Toxicological Sciences 54, 42-51 (2000)
Copyright © 2000 by the Society of Toxicology
Utility of Real Time Breath Analysis and Physiologically Based Pharmacokinetic Modeling to Determine the Percutaneous Absorption of Methyl Chloroform in Rats and Humans
* Battelle, Pacific Northwest Division, PO Box 999, Richland, Washington 99352; and
Department of Dermatology, PO Box 0989, University of California, San Francisco, California 94143
Received May 17, 1999; accepted November 1, 1999
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Due to the large surface area of the skin, percutaneous absorption has the potential to contribute significantly to the total bioavailability of some compounds. Breath elimination data, acquired in real-time using a novel MS/MS system, was assessed using a PBPK model with a dermal compartment to determine the percutaneous absorption of methyl chloroform (MC) in rats and humans from exposures to MC in non-occluded soil or occluded water matrices. Rats were exposed to MC using a dermal exposure cell attached to a clipper-shaved area on their back. The soil exposure cell was covered with a charcoal patch to capture volatilized MC and prevent contamination of exhaled breath. This technique allowed the determination of MC dermal absorption kinetics under realistic, non-occluded conditions. Human exposures were conducted by immersing one hand in 0.1% MC in water, or 0.75% MC in soil. The dermal PBPK model was used to estimate skin permeability (KP) based on the fit of the exhaled breath data. Rat skin KPs were estimated to be 0.25 and 0.15 cm/h for MC in water and soil matrices, respectively. In comparison, human permeability coefficients for water matrix exposures were 40-fold lower at 0.006 cm/h. Due to evaporation and differences in apparent KP, nearly twice as much MC was absorbed from the occluded water (61.3%) compared to the non-occluded soil (32.5%) system in the rat. The PBPK model was used to simulate dermal exposures to MC-contaminated water and soil in children and adults using worst-case EPA default assumptions. The simulations indicate that neither children nor adults will absorb significant amounts of MC from non-occluded exposures, independent of the length of exposure. The results from these simulations reiterate the importance of conducting dermal exposures under realistic conditions.
Key Words: methyl chloroform; percutaneous absorption; permeability coefficients; physiologically based pharmacokinetic model.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Assessment of dermal exposure is an important component of risk assessment for any compound that may contact the skin. The a priori assumption that oral and/or inhalation routes of exposure are the most important may be an oversimplification, as the dermal route may significantly contribute to total body burdens under certain conditions (Dourson and Felter, 1997
; Guy and Potts, 1993; Jo et al., 1990; Roy et al., 1998; Weisel and Jo, 1996; Wester and Maibach, 1989). Dermal exposures can occur from water or soil contact during many everyday activities such as washing, swimming, and gardening, as well as through many work-related activities.
The extent to which a chemical is absorbed through the skin can vary greatly depending on multiple factors, including: chemical properties and concentration at the skin surface, temperature, location and surface area exposed, duration of exposure, exposure matrix, skin hydration, and whether or not the exposures are occluded (U.S. EPA, 1992). Quantitating the dermal penetration rate, or flux, is an integral part of dermal exposure risk assessment. Generally, the skin is assumed to act like a simple membrane, and Fick's law is often used to describe transdermal flux at steady state:
 |
C (mg/cm3). The Fick's law equation can be incorporated into a physiologically based pharmacokinetic (PBPK) model to determine the transdermal flux under non-steady state absorption conditions (Corley et al., 1997., 1999; Jepson and McDougal, 1997; McDougal et al., 1990; Morgan et al., 1991; Roy et al., 1998).Most in vivo animal and human dermal penetration studies involve the use of a radiotracer or chemical-specific analysis of blood and/or excreta over time. Such studies can be labor-intensive. Furthermore, it is often difficult to collect sufficient numbers of biological samples (e.g., blood) from human volunteers to fully characterize the uptake, distribution, and clearance phases in dermal kinetic studies. Breath measurements have proven to be a useful alternative in dermal absorption studies by supplying a non-invasive means to analyze numerous biological samples collected in real time (Corley et al., 2000; Gordon et al., 1998).
