COMMITTEE ON MUTAGENICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT (COM)
MINUTES OF 20TH MAY 1999 MEETING
MUT/MIN/99/2
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COMMITTEE ON MUTAGENICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT (COM) MINUTES OF 20TH MAY 1999 MEETING MUT/MIN/99/2 |
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COMMITTEE ON MUTAGENICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT Minutes of the meeting held on Thursday 20 May 1999 at 10.30 am, in Room 136/7B, Skipton House, 80 London Road, Elephant and Castle, London SE1 6LW. PRESENT: Chairman: Professor J M Parry Members: Professor C Cooper Professor D Davies Professor MHL Green 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 C Fisher (MAFF-JFSSG) Dr A Smith (HSE) Dr Shillaker (PSD) In attendance: Dr J Shavila (DH - JFSSG) Mr P Mongelard (MAFF-JFSSG) Mr G Kowalcyzk (DH) AGENDA
ITEM 1: APOLOGIES FOR ABSENCE 1. Apologies for absence were received from Professor Newbold, Professor Ashby and Dr Bryant. Announcements 2. Members were reminded of the need to declare any interests. They were notified that the new lay member of the Committee was unable to attend this meeting due to procedural problems over her appointment. Openness 3. Members were reminded that in line with arrangements agreed over greater openness of Committee business, the minutes of meetings would be published on the Committee's Internet site approximately 1 month after finalisation. Members were informed that the Committee's discussions on confidential items were presented as an addendum to the minutes. The COM's conclusions on these confidential items would be placed on the Internet once finalised. Members noted that once the conclusions were agreed it would not be possible to make further amendments. However, members could request the revision of the statement or conclusions in light of new evidence or data. ITEM 2: MINUTES OF THE MEETING HELD ON 4TH FEBRUARY 1999 (MUT/MIN/99/1) 4. The minutes of the meeting held on 4th February 1999 were agreed subject to a number of minor typographical amendments detailed below. Item 2, paragraph 3, line 1 The minutes of the meeting held on 10 October 1998 was were agreed subject to a number of minor typographical amendments. Item 2 (Comet Assay), paragraph 4, line 2 The conclusions were agreed subject to revision of conclusion iii), "useful supplementary data on a case by case basis to compliment complement the in vitro..." Item 3 (TCDD), paragraph 10, line 4 The toxicological properties and potencies of PCDDs and PCDFs could all be related to the known effects 2,3,7,8-TCDD or TCDD (2,3,7,8 tetrachlorodibenzo[b,e][1,4]dioxin) through the use of toxic equivalency factors (TEFs). ITEM 3: DRAFT CONCLUSIONS FOR MEETING HELD ON 4TH FEBRUARY 1999 (MUT/99/19) 5. The draft conclusions on TCDD and ozone (MUT/99/19) were endorsed by the Committee. ITEM 4: MATTERS ARISING 4.1 Malachite Green 6. The Committee was informed that the COT had now completed its consideration of malachite green. A statement was agreed that incorporated the COM's conclusions and this was tabled for information. Matter arising not covered by later agenda items: 4.2 CS Spray 7. In response to a question concerning recent publicity, members were informed that a few police forces had historically not used CS spray in the UK. The COT were continuing their discussions regarding CS spray and hoped to finalise a statement at its July meeting. This will be circulated to the Committee for information in due course. ITEM 5: DI-ISOPROPYLNAPHTHALENE (DPIN) (MUT/99/18) 8. Confidential item: The minutes and conclusions on this item will be available when the COT has finalised its conclusions. ITEM 6: 3-MONOCHLOROPROPANE 1,2-DIOL (MCPD) (MUT/99/17) 9. 3-Monochloro propane 1,2,-diol (3-MCPD) can arise as a contaminant in food stuffs and may also be present in drinking water from the use of polyamine flocculants containing residual 3-MCPD. It was considered at the February meeting of the COM, where it was concluded that 3-MCPD was an in-vitro mutagen and should be regarded as having mutagenic potential in vivo. Members were informed that the Secretariat had now obtained a confidential copy of the in vivo bone marrow micronucleus report referred to at the February meeting. In addition, data from a colonic micronucleus test was available. The results of these two in vivo assays were summarised in paragraph 6-10 of the report and in Tables 1 and 2. Draft conclusions were provided in paragraph 12. The Committee was asked to advise on the newly available data. 10. Members were reminded that 3-MCPD has been evaluated by the EC Scientific Committee on Food (SCF) which had concluded that 3-MCPD was a genotoxic carcinogen. Regulatory action had already been taken by MAFF to eliminate or minimise exposure from food sources. With regard to its potential presence in drinking water, an opinion was sought from the COM and COC as to the carcinogenic risk, if any, associated with the use of certain flocculants containing 3-MCPD as a contaminant. Members were notified that the Drinking