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

R. A. Corley*,1, S. M. Gordon{dagger} and L. A. Wallace{ddagger}

* Battelle Memorial Institute, Pacific Northwest Division, Chemical Dosimetry, Post Office Box 999, P7-59, 902 Battelle Boulevard, Richland, Washington 99352; {dagger} Battelle Memorial Institute, Atmospheric Science and Applied Technology, Columbus, Ohio 43201; {ddagger} Office of Research and Development, U.S. Environmental Protection Agency, Reston, Virginia 20192

Received March 30, 1999; accepted August 25, 1999


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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°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°C, no differences were observed between males and females. Therefore, Kps were determined (~0.06 cm/hr) at a skin blood flow rate of 18% of the cardiac output. At 30 and 35°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 µg for males and 11.5 and 39.9 µg for females exposed at 35 and 40°C, respectively. At 30°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 µg 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.

Key Words: chloroform; PBPK modeling; dermal bioavailability; temperature dependence; human.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The major source for human exposures to chloroform is as a byproduct of water disinfection in those areas where chlorination processes are used (Wallace, 1997Go). Although there are a myriad of uses for chlorinated water and thus potentials for exposure, finished drinking water standards have generally been based on conservative estimates of oral consumption (McKone, 1993Go). In recent years, however, other routes of exposure have been evaluated as potentially significant contributors to total body burdens. Cooking, or washing clothes and dishes may contribute to indoor air concentrations of chloroform. Activities such as swimming, showering, or bathing result in the potential for both inhalation and dermal exposure. Wallace (1997) recently published an extensive summary of human exposures and total body burdens for chloroform and other trihalomethanes from air, water, and food.

Several attempts have been made to characterize the relative contributions of oral, dermal, and inhalation exposures of humans to total body burdens of chloroform. Studies have included evaluations of blood/plasma or urine concentrations (Aggazzoti et al., 1990; Aiking et al., 1994Go; Dick et al., 1995Go) but most have utilized analysis of exhaled breath samples (Aggazzotti et al., 1993Go; Dick et al., 1995Go; Jo et al., 1990a and b; Levesque et al., 1994Go; Lindstrom et al., 1997Go; Weisel et al., 1992Go; Weisel and Jo, 1996Go; Weisel and Shepard, 1994Go). Although analyzing bag, canister, or other "grab" samples of exhaled breath provides a relatively simple, noninvasive technique for evaluating the kinetics of volatile chemicals, only a limited number of samples can be collected to adequately describe the kinetics of uptake and clearance of a rapidly absorbed and metabolized chemical such as chloroform.

Breath analysis techniques have recently been improved by coupling an atmospheric sampling glow discharge ionization source (ASGDI) with a mass spectrometer (MS/MS) system to continuously measure volatile organic compounds (VOC) in air or exhaled breath of laboratory animals and humans at low (ppb) environmental exposure (Gordon et al., 1992Go; Thrall and Kenny, 1996Go). This new approach has made it possible to obtain copious real-time data during uptake or elimination of VOCs and provide far more detailed information than previous discrete-sample methods on VOC kinetics through various exposure pathways. Gordon et al. (1998) recently used an ASGDI-MS/MS system to determine the temperature-dependent kinetics of human dermal absorption of chloroform while bathing. In their study, nine subjects bathed in domestic tap water for 20–30 min, breathing pure air through a face mask to eliminate inhalation exposure. Seven of the nine subjects bathed in water at two or three different temperatures, ranging from 30°C to 40°C. A significant relationship between water temperature and exhaled chloroform was observed. Subjects at the highest temperatures exhaled about 30 times more chloroform than the same subjects at the lowest temperatures. This was assumed to be due to a decline and/or shunting of blood flow to the skin at the lower temperatures as the body conserved heat, which forced chloroform to diffuse over a greater distance through the skin before encountering the blood.