In this study, methods were developed to study the percutaneous absorption of volatile chemicals in humans. Our approach employed exhaled-breath elimination profiles coupled with an established PBPK model to assess the bioavailability of methyl chloroform (1,1,1-trichloroethane, MC) following dermal exposures in aqueous or soil matrices. MC was chosen as a pilot chemical to develop the exposure methodology for the following reasons: (1) MC is not extensively metabolized (Schumann et al., 1982), and thus the detection of parent compound is not complicated by competing liver metabolism, and (2) a validated PBPK model was already available (Reitz et al., 1988). Methods were also developed to assess the percutaneous absorption of MC in rats to directly compare the percutaneous absorption between humans and rats, a species that is commonly used in toxicity testing and dermal absorption studies. To conduct these studies under realistic environmental exposure conditions, a non-occluded patch system was developed that allowed for volatilization of MC from the soil without contamination of inhaled or exhaled breath.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Animals and Chemicals
Adult male, F344 rats (200–250 g) were obtained from Charles River, Inc. (Raleigh, NC). Prior to use, animals were housed in solid-bottom cages with hardwood chips, and were acclimated in a humidity- and temperature-controlled room with a 12-h light/dark cycle. Rodent feed (Purina rodent chow) and water were provided ad libitum.
HPLC grade (99.9%) 1,1,1-trichloroethane (methyl chloroform, CAS #71–55–6) was obtained from Sigma Chemical Co. (St. Louis, MO.). All other chemicals were reagent grade or better and were obtained from Sigma Chemical Co.
Human Subjects
Six healthy Caucasian male volunteers participated in the study; medical histories and demographic data, including age, body weight, and height, are given in Table 1. The studies were conducted under approval from both the Pacific Northwest National Laboratory human subjects Institutional Review Board (IRB), in compliance with multiple project assurance number DOE.MPA.PNNL96-2000, and the University of California San Francisco IRB. Formal, written consent was obtained from all subjects prior to their participation. Subjects reported no chronic conditions, significant cardiovascular, hepatic, central nervous system, renal, hematological, or gastrointestinal diseases, and no dermatological problems. Since MC is highly lipophilic, MC pharmacokinetics are sensitive to the amount of body fat. Therefore, the percen body fat for each subject was determined using a hand-held, near-infrared body-fat analyzer (Futrex®, Gaithersburg, MD).
|
Rat Exposure Conditions
Dermal exposures to MC were conducted using both soil and water matrices. The day prior to exposure, male F-344 rats were anesthetized with a ketamine/xylazine mixture and the hair on the lower back shaved with clippers. The water exposure system consisted of a 2.5-cm diameter hand-blown glass cell (O.Z. Glass Co., Pinole, CA) with a needle hole opening in the top to allow addition of the dosing solution. The glass cell was attached to the clipped area using a cyanoacrylate adhesive. The 0.1% water MC dosing solution was made fresh the day of exposure and injected into the glass cell through the needle hole drilled in the top. Immediately after filling the cell, the needle hole was sealed with silicone glue. Syringe weights were recorded before and after application of the dose to determine the weight of administered dose. Samples of the water were taken before and after exposure and analyzed for MC using headspace methods described below.
Rats were exposed to MC in 600 mg of soil at target concentrations ranging from 0.05–0.5% MC. The soil sample used in these studies was collected in California (Yolo County). Soil was prepared by passing through a 40-mesh sieve and retaining on an 80-mesh sieve. The soil consisted of 30% sand, 18% clay, and 52% silt, with an organic content of 1.3%, and a pH of 6.8. A ring of DuoDerm® (Bristol-Myers Squibb, Princeton, NJ) was attached to theclipped area on the back of the rats using a cyanoacrylate adhesive. The topical dose of MC-spiked soil was applied to the 8-cm2 area bounded by the DuoDerm® and covered with Bioclusive® transparent dressing (Johnson & Johnson, Arlington, TX). The transparent dressing allowed free passage of moisture, thereby mimicking realistic exposure scenarios. To prevent the rats from breathing the MC volatilized from the patch, a weighboat with holes drilled in the center was placed over the transparent dressing to permit the movement of air, and was covered with a muslin patch containing activated charcoal. The entire patch system was secured with self-adherent wrap (Fig. 1). Preliminary studies confirmed that the patch system efficiently trapped volatilized MC and prevented contamination of the chamber air. An 8-cm2-patch area, representing approximately 3% of the total skin surface area, was chosen to mimic limited exposure situations.
|
Immediately following dermal application, rats were individually placed in small off-gassing chambers as described by Gargas (1990). Breathing air was continually supplied to the rat through the lid of the off-gassing chamber at a measured rate (200 ml/min). Airflow rates were measured using flow meters from Sierra Instruments (Carmel Valley, CA) and were calibrated prior to use. A Teledyne Discovery II MS/MS equipped with an atmospheric sampling glow discharge ionization (ASGDI) source sampled from the off-gassing chamber (representing exhalation from the animal) approximately every 5 s. The ASGDI source derives reagent ions directly from the volatile chemicals in the sampled air. A positive ion mode was established by applying a potential of 400 V between 2 half plates. Ions were then focused onto the MS/MS trap. Helium was used as a buffer and collision gas. The intensity data from the MS/MS was converted to concentration (ppb), using external standards prepared in Tedlar® bags. A standard curve was generated on each day of experimentation. MC was quantitated by selective ion monitoring of the m - 1 (m/z 97) and m + 1 (m/z 99) ions of the MC daughter, produced after the loss of a chlorine.
