* The K. S. Crump Group, Inc., ICF Consulting, 602 East Georgia Avenue, Ruston, Louisiana 71270;
ManTech Environmental Technology, Inc., Dayton, Ohio;
Lyondell Chemical Company, Houston, Texas; and
Colorado State University, Fort Collins, Colorado
Received January 17, 2001; accepted July 17, 2001
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ABSTRACT |
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Key Words: PBPK model; isopropanol; CAS# 67-63-0; acetone; CAS# 67-64-1.
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INTRODUCTION |
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The second challenge associated with the use of animal data for IPA in a human health risk assessment is uncertainty regarding the appropriate approach for performing cross-species dosimetry from the experimental animal to the human. The U.S. EPA RfC dosimetry guidelines (U.S. EPA, 1994) represent an important step forward in this regard, by providing multiple default approaches for cross-species dosimetry depending on the physicochemical properties of the compound and the nature of its toxicity. In these guidelines, inhaled vapors are classified into one of three categories: category 1 for reactive or readily metabolized gases and vapors for which accumulation in the systemic blood is unlikely (e.g., formaldehyde); category 2 for chemicals with intermediate properties; and category 3 for unreactive, poorly water-soluble chemicals that rapidly achieve a steady-state blood concentration (e.g., styrene). As an unreactive but highly water-soluble chemical, IPA cannot readily be classified into either category 1 or 3. Unfortunately, default dosimetry for category 2 chemicals is currently under development. However, even if such a default was available, the U.S. EPA guidelines indicate that the preferred methodology for cross-species extrapolation is the use of a validated PBPK model.
The purpose of the work described in this paper was to develop and validate a PBPK model for IPA and its principal metabolite, acetone, in the rat and human. The model was designed with the goal of providing a useful tool for integrating the existing toxicological data on IPA into a human health risk assessment. Specifically, the PBPK model is intended to perform route-to-route and cross-species dosimetry in support of the derivation of RfC and RfD values for IPA based on the results from toxicity studies in animals. Of course, the model could also be used in the same fashion to support a risk assessment for acetone exposure. This paper describes the development and validation of the basic PBPK model, with only one potential target tissue included (the brain, for acute neurological effects). Expansion of the model to support risk assessments for other potential target tissues will be the subject of a subsequent paper.
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MATERIALS AND METHODS |
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The model provides the capability for simulating multiple routes of IPA or acetone exposure: intravenous injection, intraperitoneal administration, oral gavage, inhalation, and dermal application. Inhalation and oral exposure to acetone can also be described. For oral dosing, uptake from the gastrointestinal tract is described using a two-compartment description, representing uptake from the stomach and duodenum into the portal blood. For dermal exposure, the model includes a skin-surface compartment with diffusion-limited transport of IPA into the skin. To simulate intraperitoneal injection, the administered dose is assumed to be absorbed with first-order kinetics into the tissues perfused by the portal blood. Intravenous injection is described as a pulse function of short duration, with the chemical appearing directly into the venous blood. The model was coded using the Advanced Continuous Simulation Language (ACSL®; AEgis Technologies Group, Inc., Huntsville, AL).
