Jonathan Ward

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Jonathan Ward
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Research Interests

Mutagenic Effects of Chemicals

My research addresses environmental health issues by investigating the mutagenic effects of chemicals that are frequently found in workplaces and communities. I am interested in the mechanistic basis for mutations produced when humans are exposed to low levels of chemicals. To accomplish this, I use biological markers as endpoints in human population studies. A major study is examining the effects of occupational exposure to 1,3-butadiene, a known carcinogen, by evaluating lymphocytes from workers in rubber and petrochemical plants for the frequency of mutations in a reporter gene (hprt) along with other measures of exposure. Some workers exposed to less than 1 ppm of butadiene (the current allowable exposure limit) were found to have an increased frequency of mutations, of which a disproportionate number were deletions. In animal studies, exposure to the most mutagenic metabolite of butadiene, diepoxybutane, induces deletion mutations. We have discovered that individuals who inherit a low-activity polymorphic allele of the gene encoding microsomal epoxide hydrolase are more sensitive to the mutagenic effects of butadiene. This enzyme plays a key role in neutralizing the mutagenic metabolites of butadiene. The role of this enzyme in modifying human sensitivity to butadiene is reinforced by studies we have done in mice that lack the microsomal epoxide hydrolase gene. When these mice were exposed to butadiene by inhalation or to the epoxide metabolites of butadiene, they were more sensitive than their normal counterparts to mutation induction. These studies indicate that mutagenic effects are seen workers who are exposed to low levels of butadiene. This is particularly true if they inherit a low activity for of a key detoxifying enzeme and if they are exposed for extended periods of time. Because mutagenesis is a process involved in carcinogenesis this raises concerns about occupational or community exposure to butadiene and similar chemicals.