Alachlor (2-chloro-2',6'-N(methoxymethyl)acetanilide) is a restricted-use pesticide used as a herbicide in the production of numerous crops. Alachlor (trade name Mallo) and several structurally-related chloracetanilide herbicides are used world-wide in the production of important food crops such as corn and soybeans, providing significant potential for environmental contamination and human exposure. Chronic dietary exposure to alachlor causes a variety of tumors, including adenomas and adneocarcinoams of the olfactory mucosa in rats. Preliminary data revealed that alachlor is positive in an in vitro mutagenicity assay in the presence of an olfactory mucosal S9 activating system, but non-mutagenic in the presence of an activating system prepared from the adjacent respiratory mucosa, suggesting that alachlor metabolites generated in the target tissue are mutagenic and carcinogenic. They will determine the cell type of origin of alachlor-induced olfactory mucosal tumors and characterize cellular and molecular changes associated with the progression from preneoplastic lesions to adenomas to adenocarcinomas. They will also determine the metabolic enzymes responsible for conversion of alachlor to its mutagenic metabolite(s); this information will aid in cross-species extrapolation for the risk associated with the development of alachlor-induced tumors. In addition, they will perform in vitro mutagenesis assays with alachlor and a key metabolite, 2,6-diethylaniline using human olfactory mucosal S9 as an activating system in order to validate cross-species extrapolation between rats and humans for risk assessment purposes. Finally, they will evaluate other chloracetanilide herbicides for potential mutagenicity in the olfactory mucosa in order to ensure a more complete hazard identification for this class of compounds. These studies will provide important new data on the site-specific mechanism of carcinogenesis of a widely-used class of toxicants and will aid in the refinement of risk assessment and risk management strategies for the chloracetanilide compounds.
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