Target organ toxicity in Sprague Dawley rats following oral exposure to complex groundwater mixture: Assessment of dose-response relationships using histopathological and biochemical alterations

Exposure to contaminant mixtures from industrial legacy sites presents unique challenges that require novel approaches such as effects-directed toxicity assessment. This study characterized the target organ toxicity of groundwater from a legacy contaminated pesticide plant in male and female Sprague Dawley rats exposed to low impact (10% v/v) groundwater, high impact (0.01% v/v, 0.1% v/v, 1% v/v, and 10% v/v) groundwater or tap water (control) for 60 days. Rats exposed to high impact (1% and 10%) and 10% low impact groundwater mixture showed statistically significant increases in liver necro-inflammation relative to control. A statistically significant reduction was observed in plasma albumin of exposed rats (except 0.01% high impact) and alpha 2 macroglobulin (all exposed) when compared to the control. All groundwater-exposed rats showed glomerulopathy, but there were sex-specific differences in acute tubular necrosis. Testes showed germinal cell vacuolation, necrosis, reduced seminiferous epithelial height, and Sertoli syndrome in exposed rats, accompanied by reduced plasma testosterone and increased testicular malondialdehyde. Taken together, this sub-chronic oral exposure to groundwater from a contaminated industrial site caused dose-dependent hepatic and testicular toxicity, while nephrotoxicity was both sex-dependent and dose-dependent. This study provides support for the essentiality of using effects-driven approaches in the risk assessment of complex mixtures.