MINUTES - 9TH JANUARY 2002
Present:
| Chairman: Professor P Farmer |
Members: Dr J Clements Professor C Cooper Dr N Gooderham Ms M Langley Dr I Mitchell Professor D Phillips Professor D Tweats |
Secretariat: Dr R J Fielder (Scientific DH) Dr D Benford (Scientific FSA) Mr J Battershill (Scientific DH) Mr S Robjohns (Minutes) Mr K N Mistry (Administrative) |
| Assessors: Dr D Andrew (PSD) Mr M Costigan (HSE) |
In attendance : Professor P Blain (Chair COC) Dr S Kennedy (COC) Professor J Parry (Adviser University of Wales, Swansea) Dr K Fuller (HSE) |
CONTENTS
| Item | Paragraph |
|
1. |
Announcements / Apologies for absence | 1-2 |
2. |
Minutes of meeting held on 11 October 2001 | 3 |
3. |
Matters arising | 4-5 |
| 4. | Consideration of Dichlorvos | 6-30 |
| 5. | Any other business | 31 |
6. |
Date of next meeting | 32 |
Item 1: Announcements/Apologies for absence
1. The Chairman reminded Members to declare to declare any interests that they may have in items of business. A copy of the list detailing companies, data holders and/or approval holders for pesticides containing dichlorvos was tabled.
2. This extraordinary meeting of COM has been convened to consider expert witness statements submitted to the high court during the judicial review (AMVAC Chemical UK Ltd v DEFRA/DTLR) held between 5-9 November 2001. In addition a number of further documents had been submitted to the HSE and PSD and had been provided to members for review.
Item 2: Minutes of the meeting held on 11 October 2001
3. These minutes were agreed subject to minor typographical amendments.
Item 3: Matters arising
4. A statement on the Syrian Hamster Embryo Cell Transformation Assay : Results from ILSI/HESI Research Programme was forwarded to ILSI/HESI on 7 January 2002. The ACT Steering Committee was to meet on 10/1/2002 and COM Members would be updated on the outcome of their deliberations in due course.
5. The Chairman asked that all other matters arising from the minutes be discussed at the next meeting of COM on 7 February 2002.
Item 4: Review of Dichlorvos: COM consideration of witness statements submitted during the judicial review and to regulatory authorities up to 4 January 2002.
6. The Chairman recalled that Dr Clements and Dr Benford (FSA Secretariat) both declared a lapsed non-personal non-specific interest at the 26 April 2001 meeting. Dr Clements noted that the consultancy group within Covance had received a telephone call requesting information on mutagenicity testing strategy for dichlorvos. The Chairman ruled that Dr Clements could take part in the proceedings but he would review this if Covance were contracted to undertake testing of dichlorvos in the future.
7. Members were given an overview of the events following the COM meeting of the 23 July and of the outcome of the Judicial review. Mr Justice Crane handed down his judgement on the case held in the High Court between AMVAC Chemicals UK Ltd (Claimants) and Secretary of State for Environment, Food and Rural Affairs (DEFRA) and Secretary of State for Transport, Local Government and Regions (DTLR) (Defendants) on 3rd December 2001. Essentially the Claimants won on one of the three issues they had raised namely that the decision to suspend pesticide approvals was flawed in relation to the amount of notice given to the claimant and the decision was therefore quashed. Mr Justice Crane saw no reason why those advising ministers should not review their advice, taking into account all the Claimants' submits, without significant delay.
8. The Chairman told members that the Committee had therefore been asked to ascertain whether the new information submitted to the court and to regulatory authorities up to 4 January 2002 warranted any revision of the COM statement on dichlorvos. This information essentially comprises exhibits from a number of independent scientific experts, a number of papers on the generic issues of evaluation of various types of mutagenicity assays and questions regarding the specification of the test material used in the Plesta V et al (Cancer Letters , 146, 155-160, 1999) Mutaä Mouse study and an evaluation of some historical control pathology data from the laboratory where the 1989 NTP bioassays had been undertaken.
