Physiologically Based Pharmacokinetic Modeling of the Temperature-Dependent Dermal Absorption of Chloroform by Humans following Bath Water Exposures

Abstract

The kinetics of chloroform in the exhaled breath of human volunteers exposed skin-only via bath water (concentrations < 100 ppb) were analyzed using a physiologically based pharmacokinetic (PBPK) model. Significant increases in exhaled chloroform (and thus bioavailability) were observed as exposure temperatures were increased from 30 to 40 degrees C. The blood flows to the skin and effective skin permeability coefficients (Kp) were both varied to reflect the temperature-dependent changes in physiology and exhalation kinetics. At 40 degrees C, no differences were observed between males and females. Therefore, Kps were determined (approximately 0.06 cm/hr) at a skin blood flow rate of 18% of the cardiac output. At 30 and 35 degrees C, males exhaled more chloroform than females, resulting in lower effective Kps calculated for females. At these lower temperatures, the blood flow to the skin was also reduced. Total amounts of chloroform absorbed averaged 41.9 and 43.6 microg for males and 11.5 and 39.9 microg for females exposed at 35 and 40 degrees C, respectively. At 30 degrees C, only 2/5 males and 1/5 females had detectable concentrations of chloroform in their exhaled breath. For perspective, the total intake of chloroform would have ranged from 79-194 microg if the volunteers had consumed 2 liters of water orally at the concentrations used in this study. Thus, the relative contribution of dermal uptake of chloroform to the total body burdens associated with bathing for 30 min and drinking 2 liters of water (ignoring contributions from inhalation exposures) was predicted to range from 1 to 28%, depending on the temperature of the bath.

Dermal uptake of chloroform and haloketones during bathing

“…Thus, chloroform was approximately 20-30 times more permeable than HKs. The in vivo effective skin permeability of chloroform for humans was reported to range from 0.01 to 0.42 cm/h based on physiologically based pharmacokinetic models (PBPK) and breath measurement data obtained from shower or bath studies (Jo et al, 1990;McKone, 1993;Gordon et al, 1998;Corley et al, 2000). Our estimate for chloroform is comparable to the lower bound of this reported range.…”

Reverse dosimetry: interpreting trihalomethanes biomonitoring data using physiologically based pharmacokinetic modeling

“…Moreover, a PBPK model already existed for chloroform Corley et al, 2000) and was applied in predicting human risk in several studies Delic et al, 2000;Levesque et al, 1994Levesque et al, , 2000Levesque et al, , 2002. Therefore, the structure of the existing PBPK model for chloroform (Corley et al, 2000) was taken as a generic model framework for BDCM, DBCM, and TBM (Figure 1). In the PBPK models for these THMs, the values of the physiological parameters remained unchanged from the chloroform model (Phillips et al, 1993;Brown et al, 1997;Clewell et al, 2000) ( Table 1).…”

“…In previous studies with similar volatile organic compounds (VOCs), tissue:air partition coefficients (Corley et al, 2000), bromodichloromethane, dibromochloromethane, and bromoform.…”

“…Therefore, rat tissue:air values were used when human data were not available. The skin:water and skin:air partition coefficients for chloroform were obtained from the literature (Corley et al, 2000), but such data did not exist for the other THMs. The skin:water partition coefficients of the other THMs were estimated, taking chloroform as a reference compound, using a molecular structure-based algorithm (Poulin and Krishnan, 1996).…”

“…These compounds are often referred to as disinfection byproducts as they are one of the groups of compounds formed as a result of the reaction of chlorine disinfectants with organic matter in water. Concerns regarding widespread exposures to THMs from the use of contaminated drinking water have led to numerous studies on THMs, including epidemiological studies, exposure assessments, mechanistic and toxicity studies, and risk assessments Wallace, 1997;Constan et al, 1999;Luciene da Silva et al, 1999;Backer et al, 2000;Corley et al, 2000;Kerger et al, 2000;Nieuwenhuijsen et al, 2000;Poulin and Theil, 2000;Allis and Zhao, 2002;Levesque et al, 2002;Gordon et al, 2006). Owing to its greater abundance in drinking water, the most-studied compound among the four THMs is chloroform.…”