Lung Description
Due to the high water solubility of IPA and acetone, we assumed that some absorption in the upper respiratory tract could occur during inhalation, with subsequent desorption during exhalation. This cyclic phenomenon had previously been reported for a number of water-soluble organic chemicals, including acetone (Gerde and Dahl, 1991; Johanson, 1986
; Kumagai and Matsunaga, 1995
; Kumagai et al., 1999
). Initially, a simple fractional uptake approach, suggested by Johanson (1986), was used in the model. This simple approach was able to reproduce closed-chamber gas uptake data (Corley, unpublished data; Hallier et al., 1981
) as well as blood concentration data from several of the inhalation data sets described below (Haggard et al., 1944
; Slauter et al., 1994
), using a fractional alveolar uptake of 0.7 for both IPA and acetone. However, the fractional uptake description was unable to reproduce exhaled air data from human IPA and acetone exposures (DiVincenzo et al., 1973
; Kumagai et al., 1999
; Wigaeus et al., 1981
). To adequately reproduce this exhaled air data, it was necessary to add a description of the absorption and desorption of the chemicals in the upper respiratory tract during cyclic breathing, similar to the description used by Kumagai and Matsunaga (1995) in their model of acetone inhalation in the human. The following model code, which treats inhalation and exhalation as simultaneous, parallel processes, was developed for the lung compartment in order to incorporate the reservoir effect of the mucus layer of the upper respiratory tract on exhaled air concentrations (Fig. 1
):
Amount in the mucus:
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Amount in the arterial blood:
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Amount exhaled:
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where ClMUC (l/h) represents the clearance of IPA or acetone in the upper respiratory tract, PMUC is the partition coefficient between the respiratory mucus layer and the airstream, QC (l/h) is the total cardiac output, QALV (l/h) is the alveolar ventilation rate, CINH and CALV (mg/L) are concentrations of IPA or acetone in the inhaled breath and alveolar region, respectively, and CMUC, CVEN, and CART (mg/L) are the concentrations in the mucus, venous blood, and arterial blood. In this description, ClMUC represents a clearance from the inhaled air into the mucus of the upper respiratory tract, as opposed to a fractional alveolar absorption (relative to alveolar ventilation) used in the simpler fractional uptake approach.
Model Parameters
Physiological parameters and partition coefficients were obtained from the available literature (Tables 1 and 2). Tissue volumes, blood flows, and resting ventilation rates were obtained from Brown et al. (1997). Ventilation rates and cardiac output during exercise in the human were taken from Astrand (1983). The tissueblood and bloodair partition coefficients for IPA were taken from Kaneko et al. (1994). For acetone, the tissue-air partition coefficients in the rat were obtained from Fiserova-Bergerova and Diaz (1986), while the rat blood-air partition coefficient was taken from Morris and Cavanagh (1986). The human partition coefficients for acetone, with the exception of the bloodair partition coefficient, were obtained from information provided in Kumagai and Matsunaga (1995). The human bloodair partition coefficient for acetone of 260 is an average value based on values reported in the literature ranging from 245 to 275 (Astrand, 1983
; Morris and Cavanaugh, 1986; Sato and Nakajima, 1979
).
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Model Validation
Acetone pharmacokinetics in the rat.
The closed chamber gas uptake data of Hallier et al. (1981) for four different starting concentrations of acetone were used to establish the metabolic parameters for acetone in the rat. Specifically, the Vmax and Km for acetone were estimated by fitting the model to the acetone chamber concentration data (Fig. 2a). A Vmax and Km of 7.5 mg/h/kg3/4 and 75 mg/l, respectively, were estimated from these data. These data were also used to estimate a clearance for acetone in the upper respiratory tract (ClMUC) of 11 l/h/kg3/4. (This scaled value is multiplied by the body weight raised to the three-quarters power to obtain the value used in the equations shown earlier.) All other parameters in the model were fixed. The concentration dependence of the sensitivities of the three estimated parameters to the closed chamber data was sufficiently dissimilar to permit their simultaneous estimation.
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In a study conducted by Haggard et al. (1944), groups of rats were exposed to 2258 or 4305 ppm acetone continuously by inhalation for 912 days (Fig. 2c). The model predicts a more rapid approach to steady state than suggested by the data, but the simulated steady-state venous blood concentration is only slightly greater than the data for the 2258-ppm exposure group and is very close to the data for the 4305-ppm exposure group. These results provide support for the route-to-route extrapolation capability of the model.
In another study reported by Haggard et al. (1944), inhalation exposures of rats were conducted over a range of concentrations from 2110 to 126,600 ppm, lasting from about 30 min to 5 h. As shown in Figure 2d, use of the previously estimated value for ClMUC of 11 l/h/kg3/4 provides a reasonable simulation of the data over a wide range of concentrations. The data for the individual concentrations could be more closely simulated by varying ClMUC from 22 l/h/kg3/4 at the lowest concentration to 14 l/h/kg3/4 at the highest concentration (results not shown), but a similar effect could also be obtained by reducing the pulmonary ventilation rate, so these data do not provide an unambiguous basis for identifying ClMUC.
IPA pharmacokinetics in the rat.
Data reported by Slauter et al. (1994) on venous blood concentrations of IPA and acetone in rats following a single intravenous injection of 306 mg/kg were used to estimate a Vmax and Km for the metabolism of IPA of 150 mg/hour/kg3/4 and 500 mg/l, respectively (Fig. 3a).
