Use of In Vitro Data for Construction of a Physiologically Based Pharmacokinetic Model for Naphthalene in Rats and Mice To Probe Species Differences

Abstract

A physiologically based pharmacokinetic (PBPK) model with five tissue groups (lung, liver, fat, richly perfused, and poorly perfused tissues plus venous and arterial blood compartments) has been developed from in vitro data and models of primary cell cultures for naphthalene toxicity in mice and rats. It extends a previous naphthalene PBPK model (Sweeney et al., 1996) and demonstrates a possible approach to a predictive mathematical model that requires minimal animal data. Naphthalene metabolism was examined after four exposure routes (intraperitoneal injection (ip), intravenous injection (iv), ingestion (po), and inhalation). Naphthalene and its primary metabolite, naphthalene oxide, are consumed by enzymes in pulmonary and hepatic tissues (cytochrome P450 monooxygenases, epoxide hydrolase, and glutathione-S-transferase). Additionally, the nonenzymatic reactions of naphthalene oxide in all tissues and in blood are included in the model. Kinetic constants for the model were derived primarily from cell fraction and primary cell culture incubations presented in the literature. The mouse model accurately predicts glutathione (GSH) and covalent naphthalene oxide-protein binding levels after a range of ip doses, and the rat model provides excellent estimates for mercapturate excretion following po doses; but neither model simulates well naphthalene blood concentrations after low iv doses. Good prediction of in vivo response using only in vitro data for parameter estimation (except for epoxide-protein binding rates) suggests that the assumed molecular description is a plausible representation of the underlying mechanisms of toxicity. Mice and rats show significant species differences in response to naphthalene. The model results suggest that species differences in toxicity may be explained, in part, by the lower overall rate of enzyme activities in the rat cells. Lower enzyme activities in the rat result in out-of-phase GSH minima in hepatic and lung compartments, while the simultaneous occurrence of these minima in mice results in higher naphthalene oxide concentrations, thereby allowing formation of more metabolites (e.g., covalent binding to proteins) that may be toxic.

Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action

“…If sufficient data are available, a preferred surrogate closer to the ultimate toxic form could be used, such as mean or peak intracellular concentration of (total, or only 1R,2S enantiomeric) naphthalene-oxide, or of 1,2-naphthoquinone in the target tissue. Physiologically based pharmacokinetic (PBPK) models developed for naphthalene (e.g., Sweeney et al, 1996;Quick and Shuler, 1999;Ghanem and Shuler, 2000;Willems et al, 2001) demonstrate a reasonable approach to estimate such reasonably plausible measures of surrogate biologically effective dose as a function of bioassay-administered dose. However, the current models are only capable of estimating doses for the total lung.…”

“…Current understanding of the anatomy and physiology of nasal/respiratory tissues in rodents, primates and humans is adequate to extend the PBPK models developed for naphthalene nasal and lung effects (e.g., Sweeney et al, 1996;Quick and Shuler, 1999;Ghanem and Shuler, 2000;Willems et al, 2001) to include a more detailed description of target tissues. An existing model for a similar compound, styrene (Sarangapani et al, 2002), would help to inform this effort.…”

Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

“…Physiologically based pharmacokinetic (PBPK) models developed for naphthalene (Sweeney et al, 1996), and for naphthalene and its 1,2-epoxide metabolite and associated reaction products (Quick and Shuler, 1999;Ghanem and Shuler, 2000;Willems et al, 2001), have been used to describe and explore plausible measures of biologically effective dose pertaining to naphthalene toxicity and carcinogenicity. PBPK model parameters governing naphthalene metabolism for the earlier models were estimated entirely from in vitro metabolic data, and then were compared and/or partially optimized to previously published data on levels of naphthalene in blood, tissue-specific GSH, and 14 C-radiolabeled adducts covalently bound to tissue-specific macromolecules in mice and rats exposed in vivo to naphthalene by intravenous (iv) injection, intraperitoneal (ip) injection, or oral dosing (Sweeney et al, 1996;Quick and Shuler, 1999;Ghanem and Shuler, 2000).…”

“…PBPK model parameters governing naphthalene metabolism for the earlier models were estimated entirely from in vitro metabolic data, and then were compared and/or partially optimized to previously published data on levels of naphthalene in blood, tissue-specific GSH, and 14 C-radiolabeled adducts covalently bound to tissue-specific macromolecules in mice and rats exposed in vivo to naphthalene by intravenous (iv) injection, intraperitoneal (ip) injection, or oral dosing (Sweeney et al, 1996;Quick and Shuler, 1999;Ghanem and Shuler, 2000). The Quick and Shuler (1999) model, summarized in Figure 3, predicts detailed, time-dependent patterns of covalent binding and GSH depletion in lung and in liver of mice administered naphthalene by ip injection that were shown to be reasonably consistent with a range of previously published data, including detailed data reported by Warren et al (1982) for mice ip-injected with radiolabeled naphthalene. ways.…”

“…The "distributed blood" framework was developed by Kohn (1997), who showed this approach to provide a more realistic model the kinetics of respiratory 1,3-butadiene uptake by mice. Second, Willems et al (2001) replaced the submodel for glutathione (GSH) turnover used by Quick and Shuler (1999) with the generic GSH model incorporated into the PBPK model otherwise developed specifically for 1,3-butadiene (Kohn and Melnick, 2000). Using this modified PBPK model, Willems et al (2001) estimated parameters governing CYP-mediated naphthalene metabolism in both liver and lung by fitting model predictions for naphthalene in chamber air in rats exposed for 6 hours (once, or daily for two weeks) to concentrations of 10, 30 or 60 ppm naphthalene, and for naphthalene in blood of mice exposed for 6 hours (once, or daily for two weeks) to concentrations of 10, 30 or 60 ppm naphthalene-i.e., using respiratory exposure protocols similar to those used in the NTP obtained in vivo data on naphthalene uptake and distribution in rats and mice.…”