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Role of Kinetics in Acute Lethality of Nonreactive Volatile Organic Compounds (VOCs)
TOXICOLOGICAL SCIENCES ARTICLE NO.
45, 26 –32 (1998)
TX982496
Role of Kinetics in Acute Lethality of Nonreactive Volatile Organic Compounds (VOCs) J. DeJongh,1 H. J. M. Verhaar, and J. L. M. Hermens Research Institute of Toxicology (RITOX), P.O. Box 80.176, 3508 TD Utrecht, The Netherlands Received July 21, 1997; accepted May 19, 1998
lation of compounds in lipoid membranes of nerve cells plays a key role in narcosis-related toxicity (McCarthy et al., 1991; Sikkema et al., 1995). However, as both lipophilic and hydrophilic solvents can induce narcotic toxicity, the existence of (semi)specific receptor proteins for small organic compounds in the CNS has also been suggested (Franks and Lieb, 1994). Most VOCs are rapidly cleared from the mammalian body and accumulation is usually not observed. However, marked differences exist in absorption, metabolism, and especially body distribution, due to differences in biochemical and physicochemical properties among the compounds within this group. It may reasonably be expected that differences in kinetic behavior play a role in the observed differences in narcotic potency between these compounds. The present study investigates this possible relation between external inhalation exposure parameters for lethal narcosis such as exposure concentration and length and internal exposure parameters (dose surrogates) for the CNS. LC50 inhalation exposure values for a series of solvents, including lipophilic as well as hydrophilic compounds, are considered and several dose surrogates, including blood and brain concentrations, are compared. The rat was chosen as a mammalian model species. A physiologically based pharmacokinetic (PB-PK) model was applied to incorporate physiological, physicochemical, and biochemical aspects of VOC kinetics.
Role of Kinetics in Acute Lethality of Nonreactive Volatile Organic Compounds (VOCs). DeJongh, J., Verhaar, H. J. M., and Hermens, J. L. M. (1998). Toxicol. Sci. 45, 26 –32. The role of kinetics in the acute inhalation toxicity of nonreactive, volatile organic compounds (VOCs), including lipophilic and hydrophilic compounds, was analyzed with a physiologically based pharmacokinetic (PB-PK) model for the rat. For 15 VOCs, a total of 23 LC50 values were retrieved from the literature. It was observed that the external exposure parameter (LC50 z exposure length; in ppm z h), varied approximately 60-fold. Concentrations of compounds in the lipoid brain fraction were simulated using a kinetic model. This lead to a more than 10-fold reduction in the toxic range of the 15 VOCs. The average value for this simulated dose surrogate was 70 6 31 mM for all VOCs. These observations support the presumption that nonspecific, acute narcotic lethality is directly related to the extent of VOC distribution into lipoid brain constituents. The present results can be used for estimation of the acute lethality of nonreactive VOCs on the basis of kinetic simulations. In addition, the presently calculated dose surrogate for VOC lethality in rats is found to be very similar to the reported internal lethal concentrations of so-called “baseline toxicity compounds” in fish. This indicates a common mechanism of acute VOC toxicity among mammalian and aquatic species. © 1998 Society of Toxicology.
