Evaluation of the potential carcinogenicity and genetic toxicity to humans of the herbicide acetochlor.
Comprehensive toxicological studies of the herbicide acetochlor are presented and discussed. Although it gave a negative profile of responses in the many toxicity tests conducted there were some findings that prompted further investigation. First, although non-mutagenic in the Salmonella assay, acetochlor was clastogenic to mammalian cells treated in vitro. This clastogenic potential was not expressed in vivo in four rodent cytogenetic assays (bone marrow and germ cells). Second, although acetochlor gave a negative response in rat liver UDS assays when tested at the acute MTD, gavage administration of a single, supra-MTD dose (2000 mg/kg) gave a weak positive assay response. This dose-level (2000 mg/kg) was necrotic to the liver, depressed hepatic glutathione levels by up to approximately 80%, altered the metabolism of acetochlor, and was associated with up to 33% lethality. In contrast, reference liver genotoxins such as DMN, DMH and 2AAF were shown to elicit UDS in the absence of such effects, and at approximately 400 x lower dose-levels. Finally, microscopic nasal polypoid adenomas were induced in the rat when acetochlor was administered for two years at the maximum tolerated dose (MTD). The tumours were not life-threatening, they did not metastasize, and no DNA damage was induced in the nasal cells of rats maintained on a diet containing the MTD of acetochlor for either 1 or 18 weeks (comet assay). In order to probe the mechanism of action of these high dose toxicities a series of chemical and genetic toxicity studies was conducted on acetochlor and a range of structural analogues. These revealed the chloroacetyl substructure to be the clastogenic species in vitro. Although relatively inert, this substituent is preferentially reactive to sulphydryl groupings, most evidently, to glutathione (GSH). Similar chemical reactivity and clastogenicity in vitro was observed for two related chemicals bearing a chloroacetyl group, both of which have been defined as non-carcinogens in studies reported by the US.NTP. These collective observations indicate that the source of the clastogenicity of acetochlor in vitro is also the source of its rapid detoxification in the rat in vivo, via reaction with GSH. Metabolic studies of acetochlor are described which reveal the formation of a series of GSH-associated biliary metabolites in the rat that were not produced in the mouse. The metabolism of acetochlor in the rat changes with increasing dose-levels, probably because of depletion of hepatic GSH. It is most likely that a rat-specific metabolite is responsible for the rat nasal tumours observed uniquely at elevated dose-levels. The absence of genetic toxicity to the nasal epithelium of rats exposed acutely or subchronically to acetochlor favours a non-genotoxic mechanism for the induction of these adenomas. The observation of a time- and dose-related increase in S-phase cells in the nasal epithelium is consistent with this conclusion. Despite some confusion caused by the early use of perilethal gavage administrations of acetochlor to rodents, and supra-MTD dietary concentrations in some of the chronic studies, the available MTD data are consistent with acetochlor not posing a genetic or carcinogenic hazard to humans.
Ashby
J
J
Zeneca Central Toxicity Laboratory, Macclesfield, Cheshire, UK.
Kier
L
L
Wilson
A G
AG
Green
T
T
Lefevre
P A
PA
Tinwell
H
H
Willis
G A
GA
Heydens
W F
WF
Clapp
M J
MJ
D018256:Adenomatous Polyps / Q000139:chemically induced / Q000473:pathology / Q000648:ultrastructure; D000284:Administration, Oral; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002273:Carcinogens / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D005260:Female; D005854:Germ Cells / Q000166:cytology / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006540:Herbicides / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000401:mortality; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009152:Mutagenicity Tests; D009298:Nasal Polyps / Q000139:chemically induced / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D013439:Sulfhydryl Reagents / Q000633:toxicity; D013601:T-Lymphocytes; D014052:Toluidines / Q000008:administration & dosage / Q000009:adverse effects*
D002273:Carcinogens; D006540:Herbicides; D013439:Sulfhydryl Reagents; D014052:Toluidines; C043377:acetochlor; D005978:Glutathione