Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275997400
Received May 16, 2001; accepted August 6, 2001
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ABSTRACT |
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Key Words: bioavailability; inhalation; physiologically based modeling; reinforced plastics; styrene; styrene-7,8-oxide.
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INTRODUCTION |
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Assessment of the bioavailability of SO from styrene exposure is further complicated by coexposure to airborne SO, which arises from oxidation of styrene during the manufacture of reinforced plastics. While concentrations of SO in air are typically 1/5001/1500 of those of styrene (Pfäffli and Säämänen, 1993, Tornero-Velez et al., 2000
), the high systemic availability of inhaled SO could offset its low level of exposure compared to styrene (Rappaport et al., 1996
). Pharmacokinetic studies involving ethylene and butadiene show that only minor fractions of the metabolized olefins become systemically available as the corresponding epoxides (Csanády et al., 1996
, 2000
; Filser and Bolt, 1984
; Johanson and Filser, 1993
,1996
; Kohn and Melnick, 2000
).
The notion that kinetic factors can influence bioavailability is well documented in the literature. Intestinal and hepatic first-pass effects are particularly important in this regard. For example, blood ethanol concentrations are much higher following iv administration rather than po dosing (Julkunen et al., 1985). Similarly, the immediate detoxication of SO following hepatic metabolism of styrene (more than 85% of the absorbed dose of styrene is metabolized to SO in humans [Bond, 1989
]) constitutes a hepatic-first pass effect.
The magnitude of the hepatic first-pass effect can be gauged by comparing the area under the SO blood concentration-time curve (AUCSO) following exposure to styrene [AUCSO(styrene)] with that following equivalent exposure to SO [AUCSO(SO)]. Since levels of hemoglobin and albumin adducts in blood reflect the AUC of electrophilic species under reasonable assumptions (Ehrenberg et al., 1974), these markers may be used to determine bioavailability. Measurements of SO adducts of blood proteins by Rappaport et al. (1993, 1996) indicated that the ratio AUCSO(styrene)/AUCSO(SO) was about 2% in Sprague-Dawley rats (following ip administration) and about 0.05% in reinforced plastics workers. The (human) estimate of AUCSO(styrene)/AUCSO(SO)
0.05% was complicated by the simultaneous exposures of the workers to both SO and styrene. Since the contributions to blood of "metabolic SO" (derived from styrene) and "absorbed SO" (from inhalation of SO) are indistinguishable, statistical methods were needed to ascribe the corresponding fractions of the AUC (for details see Rappaport et al., 1996
). Here we describe an alternative approach involving physiologically based pharmacokinetic (PBPK) modeling to estimate AUCSO(styrene)/ AUCSO(SO).
PBPK modeling refers to the development of mathematical descriptions of the uptake and disposition of chemicals based on biological determinants of these processes (Andersen, 1991). These determinants include physiochemical properties (partition coefficients), rates of biochemical reactions, and a large body of physiological data (Krishnan and Andersen, 1994
). PBPK models offer biologically plausible approaches to quantify bioavailability (Pastino and Conolly, 2000
) that can be used to predict the relative influences of metabolic SO and absorbed SO to the systemic dose of SO in vivo.
Csanády et al. (1994) described a PBPK model to characterize the disposition of styrene and SO. This model included metabolism of styrene to SO and elimination of SO via hydrolysis or conjugation with glutathione (GSH) but did not allow for direct absorption of SO into the blood from airborne exposure. Although the model of Csanády et al. (1994) was validated with measurements of styrene in air and SO in blood of reinforced plastics workers, simultaneous coexposure to SO was not evaluated (Korn et al., 1994). The current investigation describes modifications of the Csanády et al. (1994) model to investigate the relative contributions of absorbed and metabolic SO to AUCSO among reinforced plastics workers. The model is tested against air and blood measurements of both styrene and SO from 252 workers.
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MATERIALS AND METHODS |
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Environmental samples.
Passive monitors were used to measure personal exposures to styrene and SO repeatedly among the 328 workers (described in Tornero-Velez et al. [2000]). Large ranges of daily exposures were observed for both styrene (range: < 1 to 167 ppm [n = 1394]) and SO (range: < 1 to 187 ppb [n = 1386]). Both sets of measurements were consistent with levels reported from similar reinforced plastics facilities (summarized in Nylander French et al., 1999; Rappaport et al., 1996
; Yeowell-O'Connell et al., 1996
).
Biological samples.
