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To evaluate health effects of chemical mixtures, such as multiple heavy metals in drinking water, we have been developing efficient and accurate hazard identification strategies. Thus, in this study, we determine the cytotoxicity of arsenic, cadmium, chromium, and lead, and characterize interactions among these metals in human epidermal keratinocytes. Three immortal keratinocyte cell lines (RHEK-1, HaCaT, and NM1) and primary keratinocytes (NHEK) were used. A statistical approach applying an additivity response surface methodology was used to test the validity of the additivity concept for a 4-metal mixture. Responses of the 4 keratinocyte strains to the metal mixture were highly dose-dependent. A growth stimulatory effect (hormesis) was observed in RHEK-1, NM1, and NHEK cells with the metal mixture at low concentrations (low ppb range). This hormesis effect was not significant in HaCaT. As the mixture concentration increased, a trend of additivity changed to synergistic cytotoxicity in all 4 cell strains. However, in NHEK, RHEK-1, and HaCaT, at the highest mixture concentrations tested, the responses to the metal mixtures were antagonistic. In NM1, no significant antagonistic interaction among the metals was observed. To explore a mechanistic basis for these differential sensitivities, levels of glutathione and metallothioneins I and II were determined in the keratinocyte cell strains. Initial data are consistent with the suggestion that synergistic cytotoxicity turned to antagonistic effects because at highest mixture exposure concentrations cellular defense mechanisms were enhanced.

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1962 (4). This bioassay program was later transferred to the U.S. National Toxicology Program upon its establishment in 1978. In the bioassay program's combined 36 years of operation, approximately 500 chemicals have been studied for carcinogenicity and other chronic toxicities (5). These studies and the related range-finding and dose-setting studies are extremely expensive, they require large numbers of animals, and the study duration is long (6). Even though these studies are the gold standards, considering the approximately 70,000 to 600,000 chemicals in commerce (7-9), the number of chemicals for which we currently have adequate toxicology information for risk assessment is minuscule. At the present mode and rate of study of these chemicals, it is doubtful that our society will ever have a thorough toxicologic evaluation on the majority of the chemicals that are used now or may be used in the future.