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Committee on Mutagenicity of Chemicals in Food, Consumer Products
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| Minutes of the meeting held on Thursday 3 February
2000 at 10.30 am, in Room 136/7B Skipton House, 80 London Road, Elephant and Castle, London SE1 6LH. Present:
CONTENTS
ITEM 1: APOLOGIES FOR ABSENCE 1. Apologies for absence were received from Dr P Bryant, Professor Davies, Professor Newbold, Dr P Tromans (National Assembly of Wales), Dr Tweats, Dr Shillaker (PSD) and Dr Fisher (MAFF) and Mr Al-Derzi (Secretariat). Announcements 2. Members were reminded of the need to declare any interests before discussion of items. ITEM 2: MINUTES OF THE MEETING HELD ON 7TH OCTOBER 1999 (MUT/MIN/99/3) 3. Members agreed the minutes subject to some minor editorial changes. ITEM 3: MATTERS ARISING ISO Method for determination of the genotoxicity of water and waste water using Salmonella 4. Members comments on this proposal had been forwarded to the ISO secretariat. The UK had subsequently voted against the proposed method for determining genotoxicity of water and waste water as it was evident that the method could not provide any meaningful results. The Committee would be informed of any further developments. ITEM 4: DRAFT STATEMENT ON HYDROQUINONE AND PHENOL (MUT/2000/3) 5. There were no declarations of interest. 6. Members noted a number of typographical and minor amendments to the statement. The Committee agreed that the overall conclusions should be altered for each chemical to indicate that occupational exposure was associated with a mutagenic hazard, but it was not possible to quantify the risk. ITEM 5: GUIDANCE ON THE STRATEGY FOR TESTING AND EVALUATION OF MUTAGENICITY OF CHEMICALS (FOURTH DRAFT) (MUT/2000/1) 7. Members recalled that previous discussions had focused on the strategy for in-vitro testing (stage 1) and agreed to consider the revised draft starting from stage 2, in-vivo testing. A number of suggestions and amendments were proposed. These are summarised below. Title 8. This should be revised as evaluation of mutagenicity is to be covered in a separate document. Introduction 9. A number of minor suggestions were made, in particular to clarify that aneuploidy should be regarded as a mutagenic end-point. General Principles of Strategy 10. Members agreed that a separate document should provide advice on the testing of chemical mixtures. Stage 1 (in-vitro tests screening for mutagenic potential) 11. Members agreed that the term clastogenicity should be used in figure 1 and throughout the document. Members agreed that statement regarding the use of exposure as a criterion for determining testing requirements in figure 1 (and throughout the document) should be amended to state "...exposure to a specific chemical is likely to be ....". Figure 1 should also acknowledge that other mammalian cell mutagenicity tests might be developed which could provide equivalent data to that obtained by the Mouse Lymphoma Assay. Discussion Stage 1 12. Members agreed that it wasn't necessary to provide examples of clastogenic chemicals in the text. Members agreed that the detailed information on the use of the in-vitro micronucleus assay should be summarised in a table. Members agreed that reference to the range of chemicals considered by COM and ICH should be deleted. Members agreed that reference to the use of microscopy as a method for identifying colony size in the Mouse Lymphoma Assay could be deleted. It was agreed that both the microwell and agar methods were acceptable. Stage 2 (in-vivo assays in somatic cells) 13. Members agreed that figure 2 should be altered so that the strategy for testing short-lived reactive in-vitro mutagens was clarified. Members agreed that figure 2 should clearly state the circumstances under which it would be appropriate to proceed to stage 3 (Assessment of germ cell mutagenicity). Discussion Stage 2 14. Members agreed to delete reference to assessing micronuclei with whole chromosomes by size. Members agreed that the occurrence of significant toxicity could be used as a measure to indicate that the chemical had reached the bone marrow and it was not necessary in such instances to measure bone-marrow toxicity directly (i.e. consideration of the ratio of polychromatic to normochromatic erythrocytes). Members agreed that a reference to the necessary expertise required to undertake stage 2 tests should be made in the text. Members agreed that there was no advantage in undertaking an in-vitro UDS assay in rat hepatocytes as a preliminary test before an in-vivo rat liver UDS assay. It was agreed that table 1 of the fourth draft should be amended to provide a clear statement on acceptability of each assay and a concise summary of the advantages and disadvantages. There was a need for the table and text to clarify the role of DNA binding in stage 2. It was recommended that a statement on use of Accelerator Mass Spectrometry (AMS) be included in the document. The summary section for stage 1 needed to be amended to reflect these changes. Stage 3 (Germ cell assays) 15. Members agreed the introduction section needed to be reordered to clarify when tests for germ cell mutagenicity should be undertaken (i.e. only when a risk assessment is required for in-vivo somatic cell mutagens). It was also necessary to clarify that only a proportion of in-vivo somatic cell mutagens could be demonstrated to also be germ cell mutagens. Figure 3 should be amended accordingly to clearly state when germ cell testing should be undertaken and to specify that data on heritable effects should only be provided in cases where there was strong justification for such studies. 