Volatile organic compounds (VOCs) are widely used as solvents in industrial and household applications. Various forms of toxicity have been reported resulting from both acute and chronic exposure to these compounds (Burbacher, 1993). One common form of toxicity observed after acute inhalation exposure to high VOC concentrations is general anesthesia, possibly followed by death. Such effects have been observed for all mammalian species, including humans. General anesthesia is considered to be a nonspecific toxic effect that is related to uptake of these compounds by the central nervous system (CNS). It has traditionally been assumed that accumu-
METHODS A physiologically based-pharmacokinetic (PB-PK) model was constructed for simulation of uptake, distribution, and elimination of VOCs in the rat. The model structure (Fig. 1) was similar to that of earlier published PB-PK models for styrene and toluene (DeJongh and Blaauboer, 1996; Ramsey and Andersen, 1984). Model compartments include: (1) localized fat tissue, (2) a lumped compartment representing all slowly perfused tissues except fat tissue, (3) liver tissue, (4) a lumped compartment representing all rapidly perfused tissues except liver and brain tissue, and (5) brain (CNS) tissue. Two CNS subcompartments were defined, representing aqueous and lipoid brain components. Anatomical and physiological parameters were taken from the literature (Table 1). Blood–air and tissue– blood partition coefficients (PCs) of 15 VOCs were also obtained from the literature (Table 2). Where experimental brain– blood PC were unavailable, an estimate was made from an empirical, linear relationship between experimental fat– blood and brain– blood PCs (Fig. 2). Concentrations of compounds in brain lipids were assumed to be a function of the concentration in whole brain and were derived from octanol–water PCs (Meylan and Howard, 1995) according to the formulas in the Appendix.
1
To whom correspondence should be addressed at Research Institute of Toxicology (RITOX), Utrecht University, P.O. Box 80.176, 3508 TD Utrecht, The Netherlands. Fax: 131 30 253 5077. E-mail: J.DEJONGH@ RITOX.DGK.RUU.NL. 1096-6080/98 $25.00 Copyright © 1998 by the Society of Toxicology. All rights of reproduction in any form reserved.
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ROLE OF KINETICS IN THE LETHALITY OF VOCs
biotransformation rates (KFC) were assigned for hepatic metabolism of each compound. Biotransformation parameter values were derived from various in vivo and in vitro studies (Table 3). To account for possible differences in metabolism (Vmax and KF), ventilation rate (QP), and cardiac output (QC) among individual studies due to varying body weights, these parameters were allometrically scaled to exponential functions of whole animal body weight: V max 5 V maxC z BW0.7
(1a)
K F 5 K FC z BW20.3
(1b)
Q P 5 Q PC z BW0.7
(1c)
Q C 5 Q CC z BW
(1d)
0.7
Mass balance differential equations for the model (see Appendix) were numerically solved using the Advanced Continuous Simulation Language (ACSL) developed by Mitchell and Gauthier Associates (Concord, MA). Twenty-three LC50 values for inhalation exposure of rats to 15 different VOCs (Table 4) at varying exposure lengths were derived from various sources (Anonymous, 1987; WHO, 1983–1995). As animal body weight (BW) in individual LC50 studies were mostly unavailable, body weight was arbitrarily set to 0.35 kg for all simulations.
RESULTS
FIG. 1. Structure of the PB-PK model applied for analysis of acute inhalation lethality of volatile organic compounds. VOCs were assumed to be eliminated either by exhalation of unchanged compound or saturable and/or first-order biotransformation in the liver. Maximum metabolic rates (VmaxC), affinity constants (Km), and/or first-order
LC50 values of the compounds considered in the present study are shown in Table 4 and range from 129,000 ppm for butadiene to 3000 ppm for chlorobenzene. Since steady state may not be reached within the specified exposure lengths, LC50 values are multiplied by exposure length (LC50 z t) as an alternative measure for external exposure under nonequilibrium conditions. Thus, a range from approximately 500,000, for butadiene, to 8500 ppm z h, for pentachloroethane, is obtained.
TABLE 1 Physiological and Anatomical Parameters for the PB-PK Model
a b
Parameter
Abbreviation
Alveolar ventilation rate (liters/h*kg)a Cardiac output (liters/h*kg)a Blood flow fractionsa Liver Fat Richly perfused tissue (RPT) Slowly perfused tissue (SPT) Brain Tissue group volume fractionsa Liver Fat Richly perfused tissue (RPT) Slowly perfused tissue (SPT) Brain Target tissue volume fractionsb Brain water Brain lipids
QPC QCC
Brown et al., 1994. Widdowson and Dickerson, 1981.
