OPP - This paper provides the rationale and support for the decisions the OPP will make in requiring and reviewing mutagenicity information. The regulatory requirement for mutagenicity testing to support a pesticide registration is found in the 40 CFR Part 158. The guidance as to the specific mutagenicity testing to be performed is found in the OPP's Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation: Human and Domestic Animals (referred to as the Subdivision F guideline). A revised Subdivision F guideline has been presented that becomes the current guidance for submitters of mutagenicity data to the OPP. The decision to revise the guideline was the result of close examination of the version published in 1982 and the desire to update the guidance based on developments since then and current state-of-the-science. After undergoing Agency and public scrutiny, the revised guideline is to be published in 1991. The revised guideline consists of an initial battery of tests (the Salmonella assay, an in vitro mammalian gene mutation assay and an in vivo cytogenetics assay which may be either a bone marrow assay for chromosomal aberrations or for micronuclei formation) that should provide an adequate initial assessment of the potential mutagenicity of a chemical. Follow-up testing to clarify results from the initial testing may be necessary. After this information as well as all other relevant information is obtained, a weight-of-evidence decision will be made about the possible mutagenicity concern a chemical may present. Testing to pursue qualitative and/or quantitative evidence for assessing heritable risk in relation to human beings will then be considered if a mutagenicity concern exists. This testing may range from tests for evidence of gonadal exposure to dominant lethal testing to quantitative tests such as the specific locus and heritable translocation assays. The mutagenicity assessment will be performed in accordance with the Agency's Mutagenicity Risk Assessment Guidelines. The mutagenicity data would also be used in the weight-of-evidence consideration for the potential carcinogenicity of a chemical in accordance with the Agency's Carcinogen Risk Assessment Guidelines. In instances where there are triggers for carcinogenicity testing, mutagenicity data may be used as one of the triggers after a consideration of available information. It is felt that the revised Subdivision F guideline will provide appropriate, and more specific, guidance concerning the OPP approach to mutagenicity testing for the registration of a pesticide. It also provides a clearer understanding of how the OPP will proceed with its evaluation and decision making concerning the potential heritable effects of a test chemical. OTS - As a result of recent information in the field of mutagenicity (the Williamsburg meeting, its precedents and sequelae), a modification to the Section 4 test scheme has been proposed. In the proposal, test schemes for gene mutation and chromosomal aberrations are combined. The revision comprises three tests in the initial tier: the Salmonella assay, an in vitro assay for gene mutation and an in vivo assay for chromosomal effects which may be either a bone marrow assay for chromosomal aberrations or the micronucleus assay. Since submission of this article for publication, the proposed OTS test scheme has been approved by OTS management. The old two scheme, four test scheme is no longer in effect, and will no longer be used in future TSCA Section 4 Test Rules. Under Section 5 of TSCA ("new" chemical, or Premanufacture Notice (PMN)), mutagenicity data are used for three purposes: (1) as part of exposure based testing; (2) to assess the potential of the PMN chemical to induce heritable genetic effects; and (3) as part of the weight-of-evidence that a chemical may be a potential carcinogen. As part of the exposure based testing program, the USEPA has required testing of certain high volume chemicals with a two test battery of the Salmonella assay and a mouse micronucleus assay. In supporting a concern for potential carcinogenicity of a PMN chemical, the USEPA generally cites data on an analogue which is known to be carcinogenic (i.e., demonstrated tumor forming ability in one or more animal studies). In such instances, mutagenicity data on the PMN chemical or on the analogues are used to lend support to the case for potential carcinogenicity. Where there is no analogue of the PMN chemical which has been tested for carcinogenicity, mutagenicity data alone are generally not considered sufficient to support a concern for potential carcinogenicity. Regulatory action under Section 5 is seldom, if ever, taken on the basis of mutagenicity data alone, especially on the basis of in vitro mutagenicity data.