A method for measuring styrene and SO in blood, based upon gas chromatography-mass spectrometry with positive-ion-chemical ionization, was developed and applied to the samples (described in Tornero-Velez et al., 2001). This method permitted measurement of SO in blood at levels as low as 0.05 µg/l, a limit that is 10-fold lower than those previously reported. Large ranges of blood levels were observed for both compounds (styrene: < 0.001 to 2.05 mg/l [n = 488]; SO: < 0.050.49 µg/l [n = 302]). While blood-styrene levels were generally consistent with those reported in other studies, the corresponding levels of SO in blood were considerably lower than the few previously reported measurements (summarized in Tornero-Velez et al., 2001
).
PBPK model.
Csanády et al. (1994) described a PBPK model for styrene and SO in rats, mice, and humans that assumed that all SO was derived from styrene metabolism (hereafter "basic model"). We modified that model to include uptake of SO by inhalation (hereafter "extended model"). Although Csanády et al. (1994) did not consider SO gas-exchange, they reported a blood:air partition coefficient for SO, SO, of 2370 (SE = 499, n = 3), allowing for consideration of SO uptake via inhalation in the extended model. For both styrene and SO, the basic and extended models assume instantaneous equilibrium between circulating blood and alveolar air, as determined by the blood:air partition coefficients.
A schematic of the extended model is shown in Figure 1. The systemic circulation distributes styrene and SO to the liver (the only metabolizing tissue), fat, muscle, and the richly perfused tissues, which are all assumed to be homogenous well-mixed compartments with human physiological constants shown in Table 1
. The chemical-dependent physiochemical and biochemical constants are shown in Table 2
. Mass-balance equations were written to describe the rates of change in styrene and SO concentrations for each compartment, based upon Johanson and Filser (1993) and Csanády et al. (1994); see Appendix. With the exception of KmIH for epoxide hydrolase, the fitting procedure for which is discussed below, the parameters employed in the extended model are the same as those in the basic model. The model was coded in Matlab (The Mathworks Inc., Natick, MA) and solutions were obtained with the Matlab stiff ordinary differential equation solver ode15s.
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Elimination of SO by epoxide hydrolase (EH) was modeled with a postulated "intrahepatic" (IH) compartment, a complex containing both cytochrome P-450 (styrene SO) and EH (SO
styrene glycol) in the subcellular endoplasmic recticulum. This conceptualization stems from the work of Oesch and Daly (1972) and has been employed in models describing butadiene kinetics in rats and mice (Csanády et al., 1996
; Johanson and Filser, 1993
,1996
; Kohn and Melnick, 2000
). The postulated mechanism dictates that SO, formed in situ within the IH compartment, reaches EH faster than SO, diffusing from the cytosol. This diffusive transport of SO was modeled with an effective intrahepatic flow, QIH, between the cytosol and the IH compartment. Because QIH was not experimentally accessible, it was derived from the flow-dependent relation between apparent and intrinsic clearance (for details, see Johanson and Filser, 1993
). Two Michaelis-Menten constants are specified, an apparent constant of affinity Kmapp (0.01 mmol/l), obtained from suspensions of liver microsomes in buffer (Mendrala et al., 1993
), and an intrinsic constant of affinity KmIH (0.001 mmol/l) set to 10% of Kmapp. In this formulation, the measured enzyme constant (Kmapp) pertains to detoxication of cytosolic SO, while the derived constant (KmIH) governs the elimination of in situ SO; both are required parameters.
Because KmIH was not accessible through in vitro experimentation, Csanády et al. (1994) estimated this parameter by fitting the basic model to in vivo human data from Korn et al. (1994). That study provided end-of-shift concentrations of SO in blood and the corresponding shift-averaged concentrations of styrene in air for 14 workers in the reinforced plastics industry (Korn et al., 1994). By setting KmIH/Kmapp = 10%, Csanády et al. (1994) effectively calibrated their model to the blood levels of SO reported by Korn et al. (1994). In contrast, both Kmapp and VmaxEH were determined from in vitro experimentation (Mendrala et al., 1993
).
Calibration of the intrinsic KmIH.