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Inhalation data was also used to validate the metabolic parameters for IPA. Slauter et al. (1994) provided data for IPA kinetics in rats following inhalation exposure (Figs. 3c and 3d). In this study, groups of rats were exposed to 476 or 4960 ppm IPA for 6 h, and venous blood concentrations of both IPA and acetone were analyzed during exposure and for 6 h postexposure. The model provided a reasonable fit to these data without requiring any adjustment of the model parameters from those established by the intravenous data.
The model was also used to simulate a data set on the dermal absorption of IPA. In the Boatman et al. (1995) study, 1056 mg IPA/kg body weight was applied to a skin area of 4.3 cm2 in a sealed cell, and left in place for 4 h, at which time the unabsorbed IPA was removed. The venous blood time courses of IPA and acetone were measured during the 4-h exposure period, as well as 20 h postexposure. Simulation of these dermal absorption data for IPA in the rat with the PBPK model required a permeation coefficient of 0.0008 cm/h (Fig. 4a), which compares well with the value of 0.0014 cm/h obtained in vitro with human skin by Blank et al. (1967). Interestingly, a substantial increase of the Vmax for IPA to 400 mg/h/kg3/4 was necessary to obtain the observed ratio of IPA and acetone concentrations. To determine whether this increase reflected presystemic metabolism of IPA in the skin during absorption, the model was modified to include metabolism in the skin with the same affinity and capacity per gram of tissue as the liver. The resulting model was able to reproduce the kinetics of the dermal exposure using the same metabolic constants as for the other exposure routes (liver Vmax and Km of 150 mg/h/kg3/4 and 500 mg/l, respectively).
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During the development of the IPA model, initial results from a gas uptake study with rats conducted by Corley (unpublished data) were obtained and were used to further validate the model. The ability of the model to simulate these data (Fig. 4d) provides additional support for the metabolic parameters for IPA reported in Table 2
, as well as for the use of a value of 11 l/h/kg3/4 for ClMUC for IPA, which had been assumed by analogy to acetone.
Isopropanol pharmacokinetics in the human isopropanol pharmacokinetics in the human.
Two controlled studies in which subjects ingested IPA were available to determine the capability of the model to simulate kinetics of IPA and acetone in the human following oral exposure to IPA (Lacouture et al., 1989; Monaghan et al., 1995
). In the Monaghan et al. (1995) study, three healthy male subjects ingested 0.6 ml/kg 70% IPA in 240 ml water over a 5-min period. Venous blood samples were collected at baseline and 0.16, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h postingestion. Significant adjustments to the rat metabolism parameters for both IPA and acetone were required to reproduce these human data. Specifically, much higher affinity metabolic clearance for IPA (Vmax and Km of 300 mg/h/kg3/4 and 10.0 mg/l, respectively) was necessary to reproduce the observed IPA data in the human (Fig. 5a
). In contrast, a much lower metabolic capacity for acetone (Vmax and Km of 3.5 mg/h/kg3/4 and 10.0 mg/l, respectively) was required to provide a reasonable simulation of the observed acetone data. It was also necessary to modify the oral absorption parameters from those in the rat. As shown in Table 1
, a single set of oral uptake parameter values provided the best simulation of the human data, independent of dose.
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The results from the IPA inhalation study reported by Kumagai et al. (1999) were used to demonstrate the route-to-route extrapolation capability of the human IPA model. In this study, respiratory uptake in humans was investigated in four healthy male volunteers who inhaled concentrations of 50, 100, or 200 ppm acetone or IPA at rest for 10 min. The subjects inhaled the vapors through a mouthpiece equipped with a valve to isolate exhaled air, and samples of exhaled air were collected 1 min prior to exposure, during the 10-min exposure, and for 5 min following exposure. Exhaled air concentrations were reported both for the average concentration over an exhalation as well as for the concentration at the end of an exhalation (which would better represent air from the alveolar region). Model simulations of these data are provided in Figures 5c and 5d. The clearance in the upper respiratory tract (ClMUC) of 11 l/h/kg3/4 identified in the rat resulted in a good fit to the concentrations of IPA observed in mixed (average) exhaled air and end-exhaled (alveolar) air, but it was also necessary to use a value of 0.15 for the fraction of dead space in the lung, as opposed to the value of 0.3 that is typically used for lipophilic compounds (Ramsey et al., 1984). Because the model fit to this data was highly sensitive to this parameter, the value obtained from this study is used in the model for both the human and the rat.
