohol and cancer of the uterus was unlikely and if one were to be found it would be a very small effect. The Committee concluded that there was no need for any further work on this topic.
7. IPCS FRAMEWORK FOR CONSIDERING MODE OF ACTION OF CHEMICAL CARCINOGENS (CC/99/26)
29. Members heard that the International Programme on Chemical Safety (IPCS) had an active programme on harmonisation of approaches to the assessment of health risks from exposure to chemicals. A greater understanding of the approaches used by different regulatory authorities/agencies in different countries would increase confidence in the assessments reached with the long-term objective of convergence in risk assessments. A priority area was chemical carcinogens. A major outcome of the work in this area was a conceptual framework for considering mode of action data. This was intended to be used by regulators as part of their hazard assessment process, as an analytical tool when considering mode of action data. It should enable thought processes to be transparent and thus increase mutual understanding between regulatory authorities. The framework document had been circulated to regulatory agencies in different countries and in regional (EU) and international bodies (e.g JMPR, JECFA) for feedback as to its value.
30. Members noted that the document was solely concerned with mode of action of specific tumours in animals and didn't address extrapolation to humans. The framework did however, recognise that this was an important area for future consideration but did not address the extrapolation of animal carcinogenicity to the assessment of potential hazards to humans. It was agreed that the IPCS should be encouraged to carry out further work in exploring a framework to cover this area. Members noted that the framework for considering mode of action was most suited to data rich chemicals such as those undergoing regulatory approval.
8. PRESENTATION ON VALIDATION OF SHORT-TERM CARCINOGENICITY TESTS USING TRANSGENIC ANIMALS (CC/99/28, CC/99/30, CC/99/32).
31. Dr Denise Robinson from the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute (ILSI) made a presentation to the COC. This concerned the ongoing work of HESI regarding the utility of short-term carcinogenicity tests (including transgenic animals) specified in the ICH (International Conference on Harmonisation) guidelines for the testing for carcinogenicity of pharmaceuticals. Members were given details of the scope of the programme of work and information regarding the input from laboratories from U.S.A, Japan and Europe where the tests were being undertaken. Members reiterated their views that it was too early in the development of transgenic animal models to be specific as to which models were the most suitable for predicting carcinogenic potential. Members heard that a preliminary report of the results generated by the HESI testing programme should be available in November 2000 and would be provided to the COC for comment. Members made a number of comments regarding the overall strategy adopted by HESI. These have been included in a full account of Dr Robinson's presentation available as an ad-hoc paper on the COC Internet site. The Committee thanked Dr Robinson for her presentation.
9. ANY OTHER BUSINESS
32. Members were asked to forward any suggestions they had in respect of an evaluation the secretariat were undertaking in conjunction with PSD regarding an assessment of an anonymised database of carcinogenicity studies in rats. In particular members were asked for any parameters they would investigate in respect of studies where survival was inadequate in comparison to OECD recommendations.
10. PAPERS FOR INFORMATION
33. Royal Commission on Environmental Pollution - Setting
Environmental Standards (CC/99/29)
34. SAHSU Study: Lymphohaematopoietic malignancy around all industrial complexes that include major oil refineries in Great Britain. (CC/99/31).
11. DATE OF NEXT MEETING:
35. The meeting ended at 2.47 pm. Next meeting 18 November 1999.