Role of tissue repair in toxicologic interactions among hepatotoxic organics

it is widely recognized that exposure to combinations or mixtures of chemic als may result in highly exaggerated toxicity even though individual chemic als might not be toxic at low doses. Chemical mixtures may also cause addit ive or less than additive toxicity. From the perspective of public health, highly exaggerated toxicity is of significant concern. Assessment of risk f rom exposure to chemical mixtures requires knowledge of the underlying mech anisms, Previous studies from this laboratory have shown that nontoxic dose s of chlordecone (10 ppm, 15 days) and carbon tetrachloride (CCl4) (100 mu l/kg) interact at the biologic interface, resulting in potentiated liver in jury and 67-fold amplification of CCl4 lethality, In contrast, although int eraction between phenobarbital and CCl4 leads to even higher injury, animal survival is unaffected because of highly stimulated compensatory tissue re pair. A wide variety of additional experimental evidence confirms the centr al role of stimulated tissue repair as a decisive determinant of the final outcome of liver injury inflicted by hepatotoxicants. These findings led us to propose a two-stage model of toxicity. in this model, tissue injury is inflicted in stage one by the well-described mechanisms of toxicity, wherea s in stage two the ultimate toxic outcome is determined by whether timely a nd sufficient tissue repair response accompanies this injury, In an attempt to validate this model, dose-response relationships for injury and tissue repair as opposing responses have been developed for model hepatotoxicants. Results of these studies suggest that tissue repair increases in a dose-de pendent manner, restraining injury up to a threshold dose, whereupon it is inhibited, allowing an unrestrained progression of injury, These findings i ndicate that tissue repair is a quantifiable response to toxic injury and t hat inclusion of this response in risk assessment may help in fine-tuning p rediction of toxicity outcomes.