To quantitate total absorbed dose, the amount of MC in the original exposure media (soil or water), the amount remaining at the end of the exposure, and the amount volatilized to the charcoal patch were analyzed. Headspace gas chromatography was used for the media and patch components. Aliquots of dosing solution (100 µl water or 100 µg of soil) and the remaining solution after exposure were placed in 20-ml headspace vials along with 0.1% trichloroethylene used as an internal standard, sealed with Teflon-lined septa, and heated at 80°C for 60 min. MC was analyzed using a Headspace Autosampler (Perkin-Elmer 40XL) linked to a Hewlett-Packard 5890 Series II GC (Avondale, PA). A Restek Rtx-Volatiles column was used (30m x 0.32mm x 1.5 µm) cross-bonded with phenylmethyl polysiloxane. The oven temperature was set at 90°C and the injection and FID detector temperatures were set at 100°C. Helium was the carrier gas at 8 psi. Charcoal from the non-occluded patch system was extracted using toluene and MC concentrations measured using similar GC conditions, except for 2 µl of toluene that was injected (splitless) onto the GC. The retention times of MC and trichloroethylene internal standard were approximately 3 and 3.7 min, respectively.
Human Exposure Conditions
Each human volunteer immersed their left hand in a container of either water (4 L) at a target concentration of 0.1%, or soil (4 kg) with a target concentration of 0.75% for 4 min after beginning to breathe into the MS/MS system. The containers were prepared in a separate room and were covered with plastic wrap prior to use. One volunteer immersed his hand in 4 L of water without MC for 2 h prior to exposure to determine the effect of pre-hydration on dermal bioavailability. Samples (water or soil) were collected from the container every 0.5 h and measured by GC headspace analysis as before, to determine the concentration of MC remaining in the exposure media over time.
Subjects were provided clean breathing air via a facemask with a 2-way non-rebreathing valve so as to eliminate inhalation exposure. The exhaled breath was passed through a heated mixing chamber (1.3 L volume) from which the MS drew a sample for analysis approximately every 5 sec. Excess exhaled air was vented from the mixing chamber to a hood with negligible flow restriction, via a large borehole exit tube.
PBPK Model
A previously established PBPK model for MC (Reitz et al., 1988) was modified to include a separate skin compartment to describe the uptake of MC following dermal exposure as described by Jepson and McDougal (1997). In addition, equations were added to describe the off-gassing chamber (for rat exposures), according to Thrall and Kenny (1996) and Gargas (1990). Equation 2 describes the amount of chemical in the off-gassing chamber in terms of input from the exhaled breath and removal from the chamber, either by re-breathing or to the MS/MS,
 |
The dermal PBPK model incorporated specific descriptions for richly and slowly perfused tissues, fat, liver, lung, and skin (Fig. 2). MC-specific parameters, including blood:tissue and skin:air partition coefficients and metabolism rates were taken from the literature (Mattie et al. 1994; Reitz et al., 1988). Media (soil and water) partition coefficients were determined using the method of Gargas et al. (1989). Briefly, quadruplicate samples of 1 g of soil or 2 ml of water were placed in sealed vials and incubated for 2 h prior to sampling the headspace for MC. The amount of MC in the headspace of vials containing soil or water was compared to empty reference vials. The soil:skin and water:skin partition coefficients were calculated by dividing the soil:air or water:air partition coefficient by the skin:air partition coefficient, respectively. Parameters for the rat and human PBPK models are given in Tables 2 and 3.