Continuous, real-time breath analysis made it possible to determine the uptake, distribution, and elimination of chloroform with greater precision than previously possible. These data also made possible a more exacting test of existing compartmental and physiologically based pharmacokinetic (PBPK) models, using human exposure data under controlled conditions. Gordon et al. (1998) fit a linear compartmental model to the uptake and decay data. Although the complicating effect of the stratum corneum lag time made it difficult to fit multiexponential curves to the data, a single-compartment model appeared to fit the data with R2 values around 0.9. In addition, it was difficult to fit a single, compartmental model to all of the individual exposure results without taking physiology into account, although several useful findings were obtained from their analysis. Perhaps the most significant finding was that determinations of processes important to dermal absorption must take temperature into account. Therefore, the objective of the present study was to reanalyze the data using a physiologically based pharmacokinetic (PBPK) model developed previously (Corley et al., 1990Go). The resulting PBPK model, combined with analyses of other human and animal data, will be useful for simulating a variety of human exposure scenarios, including bathing, showering, and swimming, and reduce the overall uncertainty in internal dosimetry estimates used in human health risk assessments for chloroform.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Model structure.
The PBPK model of Corley et al. (1990) was used to simulate the exhaled breath data of Gordon et al. (1998). The original model contained the lungs, liver, kidney, fat, and slowly perfused and richly perfused tissue groups. Metabolism was assumed to occur in both the liver and the kidneys. The model was modified to describe the dermal uptake of chloroform according to McDougal et al. (1986 and 1990). The rate of change in the amount of chloroform in the skin (ASK, mg) is a function of the rate of penetration through the skin (Fick's law of diffusion) and the rate of delivery and clearance via systemic blood circulation. The equation for the skin compartment is as follows:

dASK/dt = (KP * SA/1000) * (CliqCSK/Pskin:liq)

+ QSK*(CACVSK)

where KP is the skin permeability constant for chloroform (cm/h), SA is the surface area exposed (cm2), Cliq is the concentration of chloroform in water (mg/liter), CSK is the concentration of chloroform in skin (mg/liter), Pskin:liq is the skin:liquid partition coefficient, QSK is the blood flow to the skin (liter/h), CVSK is the concentration of chloroform in venous blood draining the skin, and CA is the concentration of chloroform in arterial blood. A diagram of the resulting model structure is shown in Figure 1Go.



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FIG. 1. Physiologically based pharmacokinetic model used to describe the disposition of chloroform in rats, mice, and humans during inhalation, oral, intraperitoneal injection, intravenous infusion, and dermal exposures.

 
Parameter estimation.
The important biochemical and physiologic parameters specific to the dermal uptake of chloroform include the surface area exposed (SA), skin:liquid partition coefficient (Pskin:liq), skin permeability coefficient (KP), and blood flow to the skin compartment (QSK). The total body surface area was estimated by the equation of DuBois and DuBois (1916) where

SA (cm2) = weight (kg)0.45 x height (cm)0.725 x 71.84.

The exposed surface area for each volunteer was calculated by subtracting the surface area of the head (9%; Guy and Maibach, 1989Go) from the total body surface area (Table 1Go).


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TABLE 1 PBPK Model Parameters
 
No skin:water or skin:blood partition coefficients were directly available for chloroform. Previous estimates, ranging from 1.9 to 12.5, used algorithms based, in part, on the lipid content of skin and the octanol:water partition coefficient (Ko:w) for chloroform (Chinery and Gleason, 1993Go; Roy et al., 1996Go). However, Gargas et al. (1989) reported a saline:air partition coefficient for chloroform of 3.38 and Mattie et al. (1994), of the same laboratory, reported skin:air partition coefficients for two very similar chemicals, methylene chloride (13.6) and carbon tetrachloride (12.4). Assuming the skin:air partition coefficient for chloroform is intermediate between methylene chloride and carbon tetrachloride, the skin:water partition coefficient for chloroform was estimated to be 3.85 (skin:air/saline:air). The skin:blood partition coefficient was similarly determined from the ratio of the estimated skin:air and the blood:air partition coefficient reported by Corley et al. (1990).

The blood flow to the skin has been shown repeatedly to be dependent upon temperature. An initial probe study from a single male volunteer was used to investigate the temperature-dependent blood flow to the skin for an individual fully immersed for 30 min in hot, 40°C water. The subject was observed to have beet-red skin during the bath water exposure and for several minutes postexposure. At a normal skin blood flow of 3% of the cardiac output, the simulated exhaled breath kinetics were linear during both the uptake and clearance phase, which was not consistent with the data or the observed skin flush (Fig. 2Go). In addition, both the peak exhaled breath concentration and area under the exhaled breath concentration-time curve (AUC) were not consistent with the data. Increasing the blood flow to the skin to a maximum of 18% while holding the total cardiac output constant provided the best fit to the data. This is well within the range of increased regional skin blood flows reported for exposures to 40°C temperatures. For the 30°C exposures, which are slightly cooler than the normal skin surface temperature of 32°C (Song et al., 1989Go), the blood flow rates were set at 3% of the cardiac output, which is at the low end of the normal range of 3 to 9% (Brown et al., 1997Go). For 35°C exposures, the blood flow to the skin was set at an intermediate level, 5%.



