Ethane sulfonate metabolite of alachlor: assessment of oncogenic potential based on metabolic and mechanistic considerations.
Chronic administration of alachlor has been shown to produce neoplastic responses in the nasal turbinate mucosa, glandular stomach mucosa, and thyroid follicular epithelium of rats. Subsequent studies have shown that specific metabolic activation of alachlor is required for nasal tumor formation, and that non-genotoxic, threshold-sensitive processes produce all three tumors. The herbicide alachlor is degraded in the soil by microbial action to the tertiary ethane sulfonate metabolite (ESA). The acute and subchronic toxicity of ESA is very low, and the metabolite did not produce developmental toxicity or genotoxicity. The studies described here were conducted to determine whether ESA shares a common mechanism of oncogenicity with alachlor in rats. Specifically, we studied ESA's pharmacokinetics and ability to produce changes that are causally associated with the oncogenicity of alachlor. These studies demonstrated that ESA was poorly absorbed and underwent minor metabolism, which contrasted with the significant absorption and substantial metabolism observed with alachlor. ESA was also excreted more quickly than alachlor and showed no evidence of accumulation in the nasal turbinates, a site of oncogenicity for alachlor in the rat. In addition, ESA did not elicit the characteristic preneoplastic changes observed in the development of alachlor-induced nasal, stomach, and thyroid tumors. The results of these studies support the conclusion that ESA does not share a common oncogenic mechanism with alachlor and would not be expected to produce the same oncogenic responses observed following chronic alachlor exposure in rats.
Heydens
W F
WF
Monsanto Company, St. Louis, Missouri 63167, USA. william.f.heydens@monsanto.com
Wilson
A G
AG
Kraus
L J
LJ
Hopkins
W E
WE
Hotz
K J
KJ
D000081:Acetamides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D000476:Alkanesulfonates / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001345:Autoradiography; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D006540:Herbicides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009297:Nasal Mucosa / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D014018:Tissue Distribution
D000081:Acetamides; D000476:Alkanesulfonates; D002273:Carcinogens; D006540:Herbicides; C000188:alachlor; C002634:ethane sulfonate