Molinate: rodent reproductive toxicity and its relevance to humans--a review.
Molinate is a thiocarbamate herbicide used on rice. During the evaluation of the compound for regulatory compliance, an adverse effect on male reproduction in rats was observed. This led to extensive investigations in rats, mice, rabbits, dogs, monkeys, and humans, resulting in a description of the cause of the effect and establishing an empirical case for rodent specificity. More recent investigations have also shown an effect on the ovaries in rodents. A series of investigations into the mechanism of action to support the view that the effect was specific to rodents has been concluded. The results from this investigation are drawn together and show that the mode of action is via a metabolite, the sulfoxide, which is primarily found in rodents, and that the lesion in both rodent sexes is elicited via inhibition of the enzyme neutral cholesterol ester hydrolase, resulting in interference with mobilization of cholesterol from high-density lipoprotein, a path specific to rodents. Thus, the mechanism of action is such that the effect cannot be elicited in other species including humans.
Zeneca Central Toxicology Laboratory, Alderley Park, Nr., Cheshire, Macclesfield, SK10 4TJ, United Kingdom.
G A
GA
Wickramaratne
J R
JR
Foster
M K
MK
Ellis
J A
JA
Tomenson
D000818:Animals; D001381:Azepines / Q000378:metabolism / Q000633:toxicity*; D002219:Carbamates; D004285:Dogs; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006540:Herbicides / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D013045:Species Specificity; D002787:Sterol Esterase / Q000037:antagonists & inhibitors*; D013859:Thiocarbamates
D001381:Azepines; D002219:Carbamates; D004791:Enzyme Inhibitors; D006540:Herbicides; D013859:Thiocarbamates; C009821:molinate; D002787:Sterol Esterase