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FIG. 2. Simulation (lines) and data (symbols) for the concentration of chloroform in the exhaled breath of a human volunteer exposed to 70 ppb of chloroform in bath water at ~40°C. Skin blood flows were increased from 3% of the total cardiac output (normal range of 3–9%) to 18% of the cardiac output while holding the effective skin permeability constant at 0.125 cm/h.

 
Once the blood flow to the skin was fixed for each exposure temperature, the skin permeability coefficient (KP, cm/h) was optimized using the maximum log-likelihood function of Simusolv® (The Dow Chemical Co., Midland, MI) for each individual exposure. An absolute determination of KP is based on the assumption that steady-state conditions are attained. This (steady state) was only approached at the highest exposure temperature. Therefore, the KPs calculated for the lower temperatures (30 and 35°C) were considered effective permeability coefficients (KPeff) where both diffusion and partitioning were taking place (McKone, 1993Go). The physiologic and biochemical parameters added to the Corley et al. (1990) human PBPK model to describe the temperature- and sex-dependent dermal absorption of chloroform are summarized in Table 1Go.

Subject demographics and exposure conditions.
A total of nine volunteers (four males and five females) were exposed to various concentrations of chloroform in bath water in two experimental phases. In Phase I, four volunteers (Subjects 1–4) were exposed to domestic tap water in a residential bathtub at a target temperature of 40°C. In Phase 2, six volunteers (Subjects 5–10) were exposed to chloroform at 30, 35, and 40°C in a 380-liter stainless steel hydrotherapy tub in a laboratory environment. One volunteer participated in both phases (designated Subject 3 in Phase I and Subject 5 in Phase 2). In all exposures, dermal absorption was isolated from the potential inhalation exposure through the use of a facemask equipped with one-way breathing valves for providing purified air and monitoring exhaled breath. The experimental design, monitoring methodology, and results are summarized in detail by Gordon et al. (1998).

A summary of each volunteer's height, weight, and exposed surface area is provided in Tables 2 and 3GoGo. The concentrations of chloroform ranged from 39.5 to 97 ppb and each exposure lasted approximately 30 min. The exhaled breath of each subject was monitored continuously throughout each 30-min exposure. Initial estimates of background chloroform were determined in the exhaled breath for a few minutes prior to each exposure. In all 40°C exposures, breath analyses continued for approximately 30–40 min postexposure to estimate the clearance rate of chloroform. The exposure conditions for each volunteer are summarized in Tables 2–6GoGoGoGoGo.


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TABLE 2 PBPK Model Results for Male Volunteers Exposed to Chloroform in 40°C Bath Water
 

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TABLE 3 PBPK Model Results for Female Volunteers Exposed to Chloroform in 40°C Bath Water
 

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TABLE 4 PBPK Model Results for Male Volunteers Exposed to Chloroform in 35°C Bath Water
 

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TABLE 5 PBPK Model Results for Female Volunteers Exposed to Chloroform in 35°C Bath Water
 

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TABLE 6 PBPK Model Results for Male and Female Volunteers Exposed to Chloroform in 30°C Bath Water
 

    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
General Observations
The modified PBPK model adequately described the data from all exposures. However, one male volunteer that participated in both phases of the study (designated as Subject 3 in Phase 1 and Subject 5 in Phase 2) was reported to have a poor-fitting face mask. This may have resulted in inadvertent inhalation of chloroform volatilized from the bath water in at least two of the exposures that this subject participated in. For example, this subject's exhaled breath concentrations following exposure to 39.5 ppb chloroform were as high as the concentrations in breath following a replicate exposure to 91 ppb at 40°C (compare Subject 3 with 5, Table 2Go). In addition, this subject's exhaled breath concentrations were higher than the other volunteers exposed at 30°C even though his exposure was the lowest concentration of chloroform (54.5 vs. 90 ppb). Although the actual exposure for this subject may be questionable, this volunteer's data were simulated and presented along with all other data sets and the results only excluded from calculations of average male parameters for these two data sets.

