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.

Challenges Associated With Applying Physiologically Based Pharmacokinetic Modeling for Public Health Decision-Making

“…Physiologically based pharmacokinetic (PBPK) modeling is a valuable tool that arose from the recognition that concentrations of chemicals at target tissues are more predictive of biological responses than are external doses (US EPA, 2006; WHO, 2010). PBPK models have been applied to organize and integrate mechanistic data, to generate hypotheses and to drive new experimental studies (Abaci and Shuler, 2015; Claassen et al , 2015; Bachler et al, 2013), to characterize physiological and pharmacokinetic variability and uncertainty (Barton et al , 2007; Beaudouin et al , 2010; Bois et al , 2010; Fierens et al , 2016; Worley et al , 2017), to support aggregate exposure assessment (Kenyon et al , 2016), to extrapolate across species, life stages, exposure routes and timing (Andersen et al , 1987; Gentry et al , 2017a; Shankaran et al , 2013; Weijs et al , 2012; Yoon and Clewell, 2016), and to interpret biomonitoring data or epidemiologic studies (Brown et al , 2015; McNally et al , 2012; Verner et al , 2015). The number of published PBPK models has increased significantly over the past 3 decades.…”

Estimating National Exposures and Potential Bladder Cancer Cases Associated with Chlorination DBPs in U.S. Drinking Water

“…More recent information has further strengthened the overall weight of evidence supporting causality. 61 , 62 Kenyon et al. 61 developed a human physiologically based model to evaluate the impact of DBP exposure on internal dose which showed the relatively large contributions of dermal and inhalation exposure routes to the internal dose reaching the systemic circulation.…”

Drinking Water Disinfection Byproducts (DBPs) and Human Health Effects: Multidisciplinary Challenges and Opportunities

“…Initial efforts weighting measured DBP concentrations by metrics of toxic potency obtained from in vitro assays have underscored the potential importance of certain unregulated, low molecular weight DBPs (e.g., haloacetonitriles). , However, research is needed regarding the bioavailability of these compounds. Researchers have evaluated the pharmacokinetics of THMs and demonstrated that exposure via inhalation and dermal contact may be more important than via ingestion . Are the unregulated halogenated DBPs sufficiently volatile such that skin absorption or inhalation during showering is important?…”

“…38,39 However, research is needed regarding the bioavailability of these compounds. Researchers have evaluated the pharmacokinetics of THMs 77 and demonstrated that exposure via inhalation and dermal contact may be more important than via ingestion. 78 Are the unregulated halogenated DBPs sufficiently volatile such that skin absorption or inhalation during showering is important?…”