Molinate: A Metabolic
Explanation for Species
Differences in Susceptibility to
Male Reproductve Toxicity-99

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Project Leader and Principal UC Investigators

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

William Phillips, postgraduate researcher, Dept. of Environmental Toxicology, UC Davis

This project has been funded for five consecutive years to determine the risk of testicular toxicity to humans after exposure to the important rice herbicide molinate at environmentally relevant exposures. 

Prior studies with rats aroused concern that molinate posed a threat to human male reproductive organs.  However, both human epidemiological and non-human primate studies have thus far given no indication that molinate causes male reproductive toxicity in humans. 

University of California environmental toxicologists have identified "metabolic pathways" in humans that lessen the threat to those working with this chemical.   Research has shown that a toxic sulfoxide byproduct or "metabolite" of molinate is what causes toxicity in rats.  This metabolite binds a protein involved in the biosynthesis of testosterone.  Humans naturally have less ability to form this toxic metabolite and a much greater capacity to form nontoxic metabolites. 

Research in 1999 obtained further evidence that the sulfoxide byproduct is responsible for toxicity and that the primary source for it is the liver.  With this information researchers have been developing a physiologically based model to determine how much sulfoxide might be expected to reach the testis in rat and humans at environmentally relevant exposure levels.  This model is a mathematical description of the movement and metabolism of a chemical in a biological organism.  Such models are commonly used to extrapolate between species and dose levels in order to predict toxicity.

Researchers also confirmed in an in vitro  cell culture of testicular cells that the sulfoxide byproduct was a more potent inhibitor of testosterone than molinate itself.   This finding further substantiates the role of the sulfoxide and not the parent compound in testicular toxicity.  Moreover, molinate only inhibited testosterone biosynthesis at high dose levels where nonspecific cell damage was apparent.  These results suggest the liver is primarily responsible for the metabolization of molinate into the sulfoxide byproduct, not the testis.

Preliminary simulations of the amount of molinate sulfoxide reaching the testis showed a substantially lower amount in humans than rats.  Further research is necessary to validate this observation.

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