Molinate 00

Molinate: A Metabolic Explana- tion for Species Differences in Susceptibility to Male Reproductve Toxicity-2000
Project Leader and Principal UC Investigators Marion G. Miller, professor, Department of Environmental Toxicology, University of California, Davis	The overall objective of this project is to investigate the role metabolism and biological events play in male reproductive damage caused by the economically important rice herbicide molinate (Ordram®). The goal is to improve our ability to assess the reproductive risk posed to humans by environmentally relevant exposures to molinate. The majority of animal studies that implicate molinate as a male reproductive toxicant have been carried out in rats. However, both human epidemiological and non-human primate studies have given no positive indication that molinate causes male reproductive toxicity in man. Moreover, previous studies have demonstrated that the sulfoxide breakdown product associated with testicular toxicity is produced in the liver and binds a protein involved in biosynthesis of testosterone. Humans naturally have less ability to form this toxic metabolite. Last year's research focused in two main areas. Scientists completed studies on the effect of molinate and the sulfoxide on testosterone production. This research confirmed that the sulfoxide - not molinate per se - inhibits testosterone production and that the liver is its primary source. However, its role in inhibiting enzymes that decrease testosterone production is not yet clear. The other main thrust of last year's research was on the development of a physiologically based model to determine how much sulfoxide might be in the blood under actual field conditions. Such models are used to extrapolate between species and dose levels in order to predict organ system exposure and hence likelihood of toxicity. While refinements were made to the model last year, it still needs to be validated in rats before it can be used to extrapolate to humans.

Molinate: A Metabolic Explana-
tion for Species Differences in
Susceptibility to Male Reproductve
Toxicity-2000

Project Leader and Principal UC Investigators

Marion G. Miller, professor, Department of Environmental Toxicology, University of California, Davis

The overall objective of this project is to investigate the role metabolism and biological events play in male reproductive damage caused by the economically important rice herbicide molinate (Ordram®). The goal is to improve our ability to assess the reproductive risk posed to humans by environmentally relevant exposures to molinate.

28Microscope.jpg (7255 bytes) The majority of animal studies that implicate molinate as a male reproductive toxicant have been carried out in rats. However, both human epidemiological and non-human primate studies have given no positive indication that molinate causes male reproductive toxicity in man. Moreover, previous studies have demonstrated that the sulfoxide breakdown product associated with testicular toxicity is produced in the liver and binds a protein involved in biosynthesis of testosterone. Humans naturally have less ability to form this toxic metabolite.

Last year's research focused in two main areas. Scientists completed studies on the effect of molinate and the sulfoxide on testosterone production. This research confirmed that the sulfoxide - not molinate per se - inhibits testosterone production and that the liver is its primary source. However, its role in inhibiting enzymes that decrease testosterone production is not yet clear.

The other main thrust of last year's research was on the development of a physiologically based model to determine how much sulfoxide might be in the blood under actual field conditions. Such models are used to extrapolate between species and dose levels in order to predict organ system exposure and hence likelihood of toxicity. While refinements were made to the model last year, it still needs to be validated in rats before it can be used to extrapolate to humans.