Water Inspectorate (DWI) would take an appropriate risk management strategy in line with the COM/COC recommendations. DWI were currently seeking to obtain information on the use of these flocculants in the UK water industry. The COC would reconsider carcinogenicity of 3-MCPD at their meeting on 24 June. 11. The Committee noted that negative results have been reported from a bone marrow micronucleus assay in mice using an oral dose of up to 120 mg/kg b/w and sampling of bone marrow at 24, 48 or 72 hours post administration. The authors stated that higher doses would result in significant weight loss and mortality. Regarding the new bone marrow assay, the Committee noted that there was no evidence for a reduction in the PCE/NCE ratio, and thus there was no evidence to show that exposure of the bone marrow to the test material and its metabolites had occurred. 12. The Committee agreed that no conclusions could be drawn from the investigation of colonic micronuclei in mice in view of the limited database available for this assay. Members agreed that further negative results from 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 was not expressed in-vivo. The Committee agreed that it was prudent to assume that 3-MCPD was an in-vivo mutagen. ITEM 7: THE EUROPEAN CHEMICALS BUREAU (MUT/99/27) & HSE'S CONCERNS RE MUTAGENICITY DATA (MUT/99/25) 13. A short presentation was given by Dr Andrew Smith (HSE) about the role of the European Chemicals Bureau (ECB) within the European Commission. As part of the Joint Research Centre (Ispra, Italy), the ECB provided a technical secretariat function mainly to DGXI (environment) in the following EU-wide areas of regulatory activity: Classification and Labelling of Dangerous Substances; Notification of New Substances; Risk Assessment of Existing Chemical Substances; Export/Import Issues; and Biocides. There were several areas in common with DG XXIV (which has a mandate to develop a consumer policy and contribute to health protection and food safety within the EU) and its expert scientific committees. The ECB did not undertake laboratory-based research itself. 14. With regard to mutagenicity evaluation, members were told that the European Commission's Working Group on Classification of Dangerous Substances had considered the extent of evidence needed for a Category 2 classification for mutagenicity (may cause heritable damage). In this respect, classification could be justified by evidence from in vivo somatic mutation studies together with toxicokinetic studies showing widespread distribution of a substance to tissues and/or its presence in germ cells. Other issues considered recently included the assessment of studies which do not meet current regulatory standards, and the use of intraperitoneal administration as an appropriate route for hazard assessment. There was also an ongoing consideration of testing strategy and classification criteria for aneugens, and the evidence required to demonstrate a threshold for such substances. 15. Dr Smith also outlined significant general mutagenicity problems that HSE had encountered in its regulatory work over the last few years. It was thought that this would help in the discussions on updating the COM guidance with regard to methodology, strategies for testing and interpretation of data. Members heard that the ECB would shortly start work on the revision of the EU strategy for investigating mutagenicity in the context of risk assessment of new and existing chemical substances. 16. The Committee thanked Dr Smith for providing written comments on issues that had arisen from the general strategy adopted by the EU for mutagenicity testing for new industrial chemicals. The document clearly showed that the revision of the COM guideline should include a section on the use of pH adjustments in in-vitro tests, testing at concentrations that lead to precipitation and the applicability of in-vivo testing of corrosive substances. Some reference to specific problems with materials that were difficult to test (such as metal salts, dusts and fibres) was required. The Committee would also need to express a view on structure activity relationships. Other aspects covered in the HSE document had been previously considered by the COM and included: the value of non regulatory tests (e.g. Comet assay, new transgenic models), in particular the value of negative results in such tests; the need for an in-vitro UDS assay before undertaking an in-vivo UDS assay; polyploidy and issues concerning the identification of germ cell mutagenicity. 