Toxicant-inflicted injury and stimulated tissue repair are opposing toxicodynamic forces in predictive toxicology

These studies were designed to investigate the dose response for liver inju ry and tissue repair induced by exposure to four structurally and mechanist ically dissimilar hepatotoxicants, individually and as mixtures. The object ive was to illuminate the impact of the extent and timeliness of tissue rep air on the ultimate outcome of toxicity. Dose-response relationships for tr ichloroethylene (TCE), allyl alcohol (AA), thioacetamide (TA), and chlorofo rm alone or as mixtures were studied. Male Sprague-Dawley rats (200-250 g) received a single intraperitoneal injection of individual toxicants as well as mixtures of these toxicants. Liver injury was monitored by plasma enzym e (ALT and SDH) levels and histopathology. Tissue regeneration was measured by [H-3]thymidine incorporation into hepatic nuclear DNA. Individually, TC E, TA, and AA administration, over a 10- to 12-fold dose range, revealed a dose-related increase in injury as well as tissue repair up to a threshold dose. Beyond this threshold, tissue repair was delayed and attenuated, and liver injury progressed. Mixtures of the four chemicals at the higher doses used in individual dose-response studies resulted in 100% mortality. Hence , mixtures at the lower two doses were selected for further study. Addition al lower doses were also included to better understand the dose-response re lationship of mixtures. Results of these studies support the observations o f individual chemicals. Higher and sustained repair was observed at low dos e levels. These studies show that the extent of injury at early time points correlates well with the maximal stimulation of the opposing response of t issue repair. It appears that the toxicity of the mixture employed in these studies is roughly additive and correlates well with tissue repair respons e. These initial studies suggest that a biologically based mathematical mod el can be constructed and tested to extrapolate the outcome of toxicity fro m a given dose of individual compounds as well as their mixtures, where the responses measured are injury on the one hand and compensatory tissue repa ir on the other. (C) 1999 Academic Press.