* Battelle Memorial Institute, Pacific Northwest Division, Chemical Dosimetry, Post Office Box 999, P7-59, 902 Battelle Boulevard, Richland, Washington 99352;
Battelle Memorial Institute, Atmospheric Science and Applied Technology, Columbus, Ohio 43201;
Office of Research and Development, U.S. Environmental Protection Agency, Reston, Virginia 20192
Received March 30, 1999; accepted August 25, 1999
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ABSTRACT |
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Key Words: chloroform; PBPK modeling; dermal bioavailability; temperature dependence; human.
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INTRODUCTION |
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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., 1994; Dick et al., 1995
) but most have utilized analysis of exhaled breath samples (Aggazzotti et al., 1993
; Dick et al., 1995
; Jo et al., 1990a and b; Levesque et al., 1994
; Lindstrom et al., 1997
; Weisel et al., 1992
; Weisel and Jo, 1996
; Weisel and Shepard, 1994
). 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., 1992; Thrall and Kenny, 1996
). 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 2030 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., 1990). 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.
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MATERIALS AND METHODS |
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dASK/dt = (KP * SA/1000) * (Cliq CSK/Pskin:liq)
+ QSK*(CA CVSK)
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 1.
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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, 1989) from the total body surface area (Table 1
).
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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. 2). 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., 1989
), 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., 1997
). For 35°C exposures, the blood flow to the skin was set at an intermediate level, 5%.
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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 14) were exposed to domestic tap water in a residential bathtub at a target temperature of 40°C. In Phase 2, six volunteers (Subjects 510) 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 3. 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 3040 min postexposure to estimate the clearance rate of chloroform. The exposure conditions for each volunteer are summarized in Tables 26
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RESULTS |
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40°C Exposures
Model simulations versus the exhaled breath data are shown in Figure 3 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 ~514 ppb in individual males and females, with a rapid clearance to near background levels by 3040 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 0.030.09 cm/h (Tables 2 and 3
).
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35°C Exposures
Model simulations versus the exhaled breath data are shown in Figure 4 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 57 ppb in males and 13 ppb in females, and effective skin permeability coefficients of 0.040.06 for males and 0.010.02 cm/h and females (Tables 4 and 5
). 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 5
.
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DISCUSSION |
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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., 1989), with blood flow rates ranging from 3 to 9% of the total cardiac output at resting conditions (Brown et al., 1997
). 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, 1989
; Rendell et al., 1993
; Song et al., 1990
; Tsuchida, 1987
; Winsor et al. 1989
). 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 (0.0160.42 cm/h) have been reported in the literature for rats, guinea pigs, and humans (Beech et al., 1980; Bogen et al., 1992
; Cleek and Bunge, 1993
; Dick et al., 1995
; Islam et al., 1995
; Islam et al., 1996
; McKone and Howd, 1992
). 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 26). 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 17% 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., 1995). 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., 1994
) and a Kp of 0.02 cm/h under the stated exposure conditions (Fig. 6
). 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. 6
). 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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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.
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NOTES |
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1 To whom correspondence should be addressed. Fax: (509) 376-9064. E-mail: ra_corley{at}pnl.gov.
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