16. Members agreed that the subtitles given in the document for stage 3 should follow a similar pattern to the rest of the guidelines. Studies to provide information on DNA damage to germ cells 17. Members considered that the title should reflect the need to provide genotoxicity or mutagenicity data. There was a need to consider the information provided in stage 2 before designing a test strategy for stage 3. Members agreed that information on the need to test aneugens in stage 3 needed to be incorporated into the text. Qualitative/Quantitative data on heritable effects 18. Members asked for a number of editorial changes, particularly to reflect that qualitative data on heritable effects could be obtained form morphological examination of clastogenic effects at all sperm stages. Summary stage 3 19. Members asked for appropriate changes to be made to this section to reflect the discussion of stage 3 tests. It was noted that there was currently no methodology for the assessment of aneuploidy in offspring. Additional Topics 20. The Committee agreed that this section should be deleted from the current guidelines and replaced by an overall summary of the strategy. It was agreed that separate papers should be produced to consider the subject of Mutational Signatures, Evaluation of mutagenicity assays and Risk Assessment of mutagens. The basic approaches used in the current drafts were acceptable but there was a need to provide detailed authoritative advice on each subject. Procedure for consultation 21. Members agreed that a revised document should be forwarded to professional societies in the UK, to European and UK regulatory Committees and Authorities for comment. It was noted that several regulatory agencies were reviewing their strategies for mutagenicity testing such as the EU Scientific Committee for Food and the strategy for testing new substances. Thus it was an appropriate time for the Committee's guidelines to be considered in these review processes. . A discussion meeting with UK professional societies should take place in May 2000 in order that comments could be incorporated into the guidelines. Members agreed that the guidelines should be finalised by the October 2000 meeting in order to maximise the input into the reviews of regulatory testing strategies. It was noted that the new COM which would meet for the first time in May 2000 would be responsible for taking forward and finalising the guidelines but the input of all members would be acknowledged. ITEM 6: DI-ISOPROPRYL NAPHTHALENE 22. No interests were declared. 23. Members were reminded that the solvent Di-isopropylnaphthalene(s) (DIPN) had been identified in samples of food packaging materials made from recycled board. DIPN had also been detected in some samples of food contained in packaging made from recycled board. DIPN was manufactured by Rÿtgers Kureha Solvents GmbH (RKS) and supplied to the printing industry. The Committee was told that recycled paper, used in paper and board manufacture, may include carbonless and thermal copy papers from office waste, in which DIPN is used as the solvent for the ink system. DIPN may not be completely removed by the treatment of the recycled fibres and may be present in the finished board and thus potentially able to migrate into food. The COT was considering the results of these surveillance investigations and concluded that the toxicological information on DIPN was inadequate. The COT recommended that additional mutagenicity data together with other toxicological data were required. 24. Members were informed that a number of mutagenicity studies using DIPN had been assessed by the COM secretariat. DIPN was negative in two bacterial mutation assays using a number of strains of Salmonella typhimurium and Escherichia coli (WP2 uvrA) and was negative in metaphase analysis in CHO cells, although the latter was inadequately conducted. A negative in-vivo micronucleus assay in mice using the intraperitoneal route had also been reported. In response to the request for additional mutagenicity data, the manufacturers had elected to undertake a mouse lymphoma assay (MLA). The Committee had advised that this study had been inadequately undertaken but that equivocal results had been obtained at the May 1999 meeting. The Committee had asked for a repeat test. 25. The contract laboratory had now provided a further Mouse Lymphoma Assay. Members agreed that quality control of this study had been satisfactory. It was noted that evidence for a mutagenic effect had been obtained in the 3 hour trials both in the presence and absence of exogenous metabolic activation. There was evidence for a dose-response effect in the 3 hour trial in the absence of exogenous metabolic activation. No evidence for a mutagenic effect had been reported in the 24 hour trial in the absence of exogenous metabolic activation. The authors had discounted these new results on the grounds that positive responses had been seen only in the presence of high levels of cytotoxicity. 26. However the Committee felt that the results of the present test were comparatively similar to the previous test considered in May 1999. Overall there was evidence for an equivocal mutagenic response in two separate Mouse Lymphoma Assays. Members noted that there was no evidence for a mutagenic effect in the other assays that had been conducted and there were no structurally alerting features for DIPNs. It was agreed that a further review of the in-vivo micronucleus assay was required before any decisions regarding further testing could be reached. The Chairman and one member of the Committee agreed to review the relevant study and provide comments to the secretariat. Revised conclusions would be drafted in due course. ITEM 7: ANY OTHER BUSINESS 27. The Chairman and Secretariat thanked members for all the hard work and contributions to the work of the Committee over the previous 3 years. 28. The next meeting of the COM would be on 25 May 2000. ACTIONS
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