9. The Chairman asked Members for general comments on the new information with regard to the mutagenicity and carcinogenicity evaluation of dichlorvos.
10. A criticism of the Plesta study had been that the test material used had not been subject to analysis and it was not possible to ensure that dichlorvos had been tested. Members noted that this study had been part of an EU project to evaluate alkylating agents. The Committee discussed this aspect of the reporting of the Plesta study in detail and agreed that it was unusual to publish results without giving information on the source of the test material. The Committee had often evaluated published papers where methods did not conform to Good Laboratory Practice in the past and each study was assessed on a case-by case basis. In this instance there was no reason to suspect that the authors had not used dichlorvos and it was noted that the test solutions were prepared freshly before dosage. Members confirmed their view that it would have been valuable if DNA adduct measurements had been undertaken following repeated dosing of dichlorvos in this study. Members noted the dose level used in the repeat dose experiment (11 mg/kg bw (ca 50% of LD50) was reported by the authors to be "poorly tolerated" and although some lethality would be expected, members felt that the observed mutagenicity seen in the Plesta study had been observed in some animals at non-lethal doses. Members noted the proposals that the mutagenic effects seen in the liver in the Plesta study were due to a toxic mechanism and recalled that a proposal that oxidative damage in the liver induced by dichlorvos had been presented to the Committee during its previous discussions. However no such supporting data specific to dichlorvos had been presented and in the absence of such data the Committee reaffirmed that the mutagenic effects seen in the Plesta study using the intraperitoneal route of administration were relevant to hazard assessment.
11. Members noted that a number of comments had been made with regard to a possible threshold for the mutagenicity of dichlorvos. Thus it was proposed that mutagenicity only occurred at dose levels which saturated the detoxification enzymes. Members did not concur with this view and recalled that the addition of exogenous metabolising fractions to in-vitro mutagenicity tests using Salmonella strains had not abolished all of the mutagenic activity. There was evidence that some of the metabolites of dichlorvos (eg dichloroacetaldehyde) were potentially reactive. On a general point members reaffirmed their view that in the absence of specific investigations concerning mechanisms and possible thresholds, the prudent assumption was that there was no threshold for in-vivo mutagens. Members recalled that sufficient data had been provided to determine the existence of a threshold for aneugens that acted by inhibition of the mitotic spindle and in the case of rapid detoxification of hydroquinone after oral administration. Such data had not been provided in the case of dichlorvos.
12. Members reaffirmed their views concerning the conduct and results of the in-vivo UDS assay in the forestomach (Benford DL et al Toxicology, 92, 203-215, 1994) vis; that it was not possible to exclude a genotoxic effect of dichlorvos in the forestomach from these results because the assay appeared to be insensitive as judged by the small increases in UDS seen in the positive control (MNNG) group.
13. The Committee noted the criticisms raised regarding the use of unvalidated tests to reach a conclusion that dichlorvos was a site-of-contact mutagen. The COM had recognised that the investigation of site-of-contact mutagenicity would present difficulties and would entail the use of test methods that had not been validated to internationally accepted standards (e.g. OECD). The COM guidance recognised that such situations needed to be approached on a case-by-case basis. The current COM guidance (published in December 2000) listed a number of non-standard test methods that could be used including the use of transgenic animal models.
14. Members concluded that the information available to the Committee to assess the potential for site-of-contact mutagenicity for dichlorvos was very limited, namely in-vivo skin micronucleus test, the intraperitoneal Muta™ mouse study and forestomach UDS assay. The design of all these studies had limitations that had been noted by the COM. However in the absence of better data, the results of these tests could not be dismissed.
