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Minutes of the meeting held on Thursday 12 October 2000 at 10.30 am, in Room 136/7B Skipton House, 80 London Road, Elephant and Castle, London SE1 6LH. Present:
ITEM 1: APOLOGIES FOR ABSENCE 1. Apologies for absence were received from Professor J Ashby and Dr R Shillaker (Mr T Holmes attending). Announcements 2. The Chairman introduced Dr Diane Benford (FSA) who is replacing Dr Greig as secretary to COT. 3. Members were reminded of the need to declare any personal and non-personal interests before the discussion of items. ITEM 2: MINUTES OF THE MEETING HELD ON 25 MAY 2000 (MUT/MIN/2000/2) 4. Minutes were agreed subject to one minor typographical change. ITEM 3: MATTERS ARISING 3.1 Carbendazim: thresholds for aneugenicity 5. The committee recalled that a statement for PSD on thresholds for aneugens such as carbendazim had been agreed in the light of the recent discussions by the EC mutagenicity experts on labelling and in particular the study by de Stoppelaar et al (Mutagenesis 14, 621-631, 1999) on germ cell effects of carbendazim. The committee had considered that this study did not provide evidence for a lower threshold for aneuploidy in germ cells compared to somatic cells. Members suggested that a more appropriate study would have been a comparison of the germ cell effects with a dose response study in the rat measuring micronuclei induction in polychromatic erythrocytes in the bone marrow of rats using a similar protocol to that of de Stoppelaar. A brief summary of a preliminary report of an appropriate study was summarised in MUT/2000/16. 6. Members agreed that the available information suggested that in a preliminary study, carbendazim was mutagenic to the bone-marrow of rats given an oral dose of 150mg/kg bw. The committee agreed that results of the follow-up study to investigate the effects of carbendazim on the bone-marrow in large group sizes was required before a final conclusion could be reached. The committee reaffirmed its previous conclusion that there is no evidence to suggest a lower threshold for aneuploidy in germ cells compared to somatic cells and agreed that there was no need to modify the advice to the Advisory Committee on Pesticides. 7. Members were told that the EU Standing Committee on Plant Protection Products was to review the significance of the EU discussions on classification and labelling of carbendazim with respect to the setting of an ADI and AOEL for this pesticide. ITEM 4: REVISED COM GUIDANCE ON STRATEGY OF TESTING CHEMICALS FOR MUTAGENICITY (MUT/2000/15) 8. Members noted the revised text (MUT/2000/15) incorporating the main comments received in the consultation document, and in particular those made at the UKEMS/IGG meeting in May. There was further discussion of the draft COM guidelines at the UKEMS meeting in July. The main points arising from the consultation process were summarised in 4 overheads that were used at the Swansea meeting. 9. Members of the previous COM who were not current members had also been asked to provide comments and these had been tabled. 10. The Chairman asked members to forward detailed editorial comments to the secretariat. He asked the committee to discuss each paragraph in turn. Members agreed the following changes. Introduction Para 3 Members agreed that the Medicines Control Agency should be cited in the preface. Para 9 Members agreed that although some tubulin inhibiting compounds had been tested for carcinogenicity, the data were relatively old. It was noted that new information on the carcinogenicity of aneugens might become available through the NTP. Para 12 Members agreed that specific reference to the negative gene mutation studies with carbendazim should be omitted as more recent studies might be available. General Principles Para 13 Members agreed that human exposure would be low to a proportion of low production volume chemicals. It was also noted that the strategy for stages 2 and 3 was more complex than stage 1. The committee agreed that all the figures should contain colour elements to facilitate interpretation of the strategy. Para 18 Members agreed that reference to the purity of test substances and the influence of toxicokinetics on the conduct and results of mutagenicity tests should be cited in this paragraph. Stage 1 Para 21 Members agreed to delete reference to carbendazim. Para 22 Members agreed that if there were indicators of aneugenicity (eg. induction of polyploidy) then this should be confirmed using appropriate staining procedures such as FISH or chromosome painting to highlight alterations in the number of copies of selected chromosomes. When cell lines were employed it was important that only those with a stable chromosome number were used. Reduced hypotonic treatment might be necessary to eliminate artifactual changes in chromosome number. Only the detection of hyperploidy (gain on number) could be considered as a clear indication of aneuploidy. Members agreed to delete the last sentence of this paragraph. Members agreed that the order of paragraphs should be rearranged so that paragraphs 31 & 32 came immediately after paragraph 27. Stage 2 Para 35 Members agreed that information on the