Molinate: A metabolic explanation for species dif... 98

Molinate: A Metabolic Explanation for Species Differences in Suscepti- bility to Male Reproductve Toxicity-98
Project Leader and Principal UC Investigators Marion G. Miller, professor, Department of Environmental Toxicology, UC Davis Will Jewell, graduate student, Department of Environmental Toxicology, UC Davis Bruce Winder, postgraduate researcher, Department of Environmental Toxicology, UC Davis	Research continued for a fourth year on the rice herbicide molinate (OrdramŽ) and its potential toxicological effects. The majority of animal studies that implicate molinate as a male reproductive toxicant have been carried out on rats. However, both human epidemiological and non-human primate studies give no indication that molinate causes male reproductive toxicity in humans. This research was undertaken to develop a more thorough understanding of the metabolic processes at play. The goal is to determine whether molinate toxicity is species specific and to assess more rationally the risk posed to humans. Although molinate has been shown to cause toxicity in the reproductive organs of male rats, environmental toxicologists have identified different "metabolic pathways" in humans that lessen the threat to those working with this chemical. Previous research showed that a toxic sulfoxide byproduct or "metabolite" of molinate is what causes toxicity in rats. Humans have less ability to form this toxic metabolite and a much greater capacity to form nontoxic metabolites. Current in vitro work on human and rat liver slices revealed a more thorough understanding of the processes involved. In low doses molinate is metabolized through a nontoxic "hydroxylation" pathway in both species. At higher doses the "sulfoxidation" pathway leading to creation of toxic metabolites is more active. Humans were found to be more capable than rats of detoxifying this metabolite than rats. Overall, the research confirms that humans are less susceptible to molinate toxicity than rats. Research also focused on the biochemical mechanisms responsible for potential toxicity. An enzyme involved in the production of testosterone is affected by the toxic molinate metabolite. Diminished production of testosterone is linked to testicular damage seen after high dose levels of molinate. Last year's work examined the reversibility of this process. Although low dose levels of molinate also affected testosterone production, normal enzyme activity returned within seven days. This research suggests that short-duration exposures to molinate do not result in testicular damage.

Molinate: A Metabolic Explanation
for Species Differences in Suscepti-
bility to Male Reproductve Toxicity-98

Project Leader and Principal UC Investigators

Marion G. Miller, professor, Department of Environmental Toxicology, UC Davis

Will Jewell, graduate student, Department of Environmental Toxicology, UC Davis

Bruce Winder, postgraduate researcher, Department of Environmental Toxicology, UC Davis

Research continued for a fourth year on the rice herbicide molinate (OrdramŽ) and its potential toxicological effects. The majority of animal studies that implicate molinate as a male reproductive toxicant have been carried out on rats. However, both human epidemiological and non-human primate studies give no indication that molinate causes male reproductive toxicity in humans. This research was undertaken to develop a more thorough understanding of the metabolic processes at play. The goal is to determine whether molinate toxicity is species specific and to assess more rationally the risk posed to humans.

Although molinate has been shown to cause toxicity in the reproductive organs of male rats, environmental toxicologists have identified different "metabolic pathways" in humans that lessen the threat to those working with this chemical. Previous research showed that a toxic sulfoxide byproduct or "metabolite" of molinate is what causes toxicity in rats. Humans have less ability to form this toxic metabolite and a much greater capacity to form nontoxic metabolites. Current in vitro work on human and rat liver slices revealed a more thorough understanding of the processes involved. In low doses molinate is metabolized through a nontoxic "hydroxylation" pathway in both species. At higher doses the "sulfoxidation" pathway leading to creation of toxic metabolites is more active. Humans were found to be more capable than rats of detoxifying this metabolite than rats. Overall, the research confirms that humans are less susceptible to molinate toxicity than rats.

Research also focused on the biochemical mechanisms responsible for potential toxicity. An enzyme involved in the production of testosterone is affected by the toxic molinate metabolite. Diminished production of testosterone is linked to testicular damage seen after high dose levels of molinate. Last year's work examined the reversibility of this process. Although low dose levels of molinate also affected testosterone production, normal enzyme activity returned within seven days. This research suggests that short-duration exposures to molinate do not result in testicular damage.