|
|
|
The uptake of MC through the skin was described by solving Fick's Law, using the PBPK model where the rate of increase in MC concentration in the skin was determined primarily by the permeability coefficient. Equations to describe the rate of change of chemical concentration across the skin (Jepson and McDougal, 1997
) and evaporation to patch components are as follows:
 |
 |
For human subjects, the observed delay before the appearance of MC in exhaled breath was estimated in an iterative manner from the exhaled breath data upon optimization of Kloss and Kp. Kloss and Kp were estimated for each individual animal or human subject using the least-squares fit of the model to the data using the SimusolvTM (Dow Chemical Co.) optimization subroutine. The percent variability explained for the optimized values using a simple well-stirred skin compartment in the PBPK model was always >86%.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Exposures of Rats to MC in Water
Actual water exposure concentrations, as determined by GC headspace analysis, ranged from 0.094 to 0.11%. A representative example of the exhaled breath concentrations of MC following a dermal exposure to 0.1% MC in 5 ml of water (5 cm2 surface area exposed) in a fully occluded patch is shown in Figure 3
. In rats, peak exhaled breath concentrations (Cmax) of approximately 1600 ppb were reached within 1 h and declined slowly over the next 8 h.
|
The PBPK model was used to estimate the permeability coefficient (KP) for dermal absorption of MC in a water matrix for each individual rat. Regardless of exposure concentrations, a single KP of 0.25 cm/h provided a good fit to all of the data sets (Table 4
). The percentage of applied MC absorbed by the rat differed with exposure duration, with 61% taken up by 4 h and 87% after 8 h of exposure. The GC analysis revealed that the remaining 39% and 13% of the applied MC dose was recovered in the dosing media after 4 h and 8 h of exposure, respectively, confirming no loss of MC to the occluded system. Figure 4 shows a comparison of the results of the GC analysis of the concentrations of MC in exposure media and patch components versus the PBPK model predictions of MC in the media and patch components.
|
|
Exposures of Rats to MC in Soil
Actual soil exposure concentrations ranged from 0.037 to 0.57%, as determined by GC headspace analysis. Peak exhaled breath concentrations were non-linear between the lowest (0.037–0.047) and the highest (0.10–0.56%) exposure concentrations. Exposures to ~0.5% MC in soil resulted in a Cmax for exhaled breath concentrations more than 20-fold higher than seen with the ~0.05% exposures (peak heights of ~1800 ppb and ~80 ppb, respectively) (Fig. 5
). However, the total amount of MC absorbed was linear across exposure concentrations. For example, PBPK estimations of total absorbed MC from an exposure to 0.49% MC in soil was 1.28 mg while the total absorbed dose from the 0.047% exposure was 0.122 mg. In contrast to the occluded water exposures, the exhaled breath concentrations for non-occluded soil exposures peaked at less than 30-min and declined rapidly.
|
The rate of loss of MC from the media to the patch system (Kloss), an integral factor in modeling the dermal uptake of MC from non-occluded soil, was optimized by the least-squares fit of the PBPK model to the concentrations of MC in the various patch components and MC remaining in the media at the end of the exposure, using the optimization subroutine of SimusolvTM (Dow Chemical Co.; Fig. 4
). The percentage of MC lost to the patch system was relatively constant for all samples at all concentrations. Although Kloss was individually optimized for each data set, a single value of 1.6 h–1 provided a good fit to all of the data. Greater than 97% of the MC lost to the patch component was recovered in the charcoal, while less than 3% was recovered in the duoderm and muslin components of the patch system. Approximately 67% of the original MC concentration was volatilized to the surrounding patch system over the 2-h exposure period, and not available to be absorbed from the non-occluded soil (Table 4; Fig. 4). In 3 of the soil samples collected at the end of the 2.5-h exposures, 0.02–0.1% of the original MC concentration still remained; no MC was detected in the other 5 soil samples. The KP for the uptake of MC from the non-occluded soil patch was estimated using the PBPK model to be 0.15 (cm/h), which was lower than that predicted for absorption of MC in water (Table 4).
Human Subjects
MC was found in the exhaled breath of human subjects with peak levels ranging from approximately 1100 ppb to 1500 ppb following exposures to 0.085–0.14% MC in water (Fig. 6). The peak exhaled breath concentration from three male subjects exposed to 0.61–0.77% MC in soil was more variable and ranged from 800–2000 ppb (Fig. 7). A lag time in the appearance of MC in exhaled breath occurred in all subjects and ranged from 0.3–1.3 h. The delay was estimated for each individual exposure by manual adjustment of the time before the PBPK model initiated the exposure. The average delay time before appearance of MC was similar for both soil (0.80 ± 0.40 h) and water (0.83 ± 0.43 h) exposures (Table 5). The termination of exposure was artificially adjusted to account for the lag time.
