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Prediction of internal dosimetry and toxicity of volatile chemicals in rats using physiologically based pharmacokinetic modeling: carbon tetrachloride as a model compound
Citation:
Williams, D., J. Simmons, J. Bruckner, AND M. Evans. Prediction of internal dosimetry and toxicity of volatile chemicals in rats using physiologically based pharmacokinetic modeling: carbon tetrachloride as a model compound. Society of Toxicology, San Antonio, Texas, March 11 - 15, 2018.
Impact/Purpose:
Volatile organic chemicals (VOCs) present in drinking water as contaminants lead to exposure by different routes of exposure. These routes include inhalation, oral (drinking water), and dermal routes. We constructed a PBPK model using carbon tetrachloride (CCl4) as a model compound having blood and organ data needed to calibrate the PBPK model. The PBPK model was then used to calculate internal dose for liver and brain. Hepatotoxicity biomarker data was then correlated with internal dose for liver using the oral route. Based on these results, the peak concentration is a major factor in determining liver toxicity. Based on correlation of internal target organ and biomarkers using PBPK models, we can quantify effect after exposure.
Description:
Prediction of internal dosimetry and toxicity of volatile chemicals in rats using physiologically based pharmacokinetic modeling: carbon tetrachloride as a model compound D.N. Williams1, J.E. Simmons2, J.V. Bruckner3, and M.V. Evans2 1ORISE, Oak Ridge, TN 37831-0117; 2US EPA/ORD/NHEERL, RTP, NC 27711; 3University of Georgia, Athens, GA 30602 Volatile organic compounds (VOCs) in drinking water can cause acute or chronic injury to the liver, kidneys, and/or central nervous system. Exposure to VOCs in contaminated water can occur via multiple routes, such as ingestion, inhalation, and dermal absorption. The extent to which each of the various routes of exposure contributes to internal dosimetry and toxicity is an important question. In the face of a large number of VOCs and limited data, computer simulations can be used to predict dosimetry in target organs of concern. Experimental data from carbon tetrachloride (CCl4) show how exposure route impacts hepatotoxicity in rats. Here, a physiologically based pharmacokinetic (PBPK) model is developed to simulate (CCl4) exposure in Sprague-Dawley rats (0.325 – 0.375 kg) through multiple routes. The inhaled concentration of carbon tetrachloride was 1000 ppm over 2 hours, which corresponds with 179 mg CCl4 /kg body weight for bolus and for 2 hours of gastric infusion. The different exposure routes and available tissue datasets allowed us to calibrate a PBPK model for CCl4, including liver as the target organ. The simulations were used to calculate different metabolic metrics, which were correlated with measured toxicity parameters. We hypothesized that similar amounts metabolized in the liver, independent of exposure route, would lead to equivalent toxicity. The model estimate of amount metabolized over 24 hours (bolus 1.2 mg, infusion 1.4 mg, and inhalation 1.2 mg) did not match with the toxicity trend (SDH 269 mU/mL, 96.9 mU/mL, and 87.6 mU/mL, respectively), but we found the predicted maximum liver concentration of CCl4 for each route of exposure (bolus 186.6 mg/L, infusion 118.3 mg/L, and inhalation 73.6 mg/L) appeared to correlate with toxicity. Validation of these mechanistic metrics can be used to predict effects from other VOCs in humans or other animals, thus streamlining future VOC experiments. (This abstract does not reflect US EPA policy).