Acetochlor-induced rat nasal tumors: further studies on the mode of action and relevance to humans.
The herbicide acetochlor, and its analogue alachlor, have similar toxicological properties, the most significant being the induction of nasal adenomas in rats in 2-year feeding studies. Previous investigations have proposed a mode of action involving metabolism to a quinone-imine, the formation of protein adducts, cell death, and compensatory hyperplasia leading to the observed adenomas. Comparisons between rats and humans of the metabolic cascade leading to the quinone-imine indicate that these chemicals do not pose a threat to humans. Further investigations with acetochlor, presented here, have revealed an additional activation pathway in which a sulfoxide metabolite of acetochlor plays a key role. The sulfoxide was found to be the major plasma metabolite in rats dosed with acetochlor. Whole-body autoradiography studies established that this metabolite selectively accumulates and persists in the olfactory epithelium of rats. Radiolabeling of the sulfoxide molecule in the phenyl ring and in the sulfoxide side-chain demonstrated that the metabolite accumulating in nasal tissues retains the sulfoxide side-chain. The formation of a quinone-imine from the sulfoxide was facilitated by hydroxylation of the phenyl ring by a cytochrome P450 isoenzyme which was specific to the nasal epithelium in the rat. This metabolic conversion could not be detected in 33 fresh human nasal tissue samples, supporting the earlier view that the acetochlor-induced rat nasal tumors do not represent a hazard for humans.
Green
T
T
Zeneca Central Toxicology Laboratory, Cheshire, Macclesfield, SK10 4TJ, United Kingdom.
Lee
R
R
Moore
R B
RB
Ashby
J
J
Willis
G A
GA
Lund
V J
VJ
Clapp
M J
MJ
D000236:Adenoma / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001345:Autoradiography; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006540:Herbicides / Q000493:pharmacokinetics* / Q000633:toxicity; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009669:Nose Neoplasms / Q000139:chemically induced / Q000473:pathology; D009831:Olfactory Mucosa / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014052:Toluidines / Q000493:pharmacokinetics* / Q000633:toxicity
D006540:Herbicides; D014052:Toluidines; C043377:acetochlor; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6