|
|
|
The exhaled breath data was analyzed using the PBPK model with physiological parameters set for humans (Table 5
). The body surface area and percent body fat were individually set for each subject based on the calculations described in Table 1, and results from the near-infrared body fat analyzer, respectively. The concentration of MC in the container of water or soil was constant over the 2-h exposure period as measured by GC analysis. Therefore, the rate of loss of MC from the exposure system (Kloss) was set to zero. For simplicity, this study assumed that all subjects had the same body weight-proportional blood flow, ventilation and metabolism rates. The Kp for human dermal absorption of MC in water estimated using the PBPK model ranged from 0.0057 to 0.0069 cm/h. Less than 0.2% of the available amount of MC in the water was absorbed by human subjects exposed for 2 h. In the human subjects, the Kp for MC in soil was approximately 1/3 of the Kp for MC in water (0.002 ± 0.0005). |
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
PBPK modeling is particularly well-suited for assessing dermal exposures under non-steady state conditions (Jepson and McDougal, 1997
). Real-time breath analysis, coupled with PBPK modeling, has been successfully used to describe the uptake, distribution, and elimination phases of dermal exposure (Corley, et al., 1999). In the study reported here, MC was eliminated in exhaled breath at levels well within the detection limit of the MS/MS system in both rats and humans. The previously validated PBPK model of Reitz et al. (1988) was modified by adding a skin compartment and used to simulate the concentration of MC in the exhaled breath of rats and humans exposed dermally to water and soil containing MC. The MC permeability coefficients determined here were within the range of previous estimates reported for similar compounds. For example, a Kp of 0.25 cm/h was determined for rats exposed to MC in water in this study. In comparision, Jepson and McDougal (1999) reported a Kp of 0.2 cm/h for dibromomethane in rats and Bogen et al. (1992) reported Kps of 0.13, 0.21 and 0.37 cm/hr for chloroform, trichloroethylene and perchloroethylene in hairless guinea pigs following exposures in a water matrix.
The octanol:water partition coefficient is often used to estimate Kp (Guy and Potts, 1993; U.S. EPA, 1992). The estimated Kp for MC based on the octanol:water partition coefficient is 0.018 cm/h (U.S. EPA, 1992), almost 3 times greater than the value predicted here for humans. The uncertainty in Kp predicted from the octanol:water partition coefficient is expected to be within an order of magnitude (U.S. EPA, 1992). Reifenrath et al. (1984) reported that penetration rates were more directly related to octanol:water partition coefficients for water-soluble compounds than for lipid soluble compounds in human skin grafted nude mice.
In this study, a simple, well-stirred skin compartment was used in the PBPK model to describe the dermal flux. Previous investigators have used models that included dual skin compartments to represent the stratum corneum and epidermis (Chinery and Gleason, 1993; Shatkin and Brown, 1991). However, the single compartment has the advantage of having fewer variables that need to be independently determined. Furthermore, models using a single skin compartment have been found to adequately describe the dermal absorption of similar test chemicals, such as; chloroform, dibromomethane, and bromochloromethane (Corley et al., 1999; Jepson and McDougal 1997). The simple, single-compartment model used here sufficiently described the exhaled breath data after a delay function was included to describe each individual human exposure.
The estimated permeability coefficients in rats were higher than those estimated in humans. This is consistent with previous studies that showed that animal skin is more permeable than human skin (Bronaugh, 1998; Jepson and McDougal, 1997; McDougal et al., 1990). Studies have shown that the percentage of percutaneous absorption can range from 1- to 20-fold higher in rats compared to humans (U.S. EPA, 1992; Bartnik et al., 1987; Bronaugh, 1998). In the present study, the human hand-water immersion exposure is essentially an occluded exposure and most closely mimics the rat occluded-water patch exposure. Under these exposure conditions, the rat Kp of 0.25 cm/h is roughly 40 x higher than observed for the human (Kp 0.0063 cm/h). Additionally, studies in human volunteers with 4 dermal exposure patches similar to the single patch used with rats, containing either water or soil matrices, resulted in no quantifiable MC in the exhaled breath. This is likely due to the small percent surface of area exposed in humans and the rapid volatilization of MC. However, these differences may also reflect variations in the permeability due to exposure site-specific factors.