Under the extended model, SO enters the blood from hepatic metabolism of styrene at a lower rate than from direct absorption following inhalation. As shown in Figure 2, we postulate that a small fraction of metabolic SO eludes the endoplasmic recticulum membrane complex and enters the cytosol where it is either conjugated with GSH or enters the systemic circulation. On the other hand, we postulate that absorbed SO is immediately available to the systemic circulation. Thus, in the extended model, the ratio KmIH/Kmapp reflects the difference in the rates of detoxication of metabolic SO versus absorbed SO. Under the basic model, SO was more rapidly eliminated from the IH compartment than the cytosol, as reflected by the ratio KmIH/Kmapp, which was set to 10% by Csanády et al. (1994). However, preliminary applications of the extended model indicated that a value of KmIH/Kmapp = 10% was much too great to adequately explain the data from our study. Values of KmIH/Kmapp = 1 and 0.5% were assigned, based upon results from SO-albumin adducts reported by Rappaport et al. (1996).
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Relative systemic availability.
The relative contributions of cumulative exposures to styrene and SO to the systemic dose of SO were computed using the following formula:
| ((1)) |
Sensitivity analysis.
The sensitivity of SO kinetics to styrene and SO parameters in the extended model was evaluated through normalized sensitivity coefficients (NSC), representing the fractional change in output associated with a fractional change in the input parameter (Clewell et al., 2000). A change of 1% in the model parameter was applied to ensure discovery of the true local sensitivity. A value of NSC greater than 1.0 would indicate that there is amplification of error from the input to the output. To evaluate the separate influences of absorbed and metabolic SO, sensitivity analysis was conducted for inhaled SO, inhaled styrene, and for the combined exposure. The output parameter was the concentration of SO in venous blood, following 8 h of exposure to 9.14 ppm styrene or 17.1 ppb SO, or both (each based on median values from the current study).
Monte Carlo evaluation of styrene kinetics.
The styrene portion of the model was evaluated by Monte Carlo analysis. This procedure randomly selected a set of parameter values from the population distributions and ran the PBPK model (8 h exposure to 2, 10, or 50 ppm styrene) to obtain the end-of-shift blood-styrene. This process was repeated with 200 iterations per exposure scenario. The population distributions for the model parameters were assumed to be either lognormal or normal (Portier and Kaplan, 1989), as shown in Tables 1
and 2
. With the exception of Vmaxmo, the distributions of model parameters were truncated at ± 3 standard deviations to eliminate values that were biologically implausible (Bois et al., 1996
). The maximum rate of styrene oxidation to SO, Vmaxmo, was bounded at ± 2 standard deviations due to its high coefficient of variation (CV) of 50%. For model stability, alveolar ventilation was set equal to cardiac output (Thomas et al., 1996
). In order to maintain mass balance, fractional blood flows (required to sum to 1), were calculated by setting the flow of the rapidly perfused tissues equal to the difference between cardiac output and the remaining compartment tissues (Thomas et al., 1996
). Similarly, the sum of the individual tissue volumes was constrained to be equal to 0.87 x body volume, equivalent to the volume of tissue participating in mass balance when the model was parameterized with mean values. This was achieved by setting the volume of muscle tissue equal to the difference between body mass and the remaining tissue volumes. Partition coefficients associated with the equilibration of styrene were not included in the model because a preliminary sensitivity analysis indicated that predicted levels of styrene in blood were not sensitive to these parameters.
Analysis of data.
Data were analyzed using SAS statistical software V8.03 (SAS Institute, Cary, NC). Due to skew in exposure distributions the geometric mean (GM) was employed unless otherwise indicated, and was estimated as GM = X, where X represents the mean of the logarithms (base e) of the measurements. The overall ratio of airborne styrene to SO was estimated by taking the ratio of GMs. Since the GM exposure to styrene among these workers was 9.14 ppm while that to SO was 17.1 ppb, a typical worker was exposed to 534 times more styrene than SO, consistent with previous observations (Nylander-French et al., 1999; Yeowell-O'Connell et al., 1996
). The relationship between SO in blood and styrene in air was based on GMs of the subject-specific GMs, averaged by facility. To reduce the effects of measurement error, only facilities with a minimum of 10 subjects were used; this restricted the useable number of facilities from 17 to 8 and the number of subjects from 328 to 252. The relationship between styrene in blood and styrene in air was based on daily end-of-shift measurements in blood and daily average exposures for this subset of 252 subjects. Of the repeated exposure measurements per subject, only measurements corresponding to the day of blood collection were used; this restricted the useable number of air-blood pairs to 348 (221 subjects). For comparison of Monte Carlo simulations with observed data, only measurements above the limit of detection were employed (190 subjects, 297 measurements).
