Toxicodynamics of low level toxicant interactions of biological significance: inhibition of tissue repair.

Because of the complexity of studying the toxicological effects of mixtures of chemicals, much of the mechanistic information has become available through work with binary mixtures of toxic chemicals. Mechanisms derived from studies employing chemicals at individually nontoxic doses are more useful than the mechanisms of interactive toxicity at high doses from the perspective of environmental and public health. Several examples of chemical combinations and interactive toxicity at low doses are now available. Chlordecone-potentiated halomethane hepatotoxicity, where suppression of cell division and tissue repair response permits very high amplification of CCl4 injury culminating in animal mortality, is one such model. Phenobarbital-potentiated CCl4 injury does not lead to animal mortality in spite of much higher liver injury in comparison to the chlordecone+CCl4 model. Much higher stimulation of tissue repair allows the animals to survive despite higher liver injury. Similar interactions have been reported between alcohols and halomethane 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 overcome that injury up to a threshold dose. Beyond this threshold, tissue repair response is both diminished and delayed allowing unrestrained progression of injury. Large doses of chemicals can be predictably lethal owing to these two latter effects on tissue repair. Dose-response paradigms in which tissue repair response is measured as a parallel but opposing effect to toxic injury might be useful in more precise prediction of the ultimate outcome of toxic injury in risk assessment. Autoprotection experiments with CCl4, thioacetamide, 2-butoxyethanol and related chemicals as well as heteroprotection against acetaminophen-induced lethality with thioacetamide are examples where tissue repair stimulation 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 opportunity to fine-tune other aspects of human health risk assessment procedure. Tissue repair mechanisms may also offer a mechanistic basis to explain species and strain differences as well as to more accurately assess inter-individual differences in human sensitivity to toxic chemicals. Because tissue repair is affected by nutritional status, assessment of risk from exposure to chemicals without attention to nutritional status may be misleading. Finally, the concept of using maximum tolerated doses (MTDs) in long-term toxicity studies such as cancer bioassays 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 in DNA replication thereby predisposing these animals to cancer. It is clear that detailed studies of toxicodynamic interaction between tissue injury and stimulated tissue repair are likely to yield significant dividends in fine-tuning risk assessment.