In rats, the permeability coefficients were constant over the exposure range (0.04–0.6% MC) in non-occluded soil. In both rats and humans, the permeability coefficients for exposures to MC in water were greater than those estimated for exposures to MC in soil. Human volunteer subject #1 participated in both the water and soil exposure trials, and provided an opportunity to compare soil versus water matrix effects. For MC dermal uptake from a soil matrix, the KP for this volunteer was 0.002 cm/h whereas the KP for the aqueous matrix was 0.0064 cm/h, indicating that exposure via the aqueous matrix leads to a higher bioavailability. The apparent Kps that best fit the data for all 3 subjects exposed to MC in soil were approximately 4 times lower than predicted based on the absorption for MC in water.
The hand of one male subject was pre-hydrated by soaking in clean water for 2 h prior to a 1-h exposure to aqueous MC (subject #4). In this subject, peak exhaled-breath concentrations were more than 7 times greater than peak concentrations observed in the other subjects (Fig. 8). Pre-hydration of the single subject resulted in a higher estimated Kp, shorter lag time, and greater percentage absorbed than expected based on data from non-prehydrated subjects (Table 5). The high Kp in this subject is consistent with the assumption that hydration results in an increased permeability to many compounds (U.S. EPA, 1992).
|
Since dermal exposure to contaminants in soil resulting from work or play generally do not involve occlusion of chemical evaporation, a patch system was developed that maintains the soil in contact with the skin while simultaneously allowing volatilization of compound. The results from this study clearly illustrated that much of the MC was volatilized, suggesting that experimental exposure systems that prevent evaporation of the chemical will result in an artificially high estimate of percentage absorbed. For example, the rat breath elimination data clearly show a sustained uptake of MC over an 8-h exposure for occluded water exposures (Fig. 3
), while all of the MC is eliminated from rats or volatilized to the charcoal within about 2 h in non-occluded exposures (Fig. 5). Ryatt, et al. (1988) suggested that occlusion prevents evaporation and thus maintains a higher concentration of chemical on the skin surface, and that occlusion may result in increased skin hydration. This may explain, in part, the differences in the rates of uptake in occluded versus non-occluded exposures described here. The percent of dose absorbed was highly dependent on hydration, length of exposure, and whether the exposure was occluded or not. Thus, a simple percent absorbed dose, or "bioavailability factor" is experiment- and exposure-specific and is difficult to generalize for use in risk assessments. These data demonstrate that appropriately defined Kps coupled with PBPK modeling should be used when available for dermal risk assessment.
For example, the dermal PBPK model for MC was used to simulate the dermal bioavailability for adults and children exposed to MC-contaminated water and soil in a residential setting, using EPA standard default factors for adult and child body weights, surface area exposed, soil burden (U.S. EPA, 1992), and parameters determined in this study (KP and Kloss) (Table 6). For these simulations, the media MC concentration was fixed at 0.01%. To demonstrate the impact of the exposure matrix (soil versus water) and occlusion on the total absorbed dose, simulations were limited to 2-h and 24-h exposures.
|
Due to loss of chemical from the exposure surface, only 0.3–6% of the available dose would be expected to be absorbed from contact to non-occluded soil in either children or adults, regardless of the length of exposure. The EPA default assumption is that 2.5 times more soil adheres to children than to adults (U.S. EPA, 1992
). In a non-occluded system, this difference in soil loading is predicted to make little difference in the amount absorbed (Fig. 9). In the non-realistic occluded exposure systems, significantly more would be expected to be absorbed over 24 h of exposure than after 2 h of exposure (Table 7), due to the greater soil loading and the larger surface area/body weight ratio in children (Plunkett et al., 1992). Using these default assumptions, children would only be expected to absorb more MC on a mg absorbed/kg body weight basis from dermal exposures than adults over long, occluded exposure periods which are unlikely to be encountered (Fig. 9). These simulations draw attention to the importance of assessing realistic, non-occluded dermal exposures in children as well as adults.
|
|
In conclusion, the combination of the real time MS/MS breath analysis system with PBPK modeling provides an opportunity to rapidly evaluate dermal exposures under various exposure conditions. The permeability coefficients, determined under these more environmentally realistic conditions, are directly applicable to risk assessments. Along with PBPK modeling, they provide a methodology to increase our understanding of the effect of various exposure scenarios on the bioavailability and internal dosimetry of volatile organic chemicals.
|
ACKNOWLEDGMENTS |
|---|
The authors wish to thank Elizabeth Farris, Mark Vucelick, and Robin Beasley for their assistance in conducting the rat exposures.
|
NOTES |
|---|
This research was supported in full under Cooperative Agreement DE-FG07-97ER62509, Environmental Management Science Program, Office of Science and Technology, Office of Environmental Management, United States Department of Energy (DOE). However, any opinions, findings, conclusions, or recommendations expressed herein are those of the authors and do not necessarily reflect the views of the DOE.
