Biological basis of chemical carcinogenesis: insights from benzene

Benzene is one of the best studied of the known human carcinogens. It causes leukemia in humans and a variety of solid tumors in rats and mice. Decades of research on benzene metabolism, pharmacokinetics, cytotoxicity, genotoxicity, and carcinogenicity in vivo and in vitro are starting to converge on a small set of overlapping hypotheses about the most probable biological mechanisms of benzene toxicity and carcinogenicity. Although there is still room for surprises, it seems likely that the ultimate answer to the mystery of how benzene exerts its multiple effects will consist of elaborations and extensions of one or more of the current hypotheses. This paper reviews benzene health effects and biology, showing how various aspects of metabolism and cytotoxicity fit together with genotoxic and nongenotoxic effects to help explain how benzene may cause cancer. Its goals are: (i) to introduce the qualitative biological background needed for detailed quantitative dose-response modeling of benzene cancer risks; and (ii) to survey a rapidly evolving area of research that shows promise of producing fundamental insights into the mechanisms of toxicity and carcinogenesis for several chemicals--benzene and perhaps phenols, catechols, and other hydroxylated ring hydrocarbons--in the decade ahead.