TOXICODYNAMICS OF LOW-LEVEL TOXICANT INTERACTIONS OF BIOLOGICAL SIGNIFICANCE - INHIBITION OF TISSUE-REPAIR

Because of the complexity of studying the toxicological effects of mix tures of chemicals, much of the mechanistic information has become ava ilable through work with binary mixtures of toxic chemicals. Mechanism s derived from studies employing chemicals at individually nontoxic do ses are more useful than the mechanisms of interactive toxicity at hig h doses from the perspective of environmental and public health. Sever al examples of chemical combinations and interactive toxicity at low d oses are now available. Chlordecone-potentiated halomethane hepatotoxi city, where suppression of cell division and tissue repair response pe rmits very high amplification of CCl4 injury culminating in animal mor tality, is one such model. Phenobarbital-potentiated CCl4 injury does not lead to animal mortality in spite of much higher liver injury in c omparison to the chlordecone + CCl4 model. Much higher stimulation of tissue repair allows the animals to survive despite higher liver injur y. Similar interactions have been reported between alcohols and halome thane toxicants. These and other studies have revealed that infliction of toxicant-induced injury is accompanied by a parallel but opposing tissue repair stimulation response which allows the animals to overcom e that injury up to a threshold dose. Beyond this threshold, tissue re pair response is both diminished and delayed allowing unrestrained pro gression of injury. Large doses of chemicals can be predictably lethal owing to these two latter effects on tissue repair. Dose-response par adigms in which tissue repair response is measured as a parallel but o pposing effect to toxic injury might be useful in more precise predict ion of the ultimate outcome of toxic injury in risk assessment. Autopr otection experiments with CCl4, thioacetamide, 2-butoxyethanol and rel ated chemicals as well as heteroprotection against acetaminophen-induc ed lethality with thioacetamide are examples where tissue repair stimu lation has been shown to rescue the animals from massive and normally lethal liver injury. The concept of toxicodynamic interaction between inflicted injury and stimulated tissue repair offers mechanistic oppor tunity to fine-tune other aspects of human health risk assessment proc edure. Tissue repair mechanisms may also offer a mechanistic basis to explain species and strain differences as well as to more accurately a ssess inter-individual differences in human sensitivity to toxic chemi cals. Because tissue repair is affected by nutritional status, assessm ent of risk from exposure to chemicals without attention to nutritiona l status may be misleading. Finally, the concept of using maximum tole rated doses (MTDs) in long-term toxicity studies such as cancer bioass ays may need to be re-examined. MTDs might be predictably expected to maximally stimulate cell division and it is known that increased cell division is likely to lead to increased number of errors iri DNA repli cation thereby predisposing these animals to cancer. It is clear that detailed studies of toxicodynamic interaction between tissue injury an d stimulated tissue repair are likely to yield significant dividends i n fine-tuning risk assessment.