Acetone pharmacokinetics in the human.
Data from Kumagai et al. (1999) were also used to validate the ability of the model to simulate inhalation of acetone in the human. The model simulations of the mixed-exhaled air and end-exhaled air following inhalation of 100 ppm acetone are presented in Figure 5d. No adjustments to the metabolic parameters were required to fit the data. Further, use of a value for ClMUC of 11 l/h/kg3/4 for acetone in the human provided simulations that were consistent with the observed data. A fractional lung dead space of 0.25, which was also necessary to reproduce these data, was used in the model for all simulations of acetone inhalation.
Data reported by DiVincenzo et al. (1973) and Wigaeus et al. (1981) were used to validate the human Vmax and Km values for acetone that were estimated from the oral IPA studies. In the DiVincenzo et al. (1973) study, nine male volunteers were exposed via inhalation to 100 ppm or 500 ppm acetone vapor for 2 h. Using the human Vmax and Km values that were estimated from the oral IPA studies, the model was able to reproduce the data from this study for the concentration of acetone in venous blood (Fig. 6a). The results shown in this figure were obtained using the default value of 11 l/h/kg3/4 for ClMUC. A better fit to the data (not shown) could be obtained by increasing ClMUC to 20 l/h/kg3/4. Reasonable agreement was also obtained with data from a similar study by Wigaeus et al. (1981) for acetone concentrations in exhaled air and arterial blood (Figs. 6b and 6c
). The default value of 11 l/h/kg3/4 for ClMUC was again used in performing this comparison. This study also provided the only data available on urinary excretion of acetone. In order to make use of this data, urinary clearance, described as a first-order clearance of the blood, was added to the model and the parameter (ClUR) was estimated by fitting the data from Wigaeus et al. (1981) on the urinary excretion of acetone, shown in Figure 6d
. The urinary clearance estimated from this data does not represent a significant route of elimination for IPA.
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RESULTS AND DISCUSSION |
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The kinetic data for oral administration of both IPA and acetone in the rat consistently requires a dose-dependent parameterization for oral uptake. As indicated in Table 1, although a single value can be used for three of the four oral absorption parameters across all of the studies and doses, the parameter describing uptake from the stomach must be varied inversely with dose. For low doses, on the order of a few hundred milligrams per kilogram or less, rapid uptake is observed, consistent with a rate constant for uptake from the stomach of 5/h. At high doses, above 1000 mg/kg, much slower uptake is observed that is most effectively modeled with a rate constant of zero for stomach uptake, resulting in the transfer of all of the chemical to the second (duodenal) compartment, where it is absorbed over a longer period. A value between these two extremes was most appropriate for intermediate doses. The cause of this dose-dependent absorption is unknown, but may be associated with a pharmacological effect of high doses of IPA/acetone on gastric absorption or gastric emptying. The evidence for its occurrence is consistent across three different studies and for both IPA and acetone. The only impact of this dose dependency is for applying the PBPK model to predict kinetics following oral gavage, in which case the model parameter for gastric absorption must be set to a value ranging from 5/h to 0/h as determined by comparing the administered dose to the ranges shown in the footnote to Table 1
.
The human kinetic data uniformly require a much higher affinity metabolic clearance for IPA in the human than that required by the kinetic data in the rodent. Unfortunately, there are no in vitro metabolic data available for IPA oxidation to support or refute the parameter values based on these in vivo data. It is possible that the apparently higher affinity of metabolism in the human reflects a contribution at low concentrations from another enzyme with a higher affinity than ADH. A low-capacity, mixed-function oxidase has been implicated in the oxidation of ethanol and trichloroethanol in the human (Muller et al., 1975).