15. The Chairman asked COC members to comment on the carcinogenicity issues.
16. COC Members noted that the absence of a full evaluation of all the carcinogenicity studies had been commented upon in several statements presented to the court. It was noted that the Advisory Committee on Pesticides (ACP) had evaluated all of the carcinogenicity data and hence the subject had not been referred to the COC for a full evaluation. The COC pathologist had provided an evaluation of the the NCI 1977 and NTP bioassays following a tabulation of the data from these bioassays presented to the ACP which had suggested that the skin and oesophagus might be potential target sites. Following review, it had been concluded that there was no evidence regarding a carcinogenic effect of dichlorvos on the skin but when the old 1977 NCI and 1989 NTP bioassays in mice were considered together there was limited evidence for an effect on squamous epithelium of the forestomach and oesophagus in mice (taking into account the limited number of oesophageal tumours reported). This view was reaffirmed.
17. COC Members reviewed the available information from the carcinogenicity bioassays reviewed in the HSE review (submitted to ACP in April 2001) and in the documents submitted to the court and most recently to the regulatory authorities as part of the data call in up to 4 January 2002. COC members considered that it was extremely difficult to assess the extent of exposure from the available information. However the evidence suggested that some exposure of the skin would have occurred during the whole body inhalation study undertaken by Blair et al in 1974. Regarding the other carcinogenicity studies in rats, COC members considered there were limitations in all of the studies (eg age of study, numbers of animals used, extent of pathology investigations) and that apart from evidence of mononuclear cell leukaemia in F344 male rats in two studies there was no consistent evidence for a carcinogenic effect in rats. It was noted that a Pathology Working Group (PWG) had subsequently discounted the finding of mononuclear cell leukaemia in the NTP bioassay in rats, but the report presenting the basis for this decision was not available to COC members. Regarding other studies in mice, COC members considered that there were similar limitations in the conduct of these studies compared to those undertaken in the rat. Members considered that it was not possible to undertake a comparison of the studies in mice where dichlorvos had been administered in corn oil and those where dichlorvos had been administered in the drinking water or as an aqueous solution by gavage. This was due to a lack of exposure data. On considering the overall package of carcinogenicity bioassays COC members felt that there was no consistent evidence for a genotoxic carcinogenic effect.
18. Members considered the potential mechanisms for the carcinogenic effects on squamous epithelia and noted that many of the exhibits referred to localised contact irritancy of dichlorvos. However there was little data available to support this view which apparently related to the finding of increased cell division and hyperplasia in the forestomach UDS assays. There was no evidence, for example, for an inflammatory response in the respiratory epithelium in the inhalation bioassay. Members concluded that a genotoxic effect could not be excluded.
19. Members then considered each of the submissions in turn. These are listed below.
New Documents (AMVAC)
1. Cancer summary - 'Dichlorvos: An Assessment of Carcinogenic Potential'.
2. Letter to Ian Chart from J A MacGregor dated 7 December 2001.
3. Letter from Dr. Ward Richter, Director of Pathology Southern Research Laboratory, dated 4 December 2001
New Documents (Other data holders)
1. Submission from Denka
2. Submission from Product Safety Assessment Ltd
Documents previously submitted during the Judicial Review proceedings
1. Written Comments submitted on 11 May 2001 to COM following the first draft COM Statement (F3 920-942).
2. Written summary submitted on 28 June 2001 prior to presentation to the 23 July 2001 COM Meeting (D1 86-93).
3. Written comments submitted on 26 July 2001 following the second draft COM statement (D1 98 - 104).
4. Expert opinion of David Brusick August 2001 (D1 117-122).
5. Expert opinion of John Ishmael August 2001 (D1 147 - 157).
6. Expert opinion of Karel de Raat August 2001 (D1 167-180).
7. Expert opinion of John Mennear August 2001 (D1 184-197).
8. First witness statement of J. A. MacGregor August 2001 (D1 217-243).
9. Second witness statement of J. A. MacGregor August 2001 (D1 312-326).
10. Third witness statement of J A MacGregor (D2 674-677).
11. Affidavit of Anju Sanehi (D1 1-7 paragraphs 13-18).
20. Members agreed that there was a degree of repetition and that many of the key points raised had already been discussed. Thus comments were restricted to the additional topics raised in these documents.