Value 14 14
Scaling factor BW0.7 BW0.7
QLC QFC QRC QSC QBrC
0.25 0.09 0.52 0.11 0.03
— — — — —
VLC VFC VRC VSC VBrC
0.04 0.07 0.09-VLC-VBrC 0.82-VFC 0.006
— — — — —
Fab Flb
0.85 0.15
— —
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DEJONGH, VERHAAR, AND HERMENS
TABLE 2 Partition Coefficients of the Compounds Partition coefficients tissue–body Compound
Reference
Kowa
Blood–air
Liver
Muscle
Fat
Brain
Brain–brain lipids
Hexane Butadiene Isoprene Methanol Acetone Dichloromethane Chloroethane 1,2-Dichloroethane 1,1,1-Trichloroethane Pentachloroethane Tetrachloroethene Benzene Toluene p-Xylene Styrene Chlorobenzene
Gargas et al., 1989 Medinski et al., 1994 Gargas et al., 1989 Kaneko et al., 1994 Kumagai and Matsunaga, 1995 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989
3.87 1.99 2.42 20.77 20.24 0.94 1.43 1.46 2.48 3.22 3.40 2.14 2.64 3.15 2.95 2.86
2.29 1.49 1.87 31342 208 9.4 4.08 30.4 5.76 104 18.9 17.8 18 41.3 40.2 59.4
2.27 0.8 1.67 0.9 1.15 0.73 0.88 1.17 1.49 2.5 3.72 0.96 4.64 2.18 3.46 1.45
1.27 0.99 1.09 1.16 0.82 0.41 0.79 0.77 0.55 0.7 1.06 0.58 1.54 0.93 1.16 0.57
69.43 14.89 38.5 0.06 0.38 6.19 9.46 11.32 45.66 39.6 86.67 28.03 56.72 42.32 86.47 21.5
3.25 1.28 2.13 1.01 0.76 0.97 1.08 1.15 2.39 2.17 3.87 1.75 2.79 2.27 3.86 1.52
21.65 8.07 13.90 0.20 0.47 3.90 5.95 6.40 15.64 14.42 25.74 11.21 18.36 15.07 25.57 10.05
a
Log octanol–water partition coefficient.
The three parameters for internal exposure (i.e., dose surrogates) in this study are the simulated concentrations in respectively venous blood (Cv), whole brain (Cwb) and brain lipids (Cbl). Cv and Cwb range from respectively 214 –2.0 and 218 – 5.3 mM with methanol at the upper and 1,1,1-trichloroethane and pentachloroethane at the lower limits of these ranges. Cbl
spans a substantially smaller range from 160 –35.5 mM with pentachloroethane and tetrachloroethylene at the lower and upper limits (Table 4). Steady state is indeed not reached within the length of exposure for all 23 LC50 studies (Table 4), and LC50 z t is considered as the preferred measure of external exposure. When comparing the range of LC50 z t values with the three simulated dose surrogates, it is observed that neither Cv nor Cwb reduces the variation in the range of LC50 z t values (Fig. 3). Only when Cbl is considered, the 60-fold difference in toxicity, expressed through the external exposure parameter LC50 z t, is reduced by more than a factor 10- to a 5-fold range (Fig. 3) with an average value of 70 6 31 mM. Simulation of five lethality studies reported on 1,1,1-trichloroethane (TCE) shows that a reduction of uncertainty may also be achieved when analyzing the acute lethality of a single compound under varying exposure lengths (Fig. 4). In this case, toxicity range of LC 50 values for TCE (100,000 –10,000 ppm z h), expressed on the basis of external exposure as LC50 z t, is substantially reduced after simulation of the corresponding dose surrogates (Cbl) for each exposure scenario (33–75 mM). The resulting average value of 52.3 6 15.3 mM of Cbl for TCE lethality also compares well with the previously calculated value of 70 6 31 mM for all 15 compounds of the present study. DISCUSSION
FIG. 2. Correlation between fat– blood (PF) and brain– blood (PBr) partition coefficients for VOCs. PBr 5 0.038 z PF 1 0.41 (n 5 50) data from Fiserova-Bergerova and Diaz (1986) and Kaneko et al. (1994).
