suggestion that TCDD causes maturational defects in developing thymocytes via inadequate epithelial support (Greenlee et al., 1985). There is evidence, however, that alterations other than that of thymic epithelium function are responsible for immunosuppression. These alternative mechanisms include direct thymolysis events (McConkey et al., 1988), alterations in regulatory T-cell function (Kerkvliet and Brauner, 1987), alterations in B-cell differentiation (Luster et al., 1988), and stem cell inhibition (Fine et al., 1989).

Polycyclic aromatic hydrocarbons (PAHs), another well-studied class of compounds, are formed as products of incomplete combustion of fossil fuels, tobacco, and coke and in automobile exhaust. Selected PAHs, including benzo[a]pyrene (B[a]P), 7,12-dimethylbenzanthracene (DMBA), and 3-methylcholanthrene (3-MC), have been shown to produce immunosuppression and myelotoxicity; they also are carcinogenic (Dean et al., 1986). There is controversy about whether the immunosuppressive properties of PAHs are a cofactor for carcinogenicity, because they allow tumor antigen (neoantigen) to bypass normal host immune surveillance. Humoral immunity is suppressed after exposure to several PAHs, including B[a]P, DMBA, and 3-MC, although humoral immunosuppression after DMBA exposure could reside at the level of T-cell regulation (Dean et al., 1990). The finding of reduced progenitor B cells in exposed animals suggests that B cells also are directly targeted early in their maturation (Ward et al., 1984). B[a]P has been shown to impair the production of interleukin-1, implicating chemical-induced defects in accessory cell function as a contributing factor in decreased production of antibody-forming cells (Lyte and Bick, 1986). Cell-mediated immunity also is inhibited by PAHs. Cytotoxic T-cell activity in mice is suppressed after in vitro and in vivo exposure to DMBA or 3-MC (Wojdani and Alfred, 1984; Dean et al., 1985a, 1986).

Hexachlorobenzene (HCB), a fungicide and an intermediate in a variety of chemical syntheses, has been shown to have immunosuppressive properties in rodents. HCB suppresses both cellular and humoral immunity in adult mice (Loose et al., 1978) and is particularly toxic to T-cell function after in utero exposure (Barnett et al., 1987). HCB stimulates immune responses in rats after adult exposure (Vos and Luster, 1989) and perinatal exposure (Vos et al., 1983).

The immunotoxicity of benzene, for which a subregistry has been established at ATSDR, has been the subject of considerable research in humans and animals, with particular emphasis on its hematologic and leukemogenic potential (Snyder, 1984). In humans and experimental animals, the predominant hemopathy associated with benzene exposure is pancytopenia, with associated bone marrow hypoplasia (Laskin and Goldstein, 1977). Although hematopoietic progenitor cells are particularly susceptible to benzene, the mature circulating lymphocyte also responds to benzene in an antiproliferative response (Snyder et al., 1980). Chronic benzene exposure has been associated with depressed serum levels of IgA, IgG, and immune-system complement in humans. Despite the myelotoxic effect produced by benzene in experimental animals, the exact relationship between benzene-induced immunosuppression and an increase in leukemia has not been determined. Using pharmacokinetics to determine amounts of total benzene metabolized in 24 hours, Beliles and Totman (1989) have established the biologically effective dose. Using pharmacokinetics as a basis for across-species extrapolation of experimental data (benzene produces leukemogenesis at dose levels of 100-300 ppm in animals), they were able to show that the human risk of leukemia estimated from the incidence of leukemia in mice was quantitatively comparable to the risk predicted from occupational epidemiologic studies.