1 To whom correspondence should be addressed at Chemical Dosimetry, Battelle, Pacific Northwest Division, PO Box 999 MSIN P7-59, Richland, WA 99352. Fax: (509) 376–9064. E-mail: torka.poet{at}pnl.gov. 
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Bartnik, F. G., Reddy, A. K., Klecak, G., Zimmermann, V., Hostynek, J. J., and Kunstler, K. (1987). Percutaneous absorption, metabolism, and hemolytic activity of n-butoxyethanol. Fundam. Appl. Toxicol. 8, 59–70.[ISI][Medline]
Bogen, K. T., Colston, B. W., and Machicao, L. K. (1992). Dermal absorption of dilute aqueous chloroform, trichloroethylene, and tetrachloroethylene in hairless guinea pigs. Fundam. Appl. Toxicol. 18, 30–39.[Medline]
Bronaugh, R. L. (1998). Current issues in the in vitro measurement of percutaneous absorption. In Dermal Absorption and Toxicity Assessment (M. S. Roberts and K. W. Walters, Eds.), pp. 155–160. Marcel Dekker, New York.
Brown, R. P., Delp, M. D., Lindstedt, S. L., Rhomberg, L. R., and Beliles, R. P. (1997). Physiological parameter values for physiologically based pharmacokinetic models. Toxicol. Ind. Health 13, 407–484.[ISI][Medline]
Chinery, R. L., and Gleason, A. K. (1993). A compartmental model for the prediction of breath concentration and absorbed dose of chloroform after expsoure while showering. Risk Anal. 13, 51–62.[ISI][Medline]
Corley, R. A., Gordon, S. M., and Wallace, L. A. (2000). Physiologically based pharmacokinetic modeling of the temperature-dependent dermal absorption of chloroform by humans following bath water exposures. Toxicol. Sci. 53, 13–23.
Corley, R. A., Markham, D. A., Banks, C., Delorme, P., Masterman, A., Houle, J. M., and Delorme, C. (1997). Physiologically based pharmacokinetics and dermal absorption of 2-butoxyethanol vapor by humans. Toxicol. Appl. Pharmacol. 39, 120–130.
Dourson, M. L., and Felter, S. P. (1997). Route-to-route extrapolation of the toxic potency of MTBE. Risk Anal. 17, 717–725.[Medline]
Gargas, M. L. (1990). An exhaled breath chamber system for assessing rates of metabolism and rates of gastrointestinal absorption with volatile compounds. J. Amer. College Toxicol. 9, 447–453.
Gargas, M. L., Burgess, R. J., Voisard, D. E., Cason, G. H., and Andersen, M. E. (1989). Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol. Appl. Pharmacol. 98, 87–99.[ISI][Medline]
Gordon, S. M., Wallace, L. A., Callahan, P. J., Kenny, D. V., and Brinkman, M. C. (1998). Effect of water temperature on dermal exposure to chloroform. Environ. Health Perspect. 106, 337–345.[Medline]
Guy, R. H., and Potts, R. O. (1993). Penetration of industrial chemicals across the skin: A predictive model. Amer. J. Ind. Med. 23, 711–719.[Medline]
Jepson, G. W., and McDougal, J. N. (1997). Physiologically based modeling of nonsteady state dermal absorption of halogenated methanes from an aqueous solution. Toxicol. Appl. Pharmacol. 144, 315–324.[ISI][Medline]
Jepson, G. W., and McDougal, J. N. (1999). Predicting vehicle effects on the dermal absorption of halogenated methanes using physiologically based modeling. Toxciol. Sci. 48, 180–188.
Jo, W. K., Weisel, C. P., and Lioy, P. J. (1990). Routes of chloroform exposure and body burden from showering with contaminated tap water. Risk Anal. 10, 575–580.[ISI][Medline]
Mattie, D. R., Bates, G. D., Jepson, G. W., Fisher, J. W., and McDougal, J. N. (1994). Determination of skin:air partition coefficients for volatile chemicals: Experimental method and application. Fundam. Appl. Toxicol. 22, 51–57.[Medline]
McDougal, J. N., Jepson, G. W., Clewell, H. J., Gargas, M. L., and Andersen, M. E. (1990). Dermal absorption of organic chemical vapors in rats and humans. Fundam. Appl. Toxicol. 55, 299–308.
