A review of the role of tissue repair as an adaptive strategy: why low doses are often non-toxic and why high doses can be fatal.

The role of tissue repair as an adaptive strategy by species is important to consider in both evolutionary and toxicological perspectives. This paper assesses the distinct and integrative roles of early phase regeneration (EPR) (i.e. arrested G2 hepatocytes chemically activated to proceed through mitosis) and secondary phase regeneration (SPR) (i.e. hepatocytes mobilized principally from G0/G1 to proceed through mitosis) in the repair of carbon tetrachloride (CCl4)-induced liver damage. The role of EPR as a triage system facilitating repair of minor toxic insults as well as providing an essential role in autoprotection as an initial step to augment and sustain SPR is proposed. The function of EPR is then compared with that of SPR in tissue recovery following more massive injury. The interrelationships of these two repair processes with EPR invoking and accelerated SPR following low-to-modest degrees of toxicant-induced hepatotoxicity as well as in auto- or hetero-protection supports the theory that the two responses are co-ordinated in time and functionality. The integration of these two repair processes as shown through experimental manipulation provides a new mechanistic framework to account for the previously reported profound (67-fold) potentiation of acute CCl4 hepatotoxicity by chlordecone (kepone) in adult male Sprague-Dawley rats as well as important interspecies variation in susceptibility to hepatotoxic agents in general and CCl4 in particular. On the basis of the distinct and integrative roles of EPR and SPR in liver responses to toxic injury, a generalized framework is presented that facilitates prediction of both toxic outcome, including shape of dose-response functions and interspecies variation to chemically induced liver damage.