AMPLIFIED INTERACTIVE TOXICITY OF CHEMICALS AT NONTOXIC LEVELS - MECHANISTIC CONSIDERATIONS AND IMPLICATIONS TO PUBLIC-HEALTH

It is widely recognized that exposure to combinations or mixtures of c hemicals may result in highly exaggerated toxicity even though the ind ividual chemicals might not be toxic. Assessment of risk from exposure to combinations of chemicals requires the knowledge of the underlying mechanism(s). Dietary exposure to a nontoxic dose of chlordecone (CD; 10 ppm, 15 days) results in a 67 fold increase in lethality of an ord inarily inconsequential dose of CCl4 (100 mu l/kg, ip). Toxicity of cl osely related CHCl3 and BrCCl3 is also enhanced. Phenobarbital (PB, 22 5 ppm, 15 days) and mirex (10 ppm, 15 days) do not share the propensit y of CD in this regard. Exposure to PB + CCl4 results in enhanced live r injury similar to that observed with CD, but the animals recover and survive in contrast to the greatly amplified lethality of CD + CCl4. Investigations have revealed that neither enhanced bioactivation of CC l4 nor increased lipid peroxidation offers a satisfactory explanation of these findings. Additional studies indicate that exposure to a low dose of CCl4 (100 mu l/kg, ipi results in limited injury, which is acc ompanied by a biphasic response of hepatocellular regeneration (6 and 36 hr) and tissue repair, which enables the animals to recover from in jury. Exposure to CD + CCl4 results in suppressed tissue repair owing to an energy deficit in hepatocytes as a consequence of excessive intr acellular influx of Ca2+ leading initially to a precipitous decline in glycogen and ultimately to hypoglycemia. Supplementation of cellular energy results in restoration of the tissue repair and complete recove ry from the toxicity of CD + CCl4 combination. In contrast, only the e arly-phase hepatic tissue repair (6 hr) is affected in PB + CCl4 treat ment, but this is adequately compensated for by a greater stimulation of tissue repair at 24 and 48 hr resulting in recovery from liver inju ry and animal survival. A wide variety of additional experimental evid ence confirms the central role of stimulated tissue repair as a decisi ve determinant of the final outcome of liver injury inflicted by CCl4. For instance, a 35-fold greater CCl4 sensitivity of gerbils compared to rats is correlated with the very sluggish tissue repair in gerbils. These findings are consistent with a two-stage model of toxicity, whe re tissue injury is inflicted by the well described ''mechanisms of to xicity,'' '' but the outcome of this injury is determined by whether o r not sustainable tissue repair response accompanies this injury. Thes e findings impact significantly on our ability to predict the ultimate outcome of toxic injury and form a firm basis for additional mechanis m-driven investigations into the endogenous tissue repair response evo ked by tissue injury. These concepts will enhance our ability to fine- tune the tools of risk assessment such as animal-to-man extrapolation and prediction of ultimate outcome of toxic injury.