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 chemicals may result in highly exaggerated toxicity even though the individual 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 ordinarily inconsequential dose of CCl4($100 \mu l/kg$, ip). Toxicity of closely related CHCl3and$BrCCl_3$is also enhanced. Phenobarbital (PB, 225 ppm, 15 days) and mirex (10 ppm, 15 days) do not share the propensity of CD in this regard. Exposure to$PB + CCl_4$results in enhanced liver injury similar to that observed with CD, but the animals recover and survive in contrast to the greatly amplified lethality of$CD + CCl_4$. Investigations have revealed that neither enhanced bioactivation of CCl4nor increased lipid peroxidation offers a satisfactory explanation of these findings. Additional studies indicate that exposure to a low dose of CCl4($100 \mu l/kg$, ip) results in limited injury, which is accompanied by a biphasic response of hepatocellular regeneration (6 and 36 hr) and tissue repair, which enables the animals to recover from injury. Exposure to$CD + CCl_4$results in suppressed tissue repair owing to an energy deficit in hepatocytes as a consequence of excessive intracellular 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 recovery from the toxicity of$CD + CCl_4$combination. In contrast, only the early-phase hepatic tissue repair (6 hr) is affected in$PB + CCl_4$treatment, but this is adequately compensated for by a greater stimulation of tissue repair at 24 and 48 hr resulting in recovery from liver injury and animal survival. A wide variety of additional experimental evidence confirms the central role of stimulated tissue repair as a decisive determinant of the final outcome of liver injury inflicted by CCl4. For instance, a 35-fold greater CCl4sensitivity 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, where tissue injury is inflicted by the well described "mechanisms of toxicity," but the outcome of this injury is determined by whether or not sustainable tissue repair response accompa