Correlation of synergistic cytotoxic effects of environmental chemicals in human fibroblasts with their lipophilicity

The cytotoxic combination effects of 2,4-D with 12 xenobiotics having different lipophilicity were investigated in human fibroblasts at their no effect concentrations (NOEC). Each of the chemicals tested in binary combinations enhanced the toxicity of 2,4-D. These synergistic combination effects were independent of the chemical structure of the test compounds. However, the NOECʹs of the xenobiotics used in the combinations varied by a factor of 10 000. For strongly lipophilic compounds the lowest NOECʹs were needed to induce synergistic cytotoxicity. A linear regression analysis of the concentrations (NOECʹs) of the 12 combined xenobiotics against their lipophilicity revealed a correlation with R = 0.96 for 11 agents. This close correlation may be explained by the membrane damaging properties of lipophilic compounds which enhance the uptake of hydrophilic agents.