40°C Exposures
Model simulations versus the exhaled breath data are shown in Figure 3Go for male and female volunteers exposed to chloroform in their bath water at a target temperature of 40°C. Peak exhaled breath concentrations ranged from ~5–14 ppb in individual males and females, with a rapid clearance to near background levels by 30–40 min postexposure. Effective skin permeability coefficients ranged from 0.04 – 0.08 cm/h for the male volunteers (excluding Subject 5). This is virtually identical to the female effective skin permeability coefficients, which ranged from 0.03–0.09 cm/h (Tables 2 and 3GoGo).



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FIG. 3. Simulation (line) and data (means [symbols] ± SD [error bars]) of the concentration of chloroform in the exhaled breath of (a) four male and (b) four female volunteers exposed to 90–97 ppb chloroform in bath water at 40°C. The simulation represents the average body weight, surface area, effective skin permeability coefficient, and exposure concentration used in the four exposures.

 
The only consistent difference between males and females exposed at 40°C was in the lag time in the appearance of chloroform in the exhaled breath. However, this difference was considered to be of little biologic significance (3.5 min in males vs. 1 min in females) at this temperature. Total calculated absorbed doses ranged from 0.42 to 0.79 µg/kg for males and 0.27 to 0.99 µg/kg for females. The calculated amounts of chloroform exhaled ranged from 23 to 34% of the amounts absorbed, which was consistent with the analysis of Gordon et al. (1997). Estimates of total amounts absorbed, metabolized, exhaled unchanged, and remaining in the body 24 h from the initiation of each exposure are summarized in Tables 2 and 3GoGo.

35°C Exposures
Model simulations versus the exhaled breath data are shown in Figure 4Go for male and female volunteers exposed to chloroform in their bath water at a target temperature of 35°C. At this temperature, there was a significant sex difference in the amounts of chloroform absorbed and exhaled, with males averaging over twice the absorbed dose than females. This resulted in peak exhaled breath concentrations of 5–7 ppb in males and 1–3 ppb in females, and effective skin permeability coefficients of 0.04–0.06 for males and 0.01–0.02 cm/h and females (Tables 4 and 5GoGo). For male subjects exposed at 35 and 40°C, the effective skin permeability coefficients were nearly identical at both temperatures. For females, the effective skin permeability coefficients were approximately 4-fold lower at 35 than at 40°C. However, the percent of the dose exhaled unchanged was much less variable at 35°C than observed at 40°C, with all subjects averaging 34%. Model estimates of total amounts absorbed, metabolized, exhaled unchanged, and remaining in the body 24 h from the initiation of each exposure are summarized in Tables 4 and 5GoGo.



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FIG. 4. Simulation (line) and data (means [symbols] ± SD [error bars]) of the concentration of chloroform in the exhaled breath of (a) three male and (b) three female volunteers exposed to 78–97 ppb chloroform in bath water at 35°C. The simulation represents the average body weight, surface area, effective skin permeability coefficient, and exposure concentration used in the four exposures.

 
30°C Exposures
Model simulations versus the exhaled breath data are shown in Figure 5Go for one male and two female volunteers exposed to chloroform in their bath water at a target temperature of 30°C. Three of the six volunteers exposed to 30°C bath water did not exhale sufficient chloroform to detect above their background levels. Peak exhaled breath concentrations averaged 0.7–1 ppb in the two males and approximately 0.3 ppb in the single female. Effective skin permeability coefficients, 0.01 and 0.02 cm/h for the two males and 0.003 cm/h for the single female volunteer, were significantly lower than at 35 and 40°C exposures (Table 6Go). Model estimates of total amounts absorbed, metabolized, exhaled unchanged, and remaining in the body 24 h from the initiation of each exposure are also summarized in Table 6Go.



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FIG. 5. Simulations (lines) and data (symbols) of the concentration of chloroform in the exhaled breath of two male (Subjects 5 and 7) and one female (Subject 6) volunteers exposed to concentrations of chloroform ranging from 54.5–91 ppb in bath water at 30°C. Exposures were conducted by submerging the volunteers to neck level for approximately 30 min.

