The elderly represent a special population who are often at increased risk for susceptibility to the toxic effects of environmental agents. Alterations in disposition and/or biotransformation of xenobiotics in aged subjects may be a contributing factor to this enhanced susceptibility. In this laboratory, work is focused on alterations occurring with age in absorption, distribution, metabolism, and excretion of environmental toxicants, using two rodent models of aging. Benzene is a widespread environmental contaminant and human carcinogen whose disposition and toxicity has not been previously assessed in elderly subjects. Disposition and metabolism of benzene were examined in aged mice at 10 and 200 mg/kg. In addition, a physiologically based pharmacokinetic model was used to gain further insight into the basis of age-related differences in benzene disposition, and implications for toxicity of benzene in older subjects. Disposition of benzene was altered with age, in that older mice appeared to retain more of a given dose of benzene. Physiologically based pharmacokinetic modeling of benzene disposition suggested that this alteration could be due to changes in total benzene metabolism or in absorption of benzene. Verification of these model predictions is currently under investigation.
