title: Development and application of a human PBPK model for bromodichloromethane to investigate the impacts of multi-route exposure.
abstract: As a result of its presence in water as a volatile disinfection byproduct, bromodichloromethane (BDCM), which is mutagenic, poses a potential health risk from exposure via oral, dermal and inhalation routes. We developed a refined human physiologically based pharmacokinetic (PBPK) model for BDCM (including new chemical-specific human parameters) to evaluate the impact of BDCM exposure during showering and bathing on important measures of internal dose compared with oral exposure. The refined model adequately predicted data from the published literature for oral, dermal and bathing/showering exposures. A liter equivalency approach (L-eq) was used to estimate BDCM concentration in a liter of water consumed by the oral route that would be required to produce the same internal dose of BDCM resulting from a 20-min bath or a 10-min shower in water containing 10 µg l(-1) BDCM. The oral liter equivalent concentrations for the bathing scenario were 605, 803 and 5 µg l(-1) BDCM for maximum venous blood concentration (Cmax), the area under the curve (AUCv) and the amount metabolized in the liver per hour (MBDCM), respectively. For a 10-min showering exposure, the oral L-eq concentrations were 282, 312 and 2.1 µg l(-1) for Cmax, AUC and MBDCM, respectively. These results demonstrate large contributions of dermal and inhalation exposure routes to the internal dose of parent chemical reaching the systemic circulation, which could be transformed to mutagenic metabolites in extrahepatic target tissues. Thus, consideration of the contribution of multiple routes of exposure when evaluating risks from water-borne BDCM is needed, and this refined human model will facilitate improved assessment of internal doses from real-world exposures. Published 2015. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
authors.affiliation: Integrated Systems Toxicology Division, U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, USA.
authors.forename: Elaina M
authors.initials: EM
authors.lastname: Kenyon
authors.affiliation: Integrated Systems Toxicology Division, U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Eklund
authors.affiliation: Pharmacokinetic Consultant, Cary, NC, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Leavens
authors.affiliation: Integrated Systems Toxicology Division, U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, USA.
authors.forename: Rex A
authors.initials: RA
authors.lastname: Pegram
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects* / Q000032:analysis; D005260:Female; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D018675:Toxicity Tests; D022882:Trihalomethanes / Q000633:toxicity; D014874:Water Pollutants, Chemical / Q000032:analysis / Q000633:toxicity; D055815:Young Adult
chemical_list: D022882:Trihalomethanes; D014874:Water Pollutants, Chemical; C025191:bromodichloromethane
keywords: PBPK model; bromodichloromethane; multi-route exposure