Morgan, D. L., Cooper, S. W., Carlock, D. L., Sykora, J. J., Sutton, B., Mattie, D. R., and McDougal, J. N. (1991). Dermal absorption of neat and aqueous volatile organic chemicals in the Fischer 344 rat. Environ. Res. 55, 51–63.[Medline]
Plunkett, L. M, Turnbull, D., Phil, D., and Rodricks, J. V. (1992). Differences between adults and children affecting exposure assessment. In Similarities and Differences Between Children and Adults, (P. S. Guzelian, C. J. Henry, and S. S Olin, Eds.), pp. 79–94. ILSI Press, Washington, DC.
Reifenrath, W. G., Chellquist, E. M., Shipwash, E. A., and Jederbert, W. W. (1984). Evaluation of animal models for predicting skin penetration in man. Fundam. Appl. Toxicol. 4(Part 2), 224–230.
Reitz, R. H., McDougal, J. N., Himmelstein, M. W., Nolan, R. J., and Schumann, A. M. (1988). Physiologically based pharmacokinetic modeling with methylchloroform: Implications for interspecies, high dose/low dose, and dose route extrapolations. Toxicol. Appl. Pharmacol. 95, 185–199.[ISI][Medline]
Roy, A., Weisel, C. P., Lioy, P. J., and Georgopoulos, P. G. (1998). A distributed parameter physiologically-based pharmacokinetic model for dermal and inhalation exposure to volatile organic compounds. Risk Anal. 16, 147–160.
Ryatt, K. S., Mobayen, M., Stevenson, J. M., Maibach, H. I., and Guy, R. H. (1988). Methodology to measure the transient effect of occlusion on skin penetration and stratum corneum hydration in vivo. Br. J. Dermatol. 119, 307–312.[Medline]
Schumann, A. M., Fox, T. R., and Watanabe, P. G. (1982). [14C]Methyl chloroform (1,1,1-trichloroethane): Pharmacokinetics in rats and mice following inhalation exposure. Toxicol. Appl. Pharmacol. 62, 390–401.[ISI][Medline]
Shatkin, J. A., and Brown, H. S. (1991). Pharmacokinetics of the dermal route of exposure to volatile organic chemicals in water: A computer simulation model. Environ. Research 56, 90–108.[Medline]
Thrall, K. D., and Kenny, D. V. (1996). Evaluation of carbon tetrachloride physiologically based pharmacokinetic model using real-time breath-analysis monitoring of the rat. Inhal. Toxicol. 8, 251–261.
U.S. EPA (1992). Dermal exposure assessment: Principles and applications. Washington, DC. EPA/600/8–91/011B.
U.S. EPA (1996). Exposure factors handbook. EPA/600/P-95/002Ba. Washington, DC.
Weisel, C. P., and Jo, W. (1996). Ingestion, inhalation, and dermal exposures to chloroform and trichloroethene from tap water. Environ. Health Perspect. 104, 48–51.[Medline]
Wester, R. C., and Maibach, H. I. (1989). Human skin binding and absorption of contaminants from ground and surface water during swimming and bathing. J. Amer. College Toxicol. 8, 853–859.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. M. Norman, J. C. Kissel, J. H. Shirai, J. A. Smith, K. L. Stumbaugh, and A. L. Bunge Effect of PBPK Model Structure on Interpretation of In Vivo Human Aqueous Dermal Exposure Trials Toxicol. Sci., July 1, 2008; 104(1): 210 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Reddy, R. J. Looney, M. J. Utell, K. P. Plotzke, and M. E. Andersen Modeling of Human Dermal Absorption of Octamethylcyclotetrasiloxane (D4) and Decamethylcyclopentasiloxane (D5) Toxicol. Sci., October 1, 2007; 99(2): 422 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. S. Poet, K. K. Weitz, R. A. Gies, J. A. Edwards, K. D. Thrall, R. A. Corley, H. Tanojo, X. Hui, H. I. Maibach, and R. C. Wester PBPK Modeling of the Percutaneous Absorption of Perchloroethylene from a Soil Matrix in Rats and Humans Toxicol. Sci., May 1, 2002; 67(1): 17 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. S. Poet, R. A. Corley, K. D. Thrall, J. A. Edwards, H. Tanojo, K. K. Weitz, X. Hui, H. I. Maibach, and R. C. Wester Assessment of the Percutaneous Absorption of Trichloroethylene in Rats and Humans Using MS/MS Real-Time Breath Analysis and Physiologically Based Pharmacokinetic Modeling Toxicol. Sci., July 1, 2000; 56(1): 61 - 72. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||