Evidence for site-specific bioactivation of alachlor in the olfactory mucosa of the Long-Evans rat.
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.
Department of Toxicology, North Carolina State University, Raleigh 27695, USA.
B A
BA
Wetmore
A D
AD
Mitchell
S A
SA
Meyer
M B
MB
Genter
D000081:Acetamides / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000378:metabolism*; D008223:Lymphoma / Q000209:etiology; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009154:Mutation; D009831:Olfactory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D012486:Salmonella typhimurium / Q000235:genetics; D013997:Time Factors
D000081:Acetamides; D006540:Herbicides; D009153:Mutagens; C000188:alachlor