17. Members confirmed their reservations regarding the testing strategy in the ICH guidelines for pharmaceuticals, in particular, the role of the mouse lymphoma assay for detecting clastogens. However, they noted that these guidelines might be used as a basis for other areas of regulatory activity. With regard to the strategy for new industrial chemicals, HSE had highlighted the choice of the 4th assay (i.e. after Ames, in-vitro chromosome aberration, mammalian cell assay) as being particularly difficult. It was necessary to establish some guideline criteria for determining whether an in-vitro or in-vivo assay should be required as the 4th test. Members confirmed that this would preferably be an in-vivo test. ITEMS 8 - 12 18. The remaining items of this meeting all concerned the updating of the COM guidelines. Members agreed that the revised document should focus on the strategy for testing and the interpretation of mutagenicity studies. ITEM 8: BIOLOGICAL RELEVANCE OF IN VITRO POSITIVES IN MAMMALIAN ASSAYS; EXPERIENCE WITH NEW ACTIVE INGREDIENTS IN PHARMACEUTICALS (MUT/99/21) 19. Members considered the paper by Dr Lutz Muller, which discussed the issue of positive results in mammalian chromosome aberration assays that were subsequently considered not relevant to the whole animal. The document was based on results obtained with pharmaceuticals, but had implications for other chemical types. The paper asserted that there were a large number of artefacts generated from in-vitro tests. 20. With regard to the specific parts of the paper, members noted comments regarding the difficulty of testing substances at cytotoxic concentrations, but agreed that this was necessary particularly for the detection of weak mutagens. It was important to recognise that the in-vitro positive data represented only the first stage of a testing strategy. Artifactual positives would be revealed by negative in-vivo data and could be discounted in many cases. Members agreed that a revised COM guideline should include a reference to chemicals giving positive results using in vivo tests but not in the recommended screening battery of three comprehensive well conducted assays. The Committee agreed that other issue raised in MUT/99/21 with regard to in-vivo assays would be covered in detail in the revision of the COM guidelines (i.e., the role of the liver UDS assay, tests in transgenic animals, the Comet assay, and DNA adduct investigations in mutagenicity testing strategies). Members agreed that the use of DNA adduct studies was critically dependent on the availability of supplementary data e.g. supporting ADME data. ITEM 9: REPORT OF THE WASHINGTON WORKSHOP ON GENOTOXICITY TEST PROCEDURES (MUT/99/20) 21. Members noted the report on the Washington workshop. Seven expert task groups met and made recommendations to the plenary meeting on the mouse lymphoma assay, the in-vitro micronucleus assay, the in-vivo micronucleus assay, the comet assay, transgenic mutation assays, photochemical genotoxicity and DNA adducts/binding assays. This would be helpful in considering which additional assays to include in the Committees revised strategy of testing. It was noted that the in-vitro micronucleus task group had come to somewhat disappointing conclusions regarding agreement on methodology. The mouse lymphoma group had been particularly well organised and constructive. Some remaining difficulties had been highlighted, for example, the value of the 24 hour treatment time, but work had been agreed to resolve these issues in the next year or so. Members noted that a report of this meeting would be sent to the OECD Secretariat for consultation with regard to updating guidelines. ITEM 10: UPDATING OF THE GUIDELINE FOR THE EVALAUION OF CHEMICALS FOR MUTAGENICITY: strategy for testing 22. Members agreed that the draft document was a good basis for discussion. It was agreed that sections from other chapters could be incorporated into this document. It was considered necessary to alter the title of the document to "Guidelines on the Strategy for Testing and Evaluation of Mutagenicity of Chemicals" to reflect the change in emphasis to both strategy and methodology. The Secretariat was asked to draw up a plan of the revised section including, allocated tasks and deadlines for action. Members noted that the document would be required by mid September, so that it could be considered at the next COM meeting and to allow consultation with professional bodies. With reference to the text, key areas for further consideration included: the selection of in vitro mutagenicity assays after a bacterial mutation assay had been completed, guidance for the selection of a second in-vivo somatic cell assay, the appropriate use of specialist non-validated studies to support a package of data and a section on risk assessment. Members agreed that worked examples would be useful. ITEMS 11 & 12: UPDATING OF THE GUIDELINE FOR THE EVALUATION OF CHEMICALS FOR MUTAGENICITY: monitoring human populations for mutational change and implications for carcinogenesis 23. Members agreed to consider the information from these documents when a revised strategy and evaluation document was available, but the emphasis and priority now would be to agree the "Strategy for Testing and Evaluation" document. ITEM 13: ANY OTHER BUISNESS 24. Members were informed that Dr Denise Robinson would make a presentation to the COC (24th June) on the use of transgenic animals for carcinogenicity testing. Members were welcome to attend. ITEM 14: DATE OF NEXT MEETING 25. The next meeting of the COM will take place on 7th October 1999. ACTIONS
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