Toxicological Sciences, Vol 49, 202-212, Copyright © 1999 by Society of Toxicology
BA Wetmore, AD Mitchell, SA Meyer and MB Genter
Alachlor (2-chloro-2',6'-diethyl-N-[methoxymethyl]-acetanilide) is a
restricted-use chloracetanilide herbicide which has been shown previously
to produce a dose-dependent incidence of olfactory mucosal tumors in rats
following chronic dietary exposure. However, the mechanism of alachlor
carcinogenicity is poorly understood. Alachlor was administered i.p. to
male Long-Evans rats for up to 28 days at doses that are carcinogenic in
chronic studies in order to study olfactory lesion development and
alterations in cell proliferation. Neither treatment-related olfactory
mucosal lesions nor regenerative cell proliferation, as assessed with BrdU
labeling, was detected. In vitro genotoxicity studies using Salmonella
typhimurium strain TA100 showed that alachlor was non-mutagenic in the
absence of metabolic activation. When pre-incubated with an olfactory
mucosal S9 activation system, alachlor induced a weak, dose-dependent
mutagenic response at 500-1250 micrograms/plate, with toxicity at higher
doses. In contrast, an S9 activation system derived from nasal respiratory
mucosa, the tissue physically juxtaposed with the olfactory mucosa but
reportedly not susceptible to alachlor-induced tumors, did not produce a
mutagenic response for alachlor or the positive control. Thus, this result
suggested site-specificity of alachlor activation consistent with the
target site of carcinogenicity. The mutagenicity of alachlor to Salmonella,
in the presence of an olfactory mucosal-activating system, was confirmed by
a limited positive response in the mouse lymphoma assay. Here there were
increases in small colony mutants (indicative of chromosomal effects) as
well as large colony mutants (which reflect gene mutations). This study
suggests that target tissue bioactivation of alachlor results in the
formation of one or more mutagenic metabolite(s), which may be critical in
alachlor-induced nasal tumorigenesis.
ARTICLES
Evidence for site-specific bioactivation of alachlor in the olfactory mucosa of the Long-Evans rat
Department of Toxicology, North Carolina State University, Raleigh 27695, USA.
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