US EPA

6640546 

Journal Article 

A physiologically based pharmacokinetic model for naphthalene with inhalation and skin routes of exposure 

Kapraun, DF; Schlosser, PM; Nylander-French, LA; Kim, D; Yost, EE; Druwe, IL 

2020 

1 

Journal of Toxicological Sciences
ISSN: 0388-1350
EISSN: 1880-3989 

177 

2 

377-391 

English 

32687177 

10.1093/toxsci/kfaa117 

WOS:000593274600007 

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85092802234&doi=10.1093%2ftoxsci%2fkfaa117&partnerID=40&md5=b37f628a76efa508d28f18c9bb17a453
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Naphthalene, a volatile organic compound present in moth repellants and petroleum-based fuels, has been shown to induce toxicity in mice and rats during chronic inhalation exposures. While simpler default methods exist for extrapolating toxicity points of departure from animals to humans, using a physiologically based pharmacokinetic (PBPK) model to perform such extrapolations is generally preferred. Confidence in PBPK models increases when they have been validated using both animal and human in vivo pharmacokinetic (PK) data. A published inhalation PBPK model for naphthalene was previously shown to predict rodent PK data well, so we sought to evaluate this model using human PK data. The most reliable human data available come from a controlled skin exposure study, but the inhalation PBPK model does not include a skin exposure route; therefore, we extended the model by incorporating compartments representing the stratum corneum and the viable epidermis and parameters that determine absorption and rate of transport through the skin. The human data revealed measurable blood concentrations of naphthalene present in the subjects prior to skin exposure, so we also introduced a continuous dose-rate parameter to account for these baseline blood concentration levels. We calibrated the three new parameters in the modified PBPK model using data from the controlled skin exposure study but did not modify values for any other parameters. Model predictions then fell within a factor of two of most (96%) of the human PK observations, demonstrating that this model can accurately predict internal doses of naphthalene and is thus a viable tool for use in human health risk assessment. 

PBPK model; skin model; computational fluid dynamics; CFD