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
With the addition of a simple skin compartment, the PBPK model of Corley et al. (1990) was able to simulate the concentration of chloroform in the exhaled breath of humans who were exposed dermally to municipal tapwater for 30 min at 30, 35, and 40°C. Others have either developed specific skin compartmental models or modified the PBPK model of Corley et al. (1990) to include a more detailed description of the skin compartment than used in this current analysis, by separating the stratum corneum from the viable skin and/or dermis (Chinery and Gleason, 1993Go; Roy et al., 1994Go; Roy et al., 1996Go; Shatkin and Brown, 1991Go). The additional complexity of the skin compartment, although biologically more realistic, must be weighed against the corresponding increase in the numbers of model parameters. This is especially problematic when there may be no specific data available to independently estimate these additional parameters. In this particular study, where only the exhaled breath was analyzed, the added complexity could not be justified. Thus, the simple perfusion-limited skin compartment structure of McDougal et al. (1990) was considered adequate to simulate the bath water exposures.

As discussed by Gordon et al. (1998), exposure temperature significantly impacted the dermal bioavailability and thus the exhaled breath concentrations of chloroform. Therefore, to adequately simulate the data from this study, the blood flow to the skin had to be varied according to the exposure temperature. Normal human skin surface temperature is approximately 32°C (Song et al., 1989Go), with blood flow rates ranging from 3 to 9% of the total cardiac output at resting conditions (Brown et al., 1997Go). Depending on the region of the body, nonlinear increases in blood flow to the skin have been observed over the range of temperatures used in this study (Richardson, 1989Go; Rendell et al., 1993Go; Song et al., 1990Go; Tsuchida, 1987Go; Winsor et al. 1989Go). For example, when various regions of the body were heated to a surface temperature of ~40°C, blood flows have been shown to increase as much as 10- to 15-fold over normal. Therefore, to simulate data sets from the 30 and 35°C exposures, the blood flow to the skin was set at the low (3%) and intermediate (5%) levels of the normal range in flow rates. At 40°C, the blood flow to the skin was increased exponentially to 18% of the cardiac output to match the kinetics of elimination of chloroform via exhaled breath. This increase was considered the maximum that was likely to occur for the total skin compartment without unrealistically impacting the flow rates to other tissue groups or changing the total cardiac output. Although these temperature-dependent changes in blood flow to the skin fit within the ranges reported for specific areas of the body, no studies are currently available that describe the blood flow to the skin when the entire body is heated. Future studies should consider direct measurements of the blood flow to the skin so that individual temperature-dependent blood flows can be accounted for. By necessity, this study assumed that all subjects had the same blood flows at a given exposure temperature with only the differences in the skin permeability coefficients accounting for the intersubject variability in exhalation of unmetabolized chloroform.

After setting the blood flow to the skin for each exposure temperature, the resulting effective skin permeability coefficients determined in this study were also observed to increase as exposure temperature increased from 30 to 40°C. It is likely that as exposure temperatures increase, capillary recruitment near the skin surface also increases with the blood flow such that the distance that chloroform must penetrate to reach the blood becomes proportionately smaller. Conversely, as temperatures decrease, blood is shunted from the surface to preserve body heat, thus increasing the distance that chloroform must penetrate to reach the circulating blood. For males, the peak effective permeability coefficient was reached between 35 and 40°C; for females, peak permeability coefficients were reached at 40°C where there were no differences observed between males and females. Wide ranges of skin permeability coefficients for chloroform (0.016–0.42 cm/h) have been reported in the literature for rats, guinea pigs, and humans (Beech et al., 1980Go; Bogen et al., 1992Go; Cleek and Bunge, 1993Go; Dick et al., 1995Go; Islam et al., 1995Go; Islam et al., 1996Go; McKone and Howd, 1992Go). With a few exceptions (low- temperature exposures) the effective skin permeability constants derived in this study were within this range.

A sex difference was observed in the exhalation of chloroform at the two lower temperatures. These differences resulted in average effective skin permeability coefficients of 0.01, 0.05, and 0.059 cm/h for males and 0.003, 0.015, and 0.059 cm/h for females exposed at 30, 35, and 40°C, respectively. Although the precise basis for the differences observed between males and females at the two lower concentrations may not be completely known, several factors associated with the skin compartment are likely to be involved. These factors may include differences in temperature-dependent capillary shunting or the subcutaneous distribution of the fat compartment, each of which may contribute to increasing the distance that chloroform must penetrate at the lower temperatures. It is unlikely that differences in metabolism or the size of the fat compartment were significant, as there were no differences observed between males and females when the kinetics of exhaled chloroform were evaluated at 40°C. Because no data were collected on either the blood flows to the skin or the size of the fat compartment in this study, the only model parameter that was changed to reflect the sex difference in exhaled chloroform was the effective skin permeability coefficient.