21. Members agreed that the excretion of 14C-labelled 7- methylguanine in the urine of mice exposed to 14C-labelled dichlorvos could have potentially resulted from incorporation of dichlorvos into the carbon pool, but this had not been proven.
22. Members considered that the discussion of mutagenicity risk assessment in several of the submissions had not taken into account the generic statement from the COM (Statement on risk assessment of in-vivo mutagens (and genotoxic carcinogens) COM/01/S3 June 2001). This stated that the "The COM reaffirmed that for in-vivo mutagens, it is prudent to assume that there is no threshold for mutagenicity. Where a potential threshold related mechanism can be identified, appropriate data should be generated on a chemical-by-chemical basis. In many situations this will involve in-vitro studies of mechanism. An appropriate strategy should be devised for each chemical under consideration and this may, in some instances, include in-vivo studies. The regulatory approach to such chemicals can then be based on the identification of a critical NOAEL and use of uncertainty factors."
23. Members agreed that in the absence of mechanistic data, the evidence of an apparent NOAEL for tumorigenesis of the forestomach in the NTP bioassay in rats could not be used to suggest that a threshold for mutagenicity had been demonstrated, given the existing data on mutagenicity of this chemical.
24. Members agreed that they had reviewed all the data from the published literature and unpublished reports submitted as is normal practice. They had not checked all the "raw laboratory data" and considered it impractical to do so.
25. The Committee agreed that the comment that acetic acid had produced a positive result in a Muta™ Mouse study was interesting but not relevant to the assessment of dichlorvos given the existing data on mutagenicity of this chemical.
26. Members noted the suggestion that the mutagenic effects in the Plesta study should have been localised in the capsule surrounding the liver and should have not been detectable in hepatocytes if a local site of contact effect was occurring but it was felt that this suggestion did not negate the positive findings which had been reported in liver, the mechanism of which was assumed to be due to mutation.
27. The Committee noted that it was important to clarify the phrase "site of contact". Members agreed that this phrase meant the initial sites of exposure. The COM felt there was no evidence for systemic mutagenic effects for dichlorvos.
28. COC members agreed that the additional data on background histopathology from the laboratory where the 1989 mouse bioassay had been undertaken was useful information in assessing the data. The COM considered that the information from the NCI 1977 bioassay in mice and the 1989 NTP bioassay in mice were useful supporting information in its deliberations, but the overall conclusions on mutagenicity of dichlorvos were based on the assessment of all the relevant data.
29. The Committee concluded that dichlorvos should be regarded as an in-vivo mutagen at the site-of-contact (i.e at the initial sites of exposure .The COM felt there was no evidence for systemic mutagenic effects.) High doses of dichlorvos induced mutagenic effects in the skin following topical application and in the liver following intraperitoneal dosing. The Committee noted the limited evidence for a carcinogenic effect of dichlorvos. This related to tumours of the forestomach in mice after gavage dosing and also the oesophageal tumours seen after dietary administration. There was no satisfactory explanation proven for the mechanisms of these tumours and the Committee felt, given the available mutagenicity data on dichlorvos, that it would be prudent to assume a genotoxic mechanism. The Committee agreed that in the absence of appropriate mechanistic data a precautionary approach should be adopted and no threshold could be assumed for the mutagenic and carcinogenic effects of dichlorvos.
30. The Committee considered a request from the Advisory Committee on Pesticides on what investigations might assist in further considering the potential for dichlorvos to act as a site of contact mutagen. Members suggested that good quality studies in transgenic animals using repeat dosing to investigate mutagenic activity in the skin following dermal application and in the gastrointestinal tract following oral administration would be appropriate.
Item 5: Any other business
31. No other items of business were discussed.
Item 6: Date of next meeting
32. 7 February 2002.