Use of in vitro data in developing a physiologically based pharmacokinetic model: Carbaryl as a case study.

In vitro-derived information has been increasingly used to support and improve human health risk assessment for exposure to chemicals. Physiologically based pharmacokinetic (PBPK) modeling is a key component in the movement toward in vitro-based risk assessment, providing a tool to integrate diverse experimental data and mechanistic information to relate in vitro effective concentrations to equivalent human exposures. One of the challenges, however, in the use of PBPK models for this purpose has been the need for extensive chemical-specific parameters.

Cytotoxicity of naphthalene toward cells from target and non-target organs in vitro.

Chronic inhalation exposure to high concentrations of naphthalene produced nasal tumors in rats and lung tumors in female mice. Naphthalene bioactivation is required for target organ toxicity and cytotoxicity in target organs may be involved in tumor development. The present studies characterized the dose-response relationships for naphthalene-induced glutathione (GSH) depletion, effects on cellular ATP, and cytotoxicity in cells from both target (lung, nasal epithelium) and non-target (liver) organs in vitro using cells from F-344 rats, B6C3F1 mice and humans.

Application of an updated physiologically based pharmacokinetic model for chloroform to evaluate CYP2E1-mediated renal toxicity in rats and mice.

Physiologically based pharmacokinetic (PBPK) models are tools for interpreting toxicological data and extrapolating observations across species and route of exposure. Chloroform (CHCl(3)) is a chemical for which there are PBPK models available in different species and multiple sites of toxicity. Because chloroform induces toxic effects in the liver and kidneys via production of reactive metabolites, proper characterization of metabolism in these tissues is essential for risk assessment.

Dose-response assessment of naphthalene-induced genotoxicity and glutathione detoxication in human TK6 lymphoblasts.

The dose-response relationship for the induction of micronuclei (MN) and the impact of glutathione (GSH) detoxication on naphthalene-induced cytotoxicity and genotoxicity were investigated in human TK6 cells. TK6 cells were exposed to 10 concentrations ranging from 0.0625 to 30μM naphthalene in the presence of β-naphthoflavone- and phenobarbital (βNP/PB)-induced rat liver S9 with a nicotinamide adenine dinucleotide phosphate-generating system.

Kinetics of arsenic methylation by freshly isolated B6C3F1 mouse hepatocytes.

The toxic and carcinogenic effects of arsenic may be mediated by both inorganic and methylated arsenic species. The methylation of arsenic(III) is thought to take place via sequential oxidative methylation and reduction steps to form monomethylarsenic (MMA) and dimethylarsenic (DMA) species, but recent evidence indicates that glutathione complexes of arsenic(III) can be methylated without oxidation. The kinetics of arsenic methylation were determined in freshly isolated hepatocytes from male B6C3F1 mice.