Acetochlor-induced rat nasal tumors: Further studies on the mode of actionand relevance to humans

The herbicide acetochlor, and its analogue alachlor, have similar toxicolog ical properties, the most significant being the induction of nasal adenomas in rats in a-year feeding studies. Previous investigations have proposed a mode of action involving metabolism to a quinone-imine, the formation of p rotein adducts, cell death, and compensatory hyperplasia leading to the obs erved adenomas. Comparisons between rats and humans of the metabolic cascad e leading to the quinone-imine indicate that these chemicals do not pose a threat to humans. Further investigations with acetochlor, presented here, h ave revealed an additional activation pathway in which a sulfoxide metaboli te 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 persi sts in the olfactory epithelium of rats. Radiolabeling of the sulfoxide mol ecule in the phenyl ring and in the sulfoxide side-chain demonstrated that the metabolite accumulating in nasal tissues retains the sulfoxide side-cha in. The formation of a quinone-imine from the sulfoxide was facilitated by hydroxylation of the phenyl ring by a cytochrome P450 isoenzyme which was s pecific to the nasal epithelium in the rat. This metabolic conversion could not be detected in 33 fresh human nasal tissue samples, supporting the ear lier view that the acetochlor-induced rat nasal tumors do not represent a h azard for humans. (C) 2000 Academic Press.