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Development of Uptake Factors for Water Use Activities for Trihalomethanes (THMs) Using a Multi-Route Human Physiologically Based Pharmacokinetic (PBPK) Model
Citation:
Kenyon, E., J. Wright, R. Shaffer, T. Luben, AND C. Eklund. Development of Uptake Factors for Water Use Activities for Trihalomethanes (THMs) Using a Multi-Route Human Physiologically Based Pharmacokinetic (PBPK) Model. Gordon Research Conference, South Hadley, MA, July 30 - August 04, 2023. https://doi.org/10.23645/epacomptox.23739093
Impact/Purpose:
Use of PBPK-derived uptake factors can provide robust estimates of internal exposure across multiple routes and allow consideration of host factors reflecting human variability (e.g., pregnancy, genetic polymorphisms). This research can have important implications for exposure assessment in epidemiological studies.
Description:
Uptake factors are used in conjunction with epidemiologic studies to refine exposure estimates to include chemical absorption during multiple water use activities (e.g., Savitz et al., 2006; Iszatt et al., 2011). For THMs, a class of volatile disinfection byproducts that are readily absorbed via dermal and inhalation routes of exposure, this enables consideration of activities that may result in a larger uptake and internal dose such as showering, bathing, and swimming. We utilized our multi-route human THM PBPK model to derive uptake factors for bathing and showering for chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM). Model structure and physiological parameters are the same as our published adult human BDCM model (Kenyon et al., 2016). The expanded model was able to predict blood or exhaled breath concentration of THMs from bathing and showering and swimming studies which increases confidence in its application. Uptake factors are expressed as minute equivalents (MinEq). MinEq are defined as the minutes of a specific water use activity required to achieve the same internal dose from drinking one liter of water containing the same concentration of each THM. Area under the curve in blood (AUCv) was used as the measure of internal dose. MinEq for showering were 4.4, 3.6, 3.6 and 3.5 minutes for TCM, BDCM, DBCM and TBM, respectively. MinEq for bathing were 3.7, 2.8, 2.5 and 2.3 minutes for TCM, BDCM, DBCM and TBM, respectively. Other studies have estimated uptake factors of 5 and 15 minutes for showering and bathing, respectively, for TCM by directly using blood concentration data from showering and bathing studies. The difference between PBPK-derived MinEq and data-derived MinEq for TCM are minor for showering, and more pronounced for bathing (~3-fold). One possible explanation for this difference is the relatively greater contribution of dermal absorption to internal exposure inferred from our model compared to other types of PK analysis. Global sensitivity analysis indicated that chemical-specific parameters for blood:air partitioning and metabolism, as well as cardiac output and alveolar ventilation are highly influential for AUCv. Future refinements to the PBPK-based approach will include incorporation of in vitro-derived human metabolism parameters and development of uptake factors for swimming. Use of PBPK-derived uptake factors can provide robust estimates of internal exposure and allow consideration of host factors reflecting human variability (e.g., pregnancy, genetic polymorphisms). This research has important implications for exposure assessment purposes in epidemiological studies. (The views expressed in this abstract are those of the authors and do not necessarily represent the views or the policies of the U.S. Environmental Protection Agency.)
URLs/Downloads:
DOI: Development of Uptake Factors for Water Use Activities for Trihalomethanes (THMs) Using a Multi-Route Human Physiologically Based Pharmacokinetic (PBPK) Model
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