Lung Description
Traditionally in PBPK modeling of organic solvents, uptake in the respiratory tract has been assumed to occur only in the alveolar region (Ramsey and Andersen, 1984). The results of experimental studies conducted by Astrand (1983) in humans indicated that uptake was much lower than expected in the case of water-soluble solvents, such as n-butanol. Astrand (1983) concluded that a water-soluble solvent can be absorbed into the mucus of the upper respiratory tract during inhalation and then desorbed during exhalation, resulting in less of these solvents reaching the alveolar region of the respiratory tract. Therefore, for water-soluble organic solvents such as acetone or IPA, the traditional description of the lung compartment does not consider the important role of the mucus layer of the upper respiratory tract in inhalation uptake.
For this model, a slightly more complex lung description was incorporated, similar to the description used by Kumagai and Matsunaga (1995) in their model of acetone inhalation in the human. It incorporates a dual compartment mucus description, with parallel subcompartments for inhalation and exhalation. A simpler fractional uptake description, as used by Johanson (1986) for modeling human inhalation of 2-butoxyethanol, provided an adequate simulation of venous blood concentrations during inhalation exposures. However, the more complex description was necessary in order to adequately describe data on concentrations of acetone and IPA in exhaled air (DiVincenzo et al., 1973; Kumagai et al., 1999
; Wigaeus et al., 1981
). With this more complex description it was possible to reproduce the role of upper respiratory tract mucus in the reversible absorption of these water-soluble compounds. It is of interest that in order to reproduce these inhalation data, it was also necessary to reduce the fractional dead space in the lung from the usual value of 0.3 for lipophilic compounds to values of 0.25 for acetone and 0.15 for IPA. The smaller apparent fractional dead space probably reflects the possibility that for highly water-soluble compounds like IPA and, to a lesser extent, acetone, uptake can extend beyond the alveolar region into the mucus-covered areas of the tracheobronchial region On the other hand, the simpler description was useful in providing a direct estimate of the fractional uptake of IPA and acetone during inhalation. For both chemicals, the available inhalation data (Corley, unpublished data; Haggard et al., 1944
; Hallier et al., 1981
; Slauter et al., 1994
) were consistent with a fractional uptake of approximately 70% of alveolar ventilation. That is, the fractional uptake of IPA and acetone was estimated to correspond to roughly 70% of that expected from the usual alveolar ventilation rates used in PBPK models of lipophilic vapors (Ramsey and Andersen, 1984
).
Published estimates of fractional uptake are more typically measured relative to total ventilation; for comparison with these other data, the fractional uptake of IPA and acetone estimated in this analysis equates to approximately 50% of total ventilation (multiplying by 0.67, the ratio of alveolar to total ventilation). A similar fractional uptake of 60% based on total ventilation was estimated by Johanson (1986) for 2-butoxyethanol, and the data reported by Astrand et al. (1976) for n-butanol are consistent with an initial pulmonary extraction of roughly 60%. Unfortunately, many estimates of fractional uptake reported in the literature have been obtained at or near steady state and are therefore highly dependent on metabolic extraction. Fractional uptakes at steady state estimated from these data are not comparable to initial fractional uptakes, which must be derived by the extrapolation of uptake data to estimate the initial extraction when the blood concentration is negligible (Astrand et al., 1976).
It was mentioned earlier that the inclusion of metabolism in the skin was necessary to reproduce data from dermal exposure to IPA. During the development of this model, we also investigated the potential impact of metabolism of IPA in the lung by including it in the model in a similar fashion to the description of metabolism in the skin. Our results indicated that the impact of lung metabolism was too small to be of consequence for the prediction of systemic exposure concentrations. In particular, the available kinetic data (particularly exhaled air data) was not consistent with a level of presystemic lung metabolism sufficiently high to alter systemic delivery. Of course, if the lung were a target tissue for toxicity, the metabolism in the Clara cellrich region would have to be described to determine its impact on local dosimetry.
Model Application
The PBPK model presented here is intended to perform route-to-route extrapolation and cross-species dosimetry in support of an IPA or acetone risk assessment. The ultimate aim of using PBPK modeling in risk assessment is to provide a suitable measure of internal exposure, referred to as the PBPK dose metric, which better represents the biologically effective dose, that is, the dose that causally relates to the toxic outcome. The PBPK dose metric can then be used in place of default dose metrics (e.g., inhalation exposure concentration or administered dose) during risk assessment calculations (Andersen et al., 1987; Clewell and Andersen, 1985
; Jarabek, 1995
; Young et al., 1996
).
