as toll-like receptors) that allow innate cells to respond to certain families of environmental molecules or toxins (e.g., endotoxin). Xenobiotics may interfere with normal immune system homeostasis by affecting the formation of immune cells; modifying cell-to-cell interactions; modifying cell activation, proliferation, or differentiation; altering cell selection; and enhancing or suppressing the release of immune products such as cytokines, chemokines, antibodies, and complement factors.

The immunotoxicity of chemicals is evaluated in animal models, in in vitro studies, and occasionally in humans after occupational or environmental exposures. Environmental epidemiology studies are often conducted to determine whether xenobiotic exposures are associated with disease. Because of the complexity of the innate and adaptive immune systems, no single assay can be used to study the potential toxicity of xenobiotics. Instead, a tiered approach has been developed and validated by several laboratories for studies in animals (Luster et al. 1988, 1992). Although there is no single immune assay or parameter that can be used to determine whether a xenobiotic exerts a toxic effect on the immune system, certain combinations of markers and functional assays can predict immunotoxicity (Luster et al. 1992). Additionally, the aforementioned assays are useful only for evaluating immunosuppressive chemicals. Few established assays exist for assessing hypersensitivity reactions of xenobiotics, and experimental models of autoimmunity are limited in their application and extrapolation to human autoimmune diseases.

ANIMAL STUDIES

Immunosuppression

The potential immunosuppressive and immunomodulating properties of trichloroethylene in acute, subchronic, and chronic exposures in animals have not been fully evaluated. Sanders et al. (1982) found that trichloroethylene at concentrations of 2.5-5 mg/mL (in drinking water for 4 or 6 months) resulted in suppression of humoral and cell-mediated immunity in female CD1 mice. Bone marrow stem cell activity was depressed at drinking water concentrations of 0.1-1 mg/mL. Male mice were less affected. Wright et al. (1991) found a depression in natural killer cell activity in the liver, decreased lipopolysaccharide lymphocyte mitogenesis, and decreased spleen weights after intraperitoneal exposures of Sprague-Dawley rats to trichloroethylene at 5 mmol/kg/day for 3 days. Natural killer cell activity in the liver was also depressed at 0.5 mmol/kg/day for 3 days. B6C3F1 mice receiving the high-dose regimen also demonstrated spleen cell toxicity, and they were more sensitive than rats to the natural killer cell suppression in the liver, with effects observed at 0.05 mmol/kg/day for 3 days. Aranyi et al.



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