toxicokinetic as well as metabolic profile should be provided when considering stage 2 testing. Members agreed that table 1 should be moved to the end of paragraph 49. It was agreed that reference to covalent binding should note that a variety of methods can be used such as those involving radioactive (eg 14C-) or isotope measurements. It was noted that very small amounts of material (nanogrammes) could be detected with AMS. Stage 3 Para 57 Members agreed that this paragraph should be redrafted to clearly state the variety of approaches which could be used including clastogenicity in spermatogonical cells and the use of trangenic animals for the investigation of mutagenic effects in germ cells. Information on the induction of DNA could be obtained from a number of methods considered in stage 2. Members agreed that paragraph 61 (summary) also needed to be amended. Members agreed that where negative results were obtained in a stage 3 assay it would be appropriate to consider all the available information in a compound before drawing a conclusion that the chemical was not a germ cell mutagen. Appendix A Members agreed that the statement in appendix A needed to be simplified so that if there were an increase in centromeric positive microneuclei then the compound should be considered as a clastogen. If there was an increase in centromeric positive micronuclei then the compound should be considered as aneugen. References Members agreed that the references needed careful checking to eliminate duplications and references no longer cited. Publication Members agreed that the guidelines should be published in both hard-copy and internet form by the end of 2000. ITEM 5: MUTAGENICITY OF MCPD; new in vivo data (MUT/2000/14) 11. Dr Julie Clements declared a non-personal, non-specific interest. The Chairman stated that she could take part in the discussion of this item but not during the consideration of conclusions. 12. MCPD was considered by the COM in 1999. At that time the Committee concluded that it would be prudent to consider that MCPD had in-vivo mutagenic potential, but agreed that further data from an in-vivo liver UDS assay would provide adequate reassurance that the activity seen in-vitro was not expressed in-vivo. Additional data, commissioned by the Drinking Water Inspectorate were examined The new studies consisted of 2 in-vivo studies, a rat bone marrow assay and a liver UDS assay. 13. Members agreed that the two new studies had been adequately undertaken. Members noted that the highest dose used in the main UDS study (100mg/kg/bw,p.o) did not result in any significant toxic effects, but had been shown in the preliminary study to be very close to the lethal dose of 3-MCPD in rats. Members agreed that the highest practicable dose (60mg/kg/bw,p.o) which did not cause lethality had been used in the bone-marrow micronucleus assay in rats. 14. The committee considered a draft revised statement and agreed that 3-MCPD had no significant in-vivo mutagenic potential. Members agreed that the statement should contain a section considering the metabolism of 3-MCPD in mammals in greater detail. Although there was evidence that 3-MCPD could be metabolised to a reactive intermediate (glycidol), the new studies suggested that reactive metabolites were not formed in the tissues where genotoxicity had been assessed. ITEM 6: MUTAGENICITY OF ALCOHOLIC BEVERAGES: an update (MUT/2000/12) 15. The COC had recently published an updated statement on the relationship between consumption of alcoholic beverages and breast cancer. The COC had recommended that COM update its 1995 statement on the mutagenicity of ethanol, acetaldehyde and alcoholic beverages. A paper had been considered at the last meeting of the COM when conclusions on ethanol and acetaldehyde were agreed, but the committee felt that further consideration was needed on the data on alcoholic beverages before final conclusions would be drawn. MUT/2000/12 presented a review of the limited amount of data on the mutagenicity on alcoholic beverages published since 1995, and also provided the data on which the previous conclusions were drawn. At that time in 1995, the committee placed most weight on a study by Jane Cole et al on the relationship between hprt mutant frequency and intake of alcoholic beverages in humans. This demonstrated no association. There were now two further studies available which provided limited information on this aspect. Again both showed no association (indeed an inverse relationship in one case). 16. Members agreed that the consumption of alcoholic beverages does not present any significant concern with respect to their mutagenic potential and agreed there was no need to alter the conclusions reached in 1995. A short statement would be drafted for publication on the internet. ITEM 7: ANY OTHER BUSINESS 17. Members were asked to consider the papers forwarded by Dr Baban and colleagues concerning the apparent increases in abortions and the congenital malformation in the Halabja region, Northern Iraq (MUT/2000/17). Members were asked to forward comments to the chairman. ITEM 8: DATE OF NEXT MEETING: 18. Thursday 8th February 2001. ACTIONS
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