In the past, risk assessments for different routes of exposure have generally been performed separately, with the quantitative dose-response calculations in each case being based solely on studies performed by the route of interest for that assessment. A drawback of this approach is that it is not possible to address concerns regarding effects observed in a study by a different route that might represent a more sensitive end point than the critical study by the route of interest. Occasionally, comparisons of inhalation and oral studies have been performed by calculating an inhaled dose, defined as the product of the inhalation concentration, the pulmonary ventilation rate, the duration of exposure, and an estimate of the fractional uptake. However, as discussed earlier, the fractional uptake for a volatile chemical can have a complex time dependence. Moreover, inhaled dose may not provide a meaningful measure of internal exposure. A more correct approach for comparing studies across routes is the use of a PBPK model. Specifically, pharmacokinetically equivalent exposures across routes (and species) can be defined as those producing the same value of the appropriate PBPK dose metric.
To illustrate the use of the PBPK model reported here to support the comparison of toxicity data across exposure routes, Figure 7 presents the model-predicted dose response for the maximum concentration (CMAX) and area under the concentration curve (AUC) for IPA and acetone in the arterial blood following single oral doses and 6-h inhalation exposures in the rat. The parameter values for the rat in Tables 1 and 2
were used for this comparison. As a simple example of the interpretation of Figure 7
, if the dose for a particular oral study in rats was 800 mg/kg and the AUC for IPA was assumed to be the appropriate measure of exposure for the end point observed in the study, Figures 7a and 7c
could be used to estimate the equivalent 6-h inhalation exposure concentration. First, from Figure 7a
it can be determined that the model-predicted value of the dose metric (AUC for IPA) for an oral dose of 800 mg/kg IPA is approximately 2300 mg-h/l. Then, from Figure 7c
, it can be determined that an AUC for IPA of 2300 is predicted to occur for a 6-h exposure to IPA at a concentration of roughly 2800 ppm. Thus, if the AUC for IPA is the appropriate basis for comparison, 6-h inhalation exposure of the rat at a concentration of 2800 ppm IPA would be predicted to result in the same potential for systemic toxicity as oral dosing with 800 mg/kg IPA.
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In an actual risk assessment, the model would be run to reproduce the specific exposure scenario in each of the studies demonstrating effects from IPA or acetone. PBPK dose metrics derived for these various studies would make it possible to determine the critical effects (those occurring at the lowest human exposure levels), based on all of the available animal studies, regardless of the route of exposure used in the different studies. Use of the appropriate PBPK dose metric for the critical effect in the animal-to-human extrapolation, in place of the application of default dosimetry, would then provide a more biologically realistic basis for evaluating the potential risks associated with human exposures to IPA or acetone.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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Andersen, M. E., MacNaughton, M. G., Clewell, H. J., and Paustenbach, D. J. (1987). Adjusting exposure limits for long and short exposure periods using a physiological pharmacokinetic model. Am. Ind. Hyg. Assoc. J. 48, 335343.[ISI][Medline]
Astrand, I. (1983). Effect of physical exercise on uptake, distribution and elimination of vapors in man. In Modeling of Inhalation Exposure to Vapors: Uptake, Distribution, and Elimination (V. Fiserova-Bergerova, Ed.), Vol. 2, pp. 107130. CRC Press, Boca Raton.
Astrand, I., Ovrum, P., Lindqvist, T., and Hultengren, M. (1976). Exposure to butyl alcohol: Uptake and distribution in man. Scand. J. Work Environ. Health 3, 165175.
Bevan, C., Tyler, T. R., Gardiner, T. H., Kapp, R. W., Andrews, L., and Beyer, B. K. (1995). Two-generation reproduction toxicity study with isopropanol in rats. J. Appl. Toxicol. 15, 117123.[ISI][Medline]
Blank, I. H., Scheuplein, R. J., and MacFarlane, D. J. (1967). Mechanisms of percutaneous absorption. III. The effect of temperature on the transport of non-electrolytes across the skin. J. Invest. Dermatol. 49, 582589.[ISI][Medline]
Boatman, R. J., Perry, L. G., and Fiorica, L. A. (1995). Dermal absorption and pharmacokinetics of isopropanol in the male and female F-344 rat. TX-95-103. Chemical Manufacturers Association, Washington, D. C. Prepared for Toxicological Sciences Laboratory, Health and Environment Laboratories, Eastman Kodak Company, Rochester, N. Y. October 12, 1995.
