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Factors Influencing Prediction of Bromodichloromethane (BDCM) in Exhaled Breath
Citation:
Kenyon, E., C. Eklund, J. Simmons, AND R. Pegram. Factors Influencing Prediction of Bromodichloromethane (BDCM) in Exhaled Breath. Society of Toxicology 2021 Virtual Annual Meeting, Virtual, NC, March 12 - 26, 2021. https://doi.org/10.23645/epacomptox.17952557
Impact/Purpose:
Poster presented to the Society of Toxicology 2021 Virtual Annual Meeting March 2021. Results of this simulation study illustrate the utility of a PBPK model for simulation of unique and complex physiology associated with swimming and water immersion.
Description:
Confidence in the predictive capability of a physiologically based pharmacokinetic (PBPK) model is increased when the model is demonstrated to predict multiple pharmacokinetic outcomes under differing exposure conditions. We previously showed that our multi-route human BDCM PBPK model adequately predicts both blood and urine BDCM concentration data from human exposure studies; activities in these studies included drinking, bathing, showering and swimming. Exhaled breath BDCM (exBDCM) was adequately predicted in subjects actively swimming. However, exBDCM was over-predicted by 7- 10-fold when compared to median experimentally measured exBDCM for unmoving subjects immersed in pool water in two different studies. We used the BDCM PBPK model to sequentially explore possible physiological explanations for this observation including temperature-dependence of cardiac output (QC), alveolar ventilation rate (QP), skin permeability and skin blood flow. These parameters were selected based on results of literature review and sensitivity analysis. Increasing QC and QP from original resting values to ones more consistent with those estimated for unmoving (non-hypothermic) water-immersed subjects resulted in 4- to 7-fold over-prediction of exBDCM. Decreasing skin blood flow by 50% resulted in slightly improved predictions, i.e. over-prediction of exBDCM was in the range of 3- to 6-fold. Also, decreasing apparent skin permeability by 75% resulted in over-prediction of exBDCM that was less than 2-fold. Decreased apparent skin permeability with decreasing water temperature has been reported for chloroform, which like BDCM is a trihalomethane. Relative decreases in skin blood flow on the order of 3-fold have been documented in the literature when water temperature is decreased from 40 – 34 °C. In studies where water temperature has been reported, the typical range for showering in 38-40 °C, whereas pool water is more typically in the range of 26-28 °C. The impact of water immersion on QP and QC is temperature-dependent and complex. Our results illustrate the utility of a PBPK model for simulation of unique and complex physiology. (This abstract does not reflect U.S. EPA policy).
URLs/Downloads:
DOI: Factors Influencing Prediction of Bromodichloromethane (BDCM) in Exhaled Breath
SOT_2021KENYON_V5.PDF (PDF, NA pp, 304.574 KB, about PDF)