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RESULTS |
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DISCUSSION |
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By relying upon an IH compartment, both the basic and extended models achieve the same objective as the recent "privileged access" model of Kohn and Melnick (2000). Although Kohn and Melnick (2000) refuted the notion of an IH compartment, they recognized evidence of a transient complex between P450 and EH residing in the endoplasmic recticulum (Oesch and Daly, 1972; Etter et al., 1991
; Oesch, 1973
, cited by Johanson and Filser, 1993
). Furthermore, Kohn and Melnick (2000) proposed that the bound substrate had greater affinity for EH than cytosolic substrate as reflected by the ratio R = Kmbound/Kmcytosolic. Thus, even though the privileged access model and the IH compartment model are based on different mechanistic hypotheses, both attempt to model sequestration of the newly formed epoxide and, therefore, include an analogous parameter, i.e., KmIH/Kmapp (in the IH compartment model) or R (in the privileged access model), which limits export of SO formed in situ.
The intrinsic affinity of SO for EH, KmIH, was identified as the sole parameter for calibration of our extended model for several reasons. First, sensitivity analysis indicated that KmIH had a major influence on human SO kinetics whereas that of glutathione conjugation was minimal. Second, KmIH could not be estimated through experimental in vitro techniques whereas VmaxEH, had been estimated experimentally (Mendrala et al., 1993). And finally, in developing the basic model, Csanády et al. (1994) did not include concurrent SO exposure when fitting KmIH to the human data of Korn et al. (1994); although direct exposure to SO undoubtedly occurred among these reinforced plastics workers, the importance of this route was not recognized until 2 years later (Rappaport et al., 1996
; Yeowell-O'Connell, 1996).
By varying the ratio KmIH/Kmapp it was possible to fit the model to aggregated data from 8 reinforced plastics facilities as shown in Figure 4. The best fit occurred when KmIH/Kmapp = 0.5% (Figure 4
, Case C), which corresponds to a value of RSAstyrene:SO = 2.75 x 10-4. Hence, inhalation of SO was predicted to produce 3640 times more SO in blood than an equivalent exposure to styrene. Based on statistical analysis of the relative contributions of SO-albumin adducts (reflecting the dose of SO to blood) in a single reinforced plastics facility, Rappaport et al. (1996) estimated the RSAstyrene:SO to be 4.65x10-4
0.05% (95 CI: 0%, 0.10%), which is plausible based upon our fitted model. Since the ratio of airborne styrene to SO rarely exceeds 1500:1, this suggests that direct inhalation of SO poses a greater hazard to reinforced plastics workers than inhalation of styrene.
In their determination of parameters to describe SO kinetics in rodents, Csanády et al. (1994) employed data from po, ip, and iv administration of SO. They were able to adequately model SO kinetics in rats with KmIH/Kmapp = 10%. However, in mice a reasonable fit could only be achieved by reducing Kmapp from 0.74 mmol/l (determined in vitro by Mendrala et al., 1993) to 0.09 mmol/l, while simultaneously setting KmIH equal to 0.009 mmol/l. This effectively reduced KmIH to 1.2% of the value of Kmapp determined in vitro. For humans, this suggests that it is plausible for the true value of KmIH to be 1% of Kmapp. Indeed, the current study and the prior study of Rappaport et al. (1996) point to KmIH/Kmapp being near 0.51%, suggesting that direct absorption of airborne SO contributes 18003600 times more SO to the blood than metabolism of airborne styrene. Had Csanády et al. (1994) considered uptake of SO, convergence of KmIH/Kmapp with our fit (0.51%) would have been attained if the airborne ratio of styrene to SO had been about 250:1 in the factory that provided the data for their calibration (Korn et al., 1994
). For the 8 factories in our study, individual ratios of styrene:SO ranged from 337 to 1070. Given such variability among reinforced plastics factories, a ratio of airborne styrene:SO of 250: 1 is certainly plausible.
Some uncertainty persists in the modeling of absorbed SO. In particular, inhalation of SO might be subject to presystemic removal in the airways via reactions in the lung. For a number of gases the measured rate of elimination was less than that predicted by a simple inhalation model, which assumed instantaneous equilibration of the chemical between air and blood (Csanády et al., 1994,1996
,2000
; Filser et al., 1996
; Gargas et al., 1986
; Johanson and Filser, 1992
; Medinsky et al., 1994
; Reitz et al., 1990
). This effect has been ascribed to adsorption of the chemical on the walls of the upper airways (Johanson and Filser, 1992
). To explain the discrepancy between observed concentrations of ethylene oxide in exhaled breath and model predictions, Csanády et al. (2000) modified their PBPK model to account for adsorption of ethylene oxide in the upper respiratory tract.
