Mode of action: reduction of testosterone availability--molinate-induced inhibition of spermatogenesis.
Molinate is a preemergent herbicide that has been demonstrated to affect reproduction in the rat via alterations in sperm production. A wealth of standard toxicological studies and targeted research efforts relating to this adverse effect is available, and these were used to evaluate the utility of the Human Relevance Framework (HRF) for noncancer health effects. The hypothesized mode of action involved inhibition of the hydrolysis of cholesterol from high-density lipoprotein in the rat testes, followed by an androgen withdrawal syndrome on spermatogenesis. Some evidence is available that a similar mode of action would not be operable in humans. Despite the wealth of studies conducted in the rat, the weight of evidence is insufficient to define the mode of action for reproductive toxicity in the male rat. A principal deficiency in the database was discordance between the exposure levels observed to cause biochemical disturbances in the testes related to the hypothesized mode of action and the dose levels observed to induce the adverse outcome on spermatogenesis. For this reason, a complete MOA/human relevance analysis is not possible and, based on traditional risk assessment principles, any toxic effects are assumed to be relevant for human risk assessment.
Kavlock
Robert
R
US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. kavlock.robert@epa.gov
Cummings
Audrey
A
D000818:Animals; D000988:Antispermatogenic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001381:Azepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D013091:Spermatogenesis / Q000187:drug effects*; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013859:Thiocarbamates / Q000493:pharmacokinetics / Q000494:pharmacology*
D000988:Antispermatogenic Agents; D001381:Azepines; D013859:Thiocarbamates; D013739:Testosterone; C009821:molinate