Brown, R. P., Delp, M. D., Lindstedt, S. L., Rhomberg, L. R., and Beliles, R. P. (1997). Physiological parameter values of physiologically based pharmacokinetic models. Toxicol. Ind. Health 13, 407484.[ISI][Medline]
Burleigh-Flayer, H. D., Garman, R., Neptun, D., Bevan, C., Gardiner, T., Kapp, R., Tyler, T., and Wright, G. (1997). Isopropanol vapor inhalation oncogenicity study in Fischer 344 rats and CD-1 mice. Fundam. Appl. Toxicol. 36, 95111.[ISI][Medline]
Burleigh-Flayer, H. D., Gill, M. W., Strother, D. E., Masten, L. W., McKee, R. H., Tyler, T. R., and Gardiner, T. (1994). Isopropanol 13-week vapor inhalation study in rats and mice with neurotoxicity evaluation in rats. Fundam. Appl. Toxicol. 23, 421428.[ISI][Medline]
Clewell, H. J., and Andersen, M. E. (1985). Risk assessment extrapolations and physiological modeling. Toxicol. Ind. Health 1, 111131.[Medline]
Clewell, H. J., Gentry, P. R., Gearhart, J. M., Allen, B. C., and Andersen, M. E. (1995). Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants: Examples with vinyl chloride and trichloroethylene. Chemosphere 31, 25612578.[ISI][Medline]
DiVincenzo, G. D., Yanno, F. J., and Astill, B. D. (1973). Exposure of man and dog to low concentrations of acetone vapor. Am. Ind. Hyg. Assoc. J. 34, 329336.[ISI][Medline]
Fiserova-Bergerova, V., and Diaz, M. L. (1986). Determination and prediction of tissue-gas partition coefficients. Int. Arch. Occup. Environ. Health 58, 7587.[ISI][Medline]
Foureman, G. L., and Clewell, H. J. (1999). Route-to-route extrapolation with a physiologically based pharmacokinetic (PBPK) model for cumene. Toxicologist 48, 395.
Gerde, P., and Dahl, A. R. (1991). A model for the uptake of inhaled vapors in the nose of the dog during cyclic breathing. Toxicol. Appl. Pharmacol. 109, 276288.[ISI][Medline]
Gerrity, T. R., and Henry, C. J. (1990). Principles of Route-to-Route Extrapolation for Risk Assessment. Elsevier, New York.
Gill, M. W., Burleigh-Flayer, H. D., Strother, D. E., Masten, L.W., McKee, R. H., Tyler, T. R., and Gardiner, T. H. (1995). Isopropanol: Acute vapor inhalation neurotoxicity study in rats. J. Appl. Toxicol. 15, 7784.[ISI][Medline]
Haggard, H. W., Greenberg, L. A., and Turner, J. A. (1944). The physiological principles governing the action of acetone together with determination of toxicity. J. Ind. Hyg. Toxicol. 26, 133151.
Hallier, E., Filser, J. G., and Bolt, H. M. (1981). Inhalation pharmacokinetics based on gas uptake studies. Arch. Toxicol. 47, 293304.[ISI][Medline]
Jarabek, A. M. (1995). Consideration of temporal toxicity challenges current default assumptions. Inhal. Toxicol. 7, 927946.[ISI]
Johanson, G. (1986). Physiologically based pharmacokinetic modeling of inhaled 2-butoxyethanol in man. Toxicol. Lett. 34, 2331.[ISI][Medline]
Kaneko, T., Wang, P.-Y., and Sato. A. (1994). Partition coefficients of some acetate esters and alcohols in water, blood, olive oil, and rat tissues. Occup. Environ. Med. 51, 6872.[Abstract]
Kapp, R. W., Bevan, C., Gardiner, T. H., Banton, M. I., Tyler, T. R., and Wright, G. A. (1996). Isopropanol: Summary of TSCA test rule studies and relevance to hazard identification. Regul. Toxicol. Pharmacol. 23, 183192.[ISI][Medline]
Kumagai, S., and Matsunaga, I. (1995). Physiologically based pharmacokinetic model for acetone. Occup. Environ. Med. 5, 344352.