Absorbed and metabolic SO have markedly different susceptibilities to lung and liver metabolism. Glutathione S-transferase resides outside of the IH compartment (Fig. 2), offering a potentially important mechanism for removal of absorbed SO. On the contrary, sensitivity analysis showed that levels of SO in venous blood were insensitive to elimination by glutathione conjugation. This may reflect uncertainties in the model, stemming from a lack of experimental data. Only recently have the mercapturic acid conjugates arising from glutathione conjugation of SO been measured among reinforced plastics workers (Ghittori et al., 1997
). As these data were not available to Csanády et al., 1994, many of the parameters describing glutathione conjugation in humans were based on rodent kinetics (KmGSH, KmSO, KdGSH). The maximum metabolic rate VmaxGST was determined in vitro by Mendrala et al. (1993) from subcellular fractions of human liver cells but with a great deal of imprecision (due to low sensitivity, assays were conducted with high substrate concentration, and even then GST activity was barely detectable in 2 of 5 samples). Although the urinary levels of mercapturic acid conjugates are low, they may aid in delineating subtleties in the dispositions of absorbed versus metabolic SO. However, in order to evaluate this conjecture VmaxGST and the corresponding values of KmGSH and KmSO need to be determined with better precision.
Sensitivity analysis also indicated that the liver:blood partition coefficient for SO, i.e., LSO, was an important determinant of SO in blood. This parameter represents the availability of SO to the liver where it can be acted upon by hepatic GST or epoxide hydrolase. Any bias in the measurement of
LSO would lead to error in the model prediction (a modest bias of 10% in
LSO would lead to a corresponding bias of 16.4% in the predicted level of SO in blood). Although the reactivity of SO (the half-life in human blood in vitro is 42 min [Yeowell-O'Connell et al., 1997
]) would seem to present experimental difficulties in the determination of
LSO, this potential source of error was not addressed by Csanády et al. (1994).
Since styrene is the source of metabolic SO, we investigated the extended model's description of styrene kinetics through Monte Carlo analysis and compared the predictions with extensive empirical data (Fig. 6). The obvious agreement between observed and predicted values point to prior validation of that portion of the PBPK model by several investigators (Filser et al., 1993
; Löf and Johanson, 1993
; Löf et al., 1986
; Ramsey and Andersen, 1984
). However, the importance of styrene kinetics to the corresponding SO kinetics is dubious since our sensitivity analysis revealed a minimal effect of styrene metabolism on levels of SO in venous blood, given coexposure to styrene and SO in air.
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APPENDIX |
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| ((A1)) |
| ((A2)) |
| ((A3)) |
| ((A4)) |
| ((A5)) |
| ((A6)) |
| ((A7)) |
| ((A8)) |
The capacity of cytochrome P450 for oxidation of S, Vmaxmo** (mmol/h) = Vmaxmo (mmol/h per g liver) x VL (kg) x 103 g/kg. The Michaelis-Menten constant is specified for liver tissue by Kmmo** = Kmmo x LSO, where Kmmo was determined for venous blood from the liver.
The metabolism of SO occurs in the cytosol (liver compartment) and in the endoplasmic recticulum (IH compartment). The SO concentration in the IH compartment arises from metabolism of S, diffusive flow of SO to/from the liver cytosol, QIH, and detoxication of SO via metabolic clearance of SO, CLSO. These processes result in the mass balance equation:
| ((A9)) |
| ((A10)) |
| ((A11)) |
| ((A12)) |
| ((A13)) |
| ((A14)) |
The change of SO concentration in the liver is controlled by transport of SO via the systemic circulation, diffusion of SO between the cytosol and the IH compartment, and conjugation of SO with glutathione according to:
| ((A15)) |
| ((A16)) |
The capacity of GST, VmaxGST* (mmol/h) = VmaxGST (mmol/h per g liver) x VL(kg) x 103 g/kg. The turnover of GSH in the cytosol is described by zero-order production and first order elimination. Conjugation of GSH with SO was modeled according to:
| ((A17)) |
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ACKNOWLEDGMENTS |
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NOTES |
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2 In personal communication, Dr. Lisa Sweeney noted a minor error in this equation as documented by Csanády et al. (1994). The investigators reported the equation as "a," where a = c KmSO + KmlH.
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