Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM)
Minutes of the meeting held on 14th December 1999
MU/MIN/99/4
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Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM) Minutes of the meeting held on 14th December 1999 MU/MIN/99/4 |
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Minutes of the meeting held on Tuesday 14th December 1999 at 10.30 am, in room LG17, Wellington House, Waterloo, London Present: Chairman: Professor J M Parry Members: Dr P Bryant Professor J Ashby Professor C Cooper Professor D Davies Professor MHL Green Ms M Langley Dr D Tweats Dr S Venitt Secretariat: Dr R J Fielder (Scientific) Mr J Battershill (Scientific) Mr M Al-Derzi (Minutes) Mr K N Mistry (Administrative) Assessors: Mr A Browning (VMD) Dr A Smith (HSE) Dr C Steele (MCA) In attendance: Miss J Andrews (DH) Mr D Renshaw (FSP(D)) CONTENTS
ITEM 1: APOLOGIES FOR ABSENCE 1. Apologies for absence were received from Professor Newbold, Dr P Tromans (National Assembly of Wales), Dr Shillaker (PSD) and Dr Fisher (MAFF). Announcements 2. Members were reminded of the need to declare any interests before discussion of items. 3. The Chairman welcomed Dr C Steele as the new assessor from the Medical Control Agency (MCA). ITEM 2: MINUTES OF THE MEETING HELD ON 7TH OCTOBER 1999 (MUT/MIN/99/3) 4. Members agreed the minutes subject to some editorial changes. The Committee made several amendments to the minutes on AMS (MUT/99/39). ITEM 3: MATTERS ARISING Hydroquinone and Phenol 5. Members were informed that the revised conclusions have yet to be drafted and would be circulated in time for the February 2000 meeting. Use of AMS to measure low levels of adducts 6. Members were informed that the COC considered AMS at their meeting in November and agreed with the COM comments on the MAFF sponsored work, but asked that the covering paper be expanded to consider the most recent published literature on the use of this technique. The Committees agreed to reconsider its conclusions on AMS when a more comprehensive literature review was available. ITEM 4: GUIDANCE ON THE STRATEGY FOR TESTING AND EVALUATION OF MUTAGENICITY OF CHEMICALS (THIRD DRAFT) [MUT/99/45, 43, 44, 28, 32, 34] 7. The Committee considered the second draft of the 'Guidance on the Strategy for Testing and Evaluation of Mutagenicity of Chemicals' at its October meeting. The third draft (MUT/99/45) incorporated the substantial number of comments made at the October meeting. 8. The Committee was provided with a brief outline of the main changes to the third document. Members noted that a number of additional background papers had been submitted (MUT/99/43, 44, 28, 32 and 34) and agreed to consider information in these papers at appropriate times during the discussion of MUT/99/45. 9. The Committee made the general comment that they wished to see a glossary section included into the finalised strategy document. The following comments were made on the text of the third document. 10. Introduction: Members commented that although the remit of the Committee was to provide advice on mutagenic risk, in practice the bulk of its work related to the assessment of mutagenic hazard (the inherent ability of a chemical to cause mutation). This should be reflected in the introductory paragraph. They also requested that a definition of risk and hazard be included and that it would be appropriate to consult the Special Issue of Mutation Research (464, 2000, pages 1-159) relating to thresholds of genotoxins. 11. General principles of the testing strategy: Redraft section and clarify the rationale for using animals in mutagenicity testing with deletion of reference to ethical justification. Emphasise that dose selection for in-vivo mutagenicity studies should be based on the determination of the maximum tolerated dose (MTD), with consideration given to target organ/tissue specific toxicity. Stage 1: In-vitro screening for mutagenic potential 12. Introduction: Revise the section and figure 1 to reflect that for most compounds 3 tests are recommended. Indicate that in those cases where there will be insignificant human exposure the first 2 tests may only be appropriate. 13. Discussions stage 1 tests: Ensure that the rationale behind the change in strategy to detect aneugenicity is included. Provide examples of aneugens (spindle inhibitors and MBC's). Indicate that the Committee believes that routine screening for aneugenicity is possible using the in vitro micronucleus assay with centromeric staining. Alternatively, assays using metaphase analysis with chromosome painting can be used. Highlight the equivalent status of these two assays for the detection of both clastogenic and aneugenic activity. 14. The role of the mouse lymphoma assay (MLA): The revised section should emphasise that in addition to detecting gene mutations in mammalian cells, the assay also provides information on clastogenicity. However, there is insufficient data available to assess the ability of the MLA to detect aneugens. 15. Summary stage 1: Reference should be made to figure 1. Stage 2: In-vivo somatic tests 16. Introduction: Members discussed stage 2 in detail and recommended redrafting of the text and figure 2. They agreed that before undertaking in-vivo studies it was important to pause and consider the available information on the nature of the chemical, the results obtained in stage 1 and any information available on its metabolic profile. 