Kumagai, S., Oda, H., Matsunaga, I., Kosaka, H., and Akasaka, S. (1999). Uptake of 10 polar organic solvents during short-term respiration. Toxicol. Sci. 48, 255263.[Abstract]
Lacouture, P. G., Heldreth, D. D., Shannon, M., and Lovejoy, F. H. (1989). The generation of acetonemia/acetonuria following ingestion of a subtoxic dose of isopropyl alcohol. Am. J. Emerg. Med. 7, 3840.[ISI][Medline]
Monaghan, M. S., Olsen, K. M., Ackerman, B. H., Fuller, G. L., Porter, W. H., and Pappas, A. A. (1995). Measurement of serum isopropanol and the acetone metabolite by proton nuclear magnetic resonance: Application to pharmacokinetic evaluation in a simulated overdose model. Clin. Toxicol. 33, 141149.
Morris, J. B, and Cavanagh, D. G. (1986). Deposition of ethanol and acetone vapors in the upper respiratory tract of the rat. Fundam. Appl. Toxicol. 6, 7888.[ISI][Medline]
Muller, G., Spassowski, M., and Henschler, D. (1975). Metabolism of trichloroethylene in man. III. Interaction of trichloroethylene and ethanol. Arch. Toxicol. 33, 173189.[ISI][Medline]
Nordmann, R., Ribiere, C., Rouach, H., Beauge, F., Giudicelli, Y., and Nordmann, J. (1973). Metabolic pathways involved in the oxidation of isopropanol into acetone by the intact rat. Life Sci. 13, 919932.[ISI][Medline]
Plaa, G. L, Hewitt, W. R., du Souich, P., Caille, G., and Lock, S. (1982). Isopropanol and acetone potentiation of carbon tetrachloride-induced hepatotoxicity: Single versus repetitive pretreatments in rats. J. Toxicol. Environ. Health 9, 235250.[ISI][Medline]
Ramsey, J. C., and Andersen, M. E. (1984). A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. Toxicol. Appl. Pharmacol. 73, 159175.[ISI][Medline]
Sato, A., and Nakajima, T. (1979). Partition coefficients of some aromatic hydrocarbons and ketones in water, blood and oil. Br. J. Ind. Med. 36, 231234.[ISI][Medline]
Slauter, R. W., Coleman, D. P., Gaudette, N. J., McKee, R. H., Masten, L. W., Gardiner, T. H., Strother, D. E., Tyler, T. R., and Jeffocat, A. R. (1994). Disposition and pharmacokinetics of isopropanol in F-344 rats and B6C3F1 mice. Fundam. Appl. Toxicol. 23, 407420.[ISI][Medline]
Til, H. P., Feron, V. J., and Immel, H. R. (1991). Lifetime (149-week) oral carcinogenicity study of vinyl chloride in rats. Food. Chem. Toxicol. 29, 713718.[ISI][Medline]
Tyl, R. W., Masten, L. W., Marr, M. C., Myers, C. B., Slauter, R. W., Gardiner, T. H., Strother, D. E., McKee, R. H., and Tyler, T. R. (1994). Developmental toxicity evaluation of isopropanol by gavage in rats and rabbits. Fundam. Appl. Toxicol. 22, 139151.[ISI][Medline]
U.S. EPA (1989). Isopropanol: Final test rule. Fed. Regist. 54, 4325243264.
U.S. EPA (2000). Integrated Risk Information Service (IRIS), Vinyl Chloride. Cincinnati, OH.
U.S. EPA (1994). Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F. Office of Health and Environmental Assessment, Washington, D. C.
Wigaeus, E., Holm, S., and Astrand, I. (1981). Exposure to acetone: Uptake and elimination in man. Scand. J. Work Environ. Health 7, 8494.
Young, J. F., Schwetz, B. A., Willhite, C. C., and Kacew, S. (1996). Symposium on pharmacokinetics/pharmacodynamics in the developing system and impact on risk assessment: Executive summary. J. Toxicol. Environ. Health 49, 339355.