Nonspecific narcotic lethality is generally assumed to be related to accumulation of compounds in phospholipid
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ROLE OF KINETICS IN THE LETHALITY OF VOCs
TABLE 3 Biotransformation Parameters Compound
Reference
VmaxC (mg/h/kg)
Km (mg/L)
KFC (h21 z kg21)
Hexane Butadiene Isoprene Methanol Acetone Dichloromethane Chloroethane 1,2-Dichloroethane 1,1,1-Trichloroethane Pentachloroethane Tetrachloroethylene Benzene Toluene p-Xylene Styrene Chlorobenzene
McDougal et al., 1990 Medinski et al., 1994 Longo et al., 1985 Horton et al., 1992 Kimagai and Matsunaga, 1995 Gargas et al., 1990 Gargas et al., 1990 Gargas et al., 1990 Gargas et al., 1990 Gargas and Anderson, 1989 Gargas et al., 1990 McDougal et al., 1990 Purcell et al., 1990 Tardiff et al., 1993 Ramsey and Andersen, 1984 Nakajima and Sato, 1979
6.0 3.35 1.8 15.4 18.6 4 4.0 3.25 — 9.71 — 3.3 7.5 8.4 8.4 2.22
0.4 0.2 5.44 3.91 48.4 0.4 0.1 0.25 — 0.9 — 0.6 0.3 0.2 0.4 —
3.4 — — — — 2.0 1.0 — 5.0 — 5.0 — — — — —
membrane bilayers of CNS cells. This accumulation in cell membranes is thought to induce alterations in the membrane structure that may influence the conformation of membrane-
bound proteins, like, e.g., ion channels, that are involved in the specific functions of the nerve cells (Sikkema et al., 1995).
TABLE 4 LC50 Values, Exposure Times (t), LC50 z t Products, and Simulated Concentrations in Blood (Cv), Whole Brain (Cwb), and Brain Lipids (Cbl) after Exposure at the LC50 Concentration during t Hours Compound Hexane Butadiene Isoprene Methanol Acetone Dichloromethane Dichloromethane Chloroethane 1,1,1-Trichloroethane 1,1,1-Trichloroethane 1,1,1-Trichloroethane 1,1,1-Trichloroethane 1,1,1-Trichloroethane Pentachloroethane Tetrachloroethylene Benzene Benzene Toluene Toluene Toluene p-Xylene Styrene Chlorobenzene Highest value Lowest value Mean Upper 95% confidence limit Lower 95% confidence limit
LC50 (ppm)
t (h)
LC50 z t (ppm*h)
Cv (mM)
Cwb (mM)
Cbl (mM)
Steady-State Level (%)
77000 129000 64721 64000 21874 95781 25181 59725 18000 14250 18400 10300 38000 4238 25700 3700 10000 12159 13022 8800 4550 5634 2965
1 4 4 4 8 0.25 6 2 3 7 4 6 0.25 2 1 4 7 6.5 4 4 6 2 6
77,000 516,168 258,884 256,000 174,992 23,945 151,086 119,450 54,000 99,750 73,600 61,800 9,500 8,476 25,700 54,800 70,000 79,033 52,088 35,200 27,300 11,268 17,790
5.4 7.8 4.7 213.9 11.6 22.9 17.7 9.5 3.2 2.9 3.4 2.0 4.2 2.3 5.6 7.2 6.3 5.7 5.0 3.6 3.5 2.0 3.9
19.2 10.0 10.2 218.1 85.0 24.3 17.3 10.3 8.0 7.1 8.5 5.0 11.4 5.3 24.0 12.9 11.1 16.4 14.6 9.8 8.2 8.3 6.0
127.7 63.3 66.8 42.3 52.3 97.6 69.5 56.9 52.1 46.2 55.6 32.8 74.9 35.5 159.8 82.4 70.8 107.7 96.0 64.5 54.7 55.2 39.4
84 100 97 0 62 37 100 97 85 95 89 93 58 14 40 74 87 66 55 55 50 24 55
516,168 8,476 98,167 348,933 9,142
213.9 2.0 15.4 89.8 2.0
218.1 5.0 24.0 131.6 5.2
159.8 32.8 70.0 138.9 34.6
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DEJONGH, VERHAAR, AND HERMENS
FIG. 3. Box plots of the external exposure parameters LC50 and LC50 z t and three simulated dose surrogates for 15 compounds and 23 LC50 values. Horizontal markers indicate means 6 95% confidence limits.
