Jonathan B. Ward Jr., Ph.D.

Jonathan B. Ward Jr., Ph.D.

Professor and Director

Division of Environmental Toxicology
Coordinator, Environmental Toxicology Graduate Curriculum

Education

• A. B. Whitman College
• M. S. University of Idaho
• Ph.D., Cornell University
• Post-doctoral Harvard Medical School, Massachusetts General Hospital and
• University of Texas Medical Branch

research interests

Sensitivity to genotoxic effects of butadiene
What is butadiene and why is it important? Butadiene is a chemical that is used in large volumes to manufacture synthetic rubber and other polymers. It is also a combustion product found in automobile emissions and environmental tobacco smoke. Urban air typically contains 0.1 to 10 parts per billion of butadiene. It is a potent carcinogen in mice and is a probable carcinogen in humans. Occupational exposure to butadiene has been associated with leukemia.

How do we study butadiene? We are investigating the ability of butadiene to damage the genetic apparatus, a predisposing process that can lead to cancer, in two ways. First we are conducting studies directly in human populations by using tests to measure exposure to butadiene, tests that measure an effect of butadiene, and a third class of tests that determine human genetic traits that may make people more or less sensitive to the toxic effects of butadiene. These tests are called biomarkers and the approach we use is often referred to as molecular epidemiology. We have conducted studies on groups of workers in chemical plants where butadiene is made or used to make polymers. In these studies we have selected workers from areas where butadiene levels are relatively high or low. We have measured the concentration of butadiene in the air the workers breath, and determined how much they actually absorbed by measuring the concentration of a metabolite of butadiene in the urine. We also measured the effects of exposure by determining the frequency of mutations at a "reporter gene" called HPRT in white blood cells. In several studies we found that the frequency of HPRT mutant lymphocytes was higher in workers with the greatest exposure to butadiene. We have also investigated the inherited traits of some workers in genes that control the way butadiene is broken down and eliminated after entering the body. We found that individuals who have a genetic trait that reduces the activity of an enzyme that breaks down the toxic metabolites of butadiene have higher HPRT mutant frequencies if they are exposed to butadiene than workers with a form of the gene that produces normal levels of enzyme activity. The enzyme is called microsomal epoxide hydrolase.

To better understand the significance of epoxide hydrolase in human sensitivity to butadiene we are conducting two kinds of studies. We have found that a strain of mice that does not have epoxide hydrolase is very sensitive to butadiene exposure. Butadiene-treated mice have higher levels of damage to DNA and mutations in the same hprt gene that we studied in humans.

We are also beginning studies of human white blood cells with different genetic forms of epoxide hydrolase to determine how these forms actually function in metabolizing butadiene. Together, the human studies and laboratory research are helping us to better understand how much butadiene workers can tolerate and they may help use to determine whether certain genetic traits make us more or less sensitive to the toxic effects of butadiene.

To better understand the significance of epoxide hydrolase in human sensitivity to butadiene we are conducting two kinds of studies. We have found that a strain of mice that does not have epoxide hydrolase is very sensitive to butadiene exposure. Butadiene-treated mice have higher levels of damage to DNA and mutations in the same hprt gene that we studied in humans. We are also beginning studies of human white blood cells with different genetic forms of epoxide hydrolase to determine how these forms actually function in metabolizing butadiene. Together, the human studies and laboratory research are helping us to better understand how much butadiene workers can tolerate and they may help use to determine whether certain genetic traits make us more or less sensitive to the toxic effects of butadiene.

Selected Publications

Abdel-Rahman, S.Z., Ammenheuser, M.M. and Ward, J.B., Jr. Human sensitivity to 1,3-butadiene: role of microsomal epoxide hydrolase polymorphisms. Carcinogenesis, vol. 22, no. 3, pp. 415-423, 2001.

Ward, J.B., Jr., Abdel-Rahman, S.Z., Henderson, R.F., Stock, T.H., Morandi, M., Rosenblatt, J.I. and Ammenheuser, M.M. Assessment of butadiene exposure in synthetic rubber manufacturing workers in Texas using frequencies of hprt mutant lymphocytes as a biomarker. Chemico-Biol Interactions, 135-136: 465-483, 2001.

Ammenheuser, M.M. Bechtold, W.E., Abdel-Rahman, S.Z., Rosenblatt, J.I., Hastings-Smith, D.A. and Ward, J.B.Jr., Assessment of 1,3-butadiene exposure in polymer production workers using hprt mutation in lymphocytes as a biomarker. Environment. Health Perspect, vol. 109, 12:1249-1255, 2001.

Abdel-Rahman, S. Z., El-Zein, R. A., Ammenheuser, M. M., Yang, Z, Stock, T. H. Morandi, M., and Ward, J. B. Jr., Variability in human sensitivity to 1,3-butadiene: Influence of allelic variations of the microsomal epoxide hydrolase gene. Environ. Molec. Mutagen. 41:140-146, 2003.

Wickliffe, JK, Ammenheuser, MM, Salazar, JA, Abdel-Rahman, SZ, Hastings-Smith, DA, Postlethwait, EM, Lloyd, RS, and Ward, JB Jr. A model of sensitivity: 1,3-butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene, Environ. Molec. Mutagen. In press.