A REVIEW OF THE ROLE OF TISSUE-REPAIR AS AN ADAPTIVE STRATEGY - WHY LOW-DOSES ARE OFTEN NONTOXIC AND WHY HIGH-DOSES CAN BE FATAL

The role of tissue repair as an adaptive strategy by species is import ant to consider in both evolutionary and toxicological perspectives. T his paper assesses the distinct and integrative roles of early phase r egeneration (EPR) (i.e. arrested G(2) hepatocytes chemically activated to proceed through mitosis) and secondary phase regeneration (SPR) (i .e. hepatocytes mobilized principally from G(0)/G(1) to proceed throug h mitosis) in the repair of carbon tetrachloride (CCl4)-induced liver damage. The role of EPR as a triage system facilitating repair of mino r toxic insults as well as providing an essential role in autoprotecti on as an initial step to augment and sustain SPR is proposed. The func tion of EPR is then compared with that of SPR in tissue recovery follo wing more massive injury. The interrelationships of these two repair p rocesses with EPR invoking an accelerated SPR following low-to-modest degrees of toxicant-induced hepatotoxicity as well as in auto- or hete ro-protection supports the theory that the two responses are co-ordina ted in time and functionality. The integration of these two repair pro cesses as shown through experimental manipulation provides a new mecha nistic framework to account for the previously reported profound (67-f old) potentiation of acute CCl4 hepatotoxicity by chlordecone (kepone) in adult male Sprague-Dawley rats as well as important interspecies v ariation in susceptibility to hepatotoxic agents in general and CCl4 i n particular. On the basis of the distinct and integrative roles of EP R and SPR in liver responses to toxic injury, a generalized framework is presented that facilitates prediction of both toxic outcome, includ ing shape of dose-response functions and interspecies variation to che mically induced liver damage.