Studies on narcotic effects in fish that were exposed to contaminated water have reported on the residues of nonreactive compounds in individual organisms that were measured directly after the onset of death. These so-called “internal lethal doses” (ILDs) or “critical body residues” (CBRs) were found to be equal for all nonreactive compounds, when expressed on a molar basis, and are basically independent of exposure time and concentration. They reflect a threshold of internal exposure above which acute lethality occurs. In aquatic toxicology, this phenomenon is also referred to as the baseline toxicity of compounds, i.e., the minimum toxicity of compounds due to their nonspecific action on the CNS (McCarthy et al., 1991; van Wezel and Opperhuizen, 1995). For cross-species comparisons, ILDs are normalized to lipid content and they may be considered equivalent to some of the dose-surrogates used in risk assessment of mammalian species (Van Vliet and DeJongh, 1996). PB-PK modeling allows for simulation of the ILD concept for inhalation exposure of mammalian species. In the present study, simulated concentrations in venous blood (Cv) and whole brain (Cwb) were examined as a refined application of the ILD concept for mammals. In addition, the possible use of the concentration in the brain’s lipid constituents (Cbl) as a dose surrogate was considered from information on the mechanisms of narcotic action. A more then 10-fold reduction of the variation in acute inhalation toxicity of the 15 compounds is achieved by application of the dose surrogate Cbl instead of a traditional external ex-
posure parameter C z t (Table 4 and Fig. 3). This clearly supports the previously discussed mechanism of narcotic action by accumulation of compounds in phospholipid bilayers in the nerve cell membrane. Comparison of the simulated values of Cbl in rats (33–160 mM; avg. 70 6 31 mM) with the ILDs (40 –160 mM, on lipid basis) reported for several fish species (van Wezel and Opperhuizen, 1995) suggest that the mechanism of lethal narcosis may be similar across species. When examining the feasibility of the studied dose surrogates, it is a prerequisite that any LC50 value that is included, results from narcosis only and does not represent other forms of acute toxicity. In addition to transformation to more polar metabolites (Jean and Reed, 1992) many VOCs may be bioactivated by, e.g., cytochrome P450IIE1 (Raucy et al., 1993). When these metabolites are not conjugated with, e.g., glutathione (Jean and Reed, 1992), they bind directly with cellular proteins leading to acute hepatic, renal, or myocardial damage. Thus, compounds like 1,1dichloro- or dibromoethane are not included in the present study. It should be realized that the Cbl values for the rat considered in the present study are simulated values. In contrast, the ILDs reported for fish are experimental values. There are some possible reasons for uncertainty in the simulated values for Cbl. (I) Strain, age, weight and sex of the rats used in the LC50 studies are not taken into account in the present model since these data were often not specified in the original study reports. All of these factors can influence the kinetics of a compound, like, e.g., the age- and sex-dependent sizes of body fat depots that may alter the
FIG. 4. Box plots of the external exposure parameter LC50 z t and the simulated dose surrogate Cbl for 1,1,1-trichloroethane (n 5 5). Horizontal markers indicate means 6 95% confidence limits.