17. The Committee was presented with mutagenicity data that highlighted limitations of the Comet assay for detecting bulky adducts. Data was presented on Dimethyldibenzo[c,g]carbazole (DMDBC), a potent mouse hepatocarcinogen, which was clearly active in the liver UDS. Positive results were also reported in the liver of mice in transgenic and DNA adduct studies. However, the Comet assay showed limited ability at detecting the activity of DMDBC in this organ. Only marginal responses were reported in the Comet assay at dose levels that were clearly positive in the UDS and which produced DNA adduct formation. It was suggested that the Comet assay was not suitable for the investigation of compounds that form bulky adducts with DNA, as these adducts were removed by the intact nucleotide excision repair mechanism of the cell and thus were not detectable in this assay. The slight response reported in the Comet assay was thought to reflect incomplete repair intermediates (apurinic sites) resulting from an impairment of the DNA repair mechanism. The Committee therefore revised its previous opinion on the Comet assay, indicating that further data was required before it could be considered to have equivalent status to the UDS assay. 18. Discussion stage 2 tests: Indicate that the in-vivo bone marrow micronucleus assay is the first choice in-vivo assay for compounds positive in one or more tests in stage 1, unless the available information on the compound (such as tissue distribution) gives indications to the contrary. 19. In cases where a compound was negative in the bone marrow micronucleus assay and positive in stage 1, members reiterated the view in their earlier guideline that additional testing was necessary in other tissue(s) to evaluate whether activity was expressed in-vivo. They noted that the selection of an appropriate test at this stage would be dependent on the structure of the chemical, the results obtained in the stage 1, and any information available on its metabolic profile. No single assay could be recommended for every circumstance and therefore the Committee agreed that it would be helpful to include a table outlining the advantages and disadvantages of each assay. These methods could then be briefly mentioned in the text. Justification for the choice of test should be given. Consideration of this area would be facilitated by a scientific rationale as to why activity seen in-vitro was not expressed in-vivo. 20. Summary stage 2 tests: Redraft section to indicate clearly when stage 2 tests are required, highlight the need for flexibility and consideration of the available information on the compound before testing. 21. Members concluded that the current section on transgenic assays was too negative and that a wide range of studies now suggested that transgenic assays may play a valuable role in the analysis of tissue specific effects. Stage 3: Evaluation of germ cell mutagenicity 22. Introduction: Redraft section and figure 3. The Committee confirmed that for most compounds identified as in-vivo somatic cell mutagens no further testing would be required. In cases where studies of germ cells activity can be justified (i.e. where there was a need to assess the risk of germ cell mutation) based on the properties of the compound, it usage pattern and anticipated human exposure, consideration should be given to the level of detail required. It was pointed out that this could range from information on germ cell hazard, to qualitative and or quantitative risk estimates of germ cell activity. 23. In vivo test in the intact germ cell system: Members commented that information on whether a compound presents a hazard as a germ cell mutagen can be obtained from a range of assays including measurement of DNA adducts, micronuclei and clastogenicity in spermatogonia, or the dominant lethal assay. They confirmed that these assays do not provide information as to whether the effects seen are heritable in future generations. In the case of the dominant lethal assay, the Committee recommended the use of the sub-acute dosing regime and single mating period in view of the very large number of animals used in the single dose multiple mating approach. 24. Indicate that qualitative information on the risk of heritable effects may be obtained by measuring chromosome aberrations and translocations in spermatocytes. 25. Summary stage 3: Clearly outline the revised strategy for the assessment of germ cell mutagenicity. 26. Members were asked to provide further comments particularly on the remainder of the third draft not discussed at this meeting by the end of the year. ITEM 5: PROPOSED ISO METHOD FOR THE DETERMINATION OF THE GENOTOXICITY OF WATER AND WASTE WATER USING SALMONELLA/MICROSOME TEST (MUT/99/46) 27. Members were asked to provide written comments on this paper before the next meeting ITEM 6. PAPERS FOR INFORMATION 28. A paper by Schmezer and Eckert (1999) was presented to the Committee for information (MUT/99/47). ITEM 7. ANY OTHER BUSINESS 29. There were no other items of business. ITEM 8. DATE OF NEXT MEETING 30. The next meeting will take pace on the 3rd February 2000.
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