J. Ashby et al., EVALUATION OF THE POTENTIAL CARCINOGENICITY AND GENETIC TOXICITY TO HUMANS OF THE HERBICIDE ACETOCHLOR, Human & experimental toxicology, 15(9), 1996, pp. 702-735
Comprehensive toxicological studies of the herbicide acetochlor are pr
esented and discussed. Although it gave a negative profile of response
s in the many toxicity tests conducted there were some findings that p
rompted further investigation. First, although non-mutagenic in the Sa
lmonella 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, altho
ugh acetochlor gave a negative response in rat liver UDS assays when t
ested at the acute MTD, gavage administration of a single, supra-MTD d
ose (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 similar to 80%, altered the metabolism of acetochlor,
and was associated with UP to 33% lethality. In contrast, reference li
ver genotoxins such as DMN, DMH and 2AAF were shown to elicit UDS in t
he absence of such effects, and at similar to 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 tolerate
d dose (MTD). The tumours were not life-threatening, they did not meta
stasize, and no DNA damage was induced in the nasal cells of rats main
tained on a diet containing the MTD of acetochlor for either 1 or 18 w
eeks (comet assay). In order to probe the mechanism of action of these
high dose toxicities a series of chemical and genetic toxicity studie
s was conducted on acetochlor and a range of structural analogues. The
se revealed the chloroacetyl substructure to be the clastogenic specie
s in vitro. Although relatively inert, this substituent is preferentia
lly reactive to sulphydryl groupings, most evidently, to glutathione (
GSH). Similar chemical reactivity and clastogenicity in vitro was obse
rved for two related chemicals bearing a chloroacetyl group, both of w
hich have been defined as non-carcinogens in studies reported by the U
S NTP. These collective observations indicate that the source of the c
lastogenicity of acetochlor in vitro is also the source of its rapid d
etoxification in the rat in vivo, via reaction with GSH. Metabolic stu
dies of acetochlor are described which reveal the formation of a serie
s of GSH-associated biliary metabolites in the rat that were not produ
ced 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 t
he rat nasal tumours observed uniquely at elevated dose-levels. The ab
sence of genetic toxicity to the nasal epithelium of rats exposed acut
ely or sub-chronically to acetochlor favours a non-genotoxic mechanism
for the induction of these adenomas. The observation of a time- and d
ose-related increase in S-phase cells in the nasal epithelium is consi
stent with this conclusion. Despite some confusion caused by the early
use of peri-lethal gavage administrations of acetochlor to rodents, a
nd supra-MTD dietary concentrations in some of the chronic studies, th
e available MTD data are consistent with acetochlor not posing a genet
ic or carcinogenic hazard to humans.