Pesticide mixtures potentiate the toxicity in murine thymocytes.

The immunotoxic risks of multiple pesticide exposure were evaluated. C57BL/6 mouse thymocytes were exposed to lindane, malathion, and permethrin, either separately or in mixtures of two pesticides, in vitro. These pesticide exposures caused both apoptotic and necrotic cell death in thymocytes as evaluated by flow cytometric analysis in combination with 7-aminoactinomycin-D (7-AAD), Annexin-V/propidium iodide (PI) staining assays and lactate dehydrogenase release assays. When cells exposed to mixtures of two pesticides, a significantly greater than additive interaction was observed in both apoptotic and necrotic populations of cells. The gel electrophoresis of DNA of cells showed DNA ladder formation with limited genomic DNA and increased laddering in mixture exposures. Based on these findings, it is suggested that these pesticides are potent immunotoxicants, in vitro, and that the mechanism of cytotoxicity observed upon exposure to these pesticides may, at least in part, be due to induction of apoptosis. We also provided evidence that induction of drug metabolizing mixed function oxidase system with lindane may, in part, be responsible for the potentiation of cytotoxicity in the combined exposures. As more information is obtained on the potential immunotoxic effects of pesticides, further insights will be gained for the risk assessment of these environmental pollutants.

Pharmacokinetics/pharmacodynamics (PK/PD) modeling of risks of kidney toxicity from exposure to cadmium: estimates of dietary risks in the U.S. population.

An analysis of epidemiological studies of associations between exposure to cadmium and kidney toxicity was conducted. Dose-response functions relating low-molecular-weight (LMW) proteinuria to various indices of cadmium dose (dietary cadmium intake, urinary cadmium excretion, or tissue cadmium burden) were obtained from 15 studies of diverse exposures (occupational, general environmental, environmental contamination). Estimates of the dose corresponding to probabilities of LMW proteinuria of 0.1, 0.15, or 0.2 were transformed from the reported dose units into corresponding estimates of target organ dose (microgram Cd/g renal cortex, RC) by simulation using a pharmacokinetics (PK) model. The median RC associated with a 0.1 probability (RC10M) of LMW proteinuria was predicted to be 153 micrograms Cd/g cortex (95% confidence interval [CI]: 84-263). The lower confidence limit on the RC10M (RC10L, 84 micrograms/g cortex) was predicted to be attained with a constant chronic intake of 1 microgram/kg/d in females or 2.2 micrograms/kg/d in males. The RC10L was 2.5-5 times higher than the median RCs predicted to result from dietary cadmium intake in U.S. nonsmokers (microgram Cd/g cortex: 33, females; 17, males) and 1.6-3 times higher than the corresponding 95th percentile RCs (53, females; 27, males). Additional exposure from smoking cigarettes (approximately 20 cigarettes/d, 3 micrograms Cd inhaled/d) was predicted to increase the median RC (microgram/g cortex) by approximately 45-70% (48, females; 29, males); however, predicted 95th percentile RCs for smokers (66, females; 38, males) were lower than the RC10L. These results indicate that, for most of the U.S. population, dietary-derived risks are likely to be negligible, in the absence of exposures from other sources.