To provide perspective on the importance of dermal uptake to other potential routes of human exposure to chloroform, the total amounts of chloroform absorbed through the skin were calculated for each subject in each experiment. The resulting individual body burdens (µg absorbed/kg body weight) were compared to a corresponding oral dose (also µg absorbed/kg body weight), assuming each subject consumed an average of 2 liters of water/70 kg body weight at the same concentration of chloroform used in the bath water exposures (Tables 2–6GoGoGoGoGo). For males and females taking a 30-min bath at 40°C, the relative contribution of dermal absorption to the total body burdens (oral + dermal) represents approximately 18%, on average. At 35°C, dermal absorption would contribute ~17% of the total body burdens for males and ~6% for females. At the lowest temperature, 30°C, dermal absorption accounts for only 1–7% of the total body burdens. If inhalation exposures were included, the relative contribution of the dermal uptake to total body burdens would be lower for each exposure. Furthermore, first-pass metabolism by the liver following oral exposure would result in a greater internal dose of reactive metabolites in target tissues by this route than would be predicted to occur following dermal or inhalation exposures.

These calculations of the relative contribution of various routes of exposure to total body burdens are exposure specific, and the role of dermal uptake can be of greater or lesser importance, depending upon the scenario. PBPK models are particularly well suited for simulating a variety of exposure scenarios. For example, swimming in a chlorinated pool results in simultaneous inhalation and dermal exposures to chloroform under exercise conditions. The current PBPK model was, therefore, used to simulate such a scenario and the results compared to a kinetic study with a human volunteer (Aggazzotti et al., 1995Go). In the study of Aggazzotti et al., the subject swam for 45 min on four separate occasions and the subject's exhaled breath was monitored periodically for up to 10 h after each exposure. The concentration of chloroform in the swimming pool ranged from 106 to 144 µg/l and the ambient air averaged 139 µg chloroform/m3 for the four sessions. Simulations of the exhaled breath concentrations of chloroform were performed using physiologic conditions associated with 50W work (Corley et al., 1994Go) and a Kp of 0.02 cm/h under the stated exposure conditions (Fig. 6Go). The total amount of chloroform absorbed using these assumptions was calculated to have been 230 µg, of which 21% (48 µg) was contributed by dermal absorption. Simulations were also conducted by reducing the alveolar ventilation rate associated with 50W exercise (57 l/h/kg) to be equivalent to the cardiac output (26 l/h/kg) in an effort to simulate the controlled breathing pattern associated with freestyle swimming by a conditioned swimmer (Fig. 6Go). The latter simulation provided the best fit with the data and more closely matched the first breath sample taken immediately postexposure. With the reduced ventilation rate, the amount of chloroform absorbed for this simulation was calculated to be 131 µg, of which 37% (also 48 µg) was contributed by dermal absorption.



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FIG. 6. Simulations (lines) and data (symbols, mean ± SD for four sessions) of the concentration of chloroform in the exhaled breath of a male volunteer swimming for 45 min (from Aggazzotti et al., 1995). The concentration of chloroform in the water averaged 125 µg/l and the ambient air concentrations averaged 139 µg/m3 over the four sessions. Simulations were conducted using physiology parameters associated with 50W work and a Kp of 0.02 cm/h (dashed line) and assuming 50W work but setting the ventilation rate equivalent to the cardiac output (solid line).

 
The physiologic assumptions associated with exercise could vary widely depending on the overall fitness of the volunteer, the intensity of the workout, and the swimming stroke or strokes employed over the 45-min workout, which were not described. However, the ability of the model to adequately simulate the data from Aggazzotti et al. (1995) with only minimal adjustments based on available physiology data further demonstrates the utility of PBPK models to describe multiroute exposures.

With the additional data and analyses from these dermal-only human exposure studies, along with other data sets in the literature, the current PBPK model can be used to develop internal dose estimates following a variety of realistic, multiroute, environmental exposure scenarios. As a result, the overall uncertainty of internal dose estimates, which may vary significantly between routes of exposure, and associated human health risk assessments can be reduced.


    NOTES
 
This work was funded by the U.S. Environmental Protection Agency under contract no. 68-D4-0023; this research has not been subjected to Agency review and does not necessarily reflect the views of the Agency, and no official endorsement should be inferred.

1 To whom correspondence should be addressed. Fax: (509) 376-9064. E-mail: ra_corley{at}pnl.gov. Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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