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ROLE OF KINETICS IN THE LETHALITY OF VOCs
body distribution of lipophilic compounds. (II) In addition, the value of some model parameters, like, e.g., ventilation and perfusion rate, may be changed as a result of the exposure and form another possible source of parameter uncertainty. (III) In contrast with ILDs for fish, simulated Cbl values do not necessarily represent the concentration after the onset of death but rather after the termination of exposure. As most LC50 studies do not specify the onset of death of the individual animals, this may be a justifiable approximation at the cost of some uncertainty. In summary, it is concluded that a dose surrogate for acute lethal toxicity by nonspecific narcosis has been identified in the rat. Quantitative comparison with previously reported data on narcosis in fish suggest that the mechanism for general narcosis may be similar across species. Studies on cellular and molecular aspects of narcotic toxicity are needed to refine the understanding of these mechanisms.
Rate of Amount (AM) Metabolized dA M /dT 5 ~V MAX z C VL!/~K M 1 C VL! 1 K F z C VL z V L Mixed Venous Blood Concentration (CV) C V 5 ~Q F z C VF 1 Q L z C VL 1 Q S z C VS 1 Q R z C VR 1 Q Br z C VBr!/Q C Rate of Change of Amount in Exhaled (AX) Air dA X/dt 5 Q P z C X C X 5 C A/P B C Xppm 5 ~0.7 z C X 1 0.3 z C I! z 24450/MW Abbreviations
APPENDIX
Mass Balance Differential Equations of the PB-PK Model Arterial Blood Concentration (CA) C A 5 ~Q C z C V 1 Q P z C I!/~Q C 1 ~Q P/P B!! Rate of Change of Amount (AT) in Noneliminating Tissues: Fat (T 5 F), Slowly (T 5 S), and Rapidly Perfused (T 5 R) Tissues dA T /dt 5 Q T z ~C A 2 C VT! C VT 5 A T /~V T z P T! C T 5 A T /V T
CA CV CVT CT Cbl Fab Flb Kow QC QT
Rate of Change of Amount (ABr) in Brain (Target) Tissues
QP CI PB PT
dA Br /dt 5 Q Br z ~C A 2 C VBr!
VT
C VBr 5 A Br /~V Br z P Br! C wb 5 A Br /V Br C bl 5 C wb /~~F ab /K ow! 1 F lb!
VMAX Km KF CX CXppm Cwb, CBr
Concentration (mg/L) in arterial blood Concentration (mg/L) in mixed venous blood Concentration (mg/L) in venous blood of noneliminating tissue (T 5 F, Br, S, R) or liver (T 5 L) Concentration (mg/L) in noneliminating tissue (T 5 F, Br, S, R) or liver (T 5 L) Concentration (mg/L) in lipid brain fraction Fraction of aquatic brain constituents Fraction of lipid brain constituents Octanol–water partition coefficient Cardiac output (L/h) Perfusion rate (L/h) of noneliminating tissue (T 5 F, Br, S, R) or liver (T 5 L) Ventilation rate (L/h) Concentration in inhaled air (mg/L) Blood–air partition coefficient Partition coefficient for noneliminating tissues (T 5 F, Br, S, R) or liver (T 5 L) Tissue volume (L) for noneliminating tissues (T 5 F, Br, S, R) or liver (T 5 L) Maximum metabolism rate (mg/h) Affinity constant (mg/L) First-order elimination rate (h21) Concentration in air released from alveoli Concentration (ppm) in air released from lung Concentration (mg/L) in (whole) brain
Rate of Change of Amount (AL) in Liver Tissue dA L /dt 5 Q L z ~C A 2 C VL! 2 dA M/dT C VL 5 A L /~V L z P L! C L 5 A L /V L
ACKNOWLEDGMENTS This study was supported by grants from the Dutch Platform for Alternatives to Laboratory Animals (PAD), Grant 94-31, and from the European Center for Validation of Alternative Methods (ECVAM), Contract 11277-95-10 F1 ED ISP NL.
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REFERENCES Anonymous (1987). Registry of Toxic Effects of Chemical Substances. U.S. Department of Health and Human Services, Cincinnati, OH. Brown, R., Foran, J., Olin, S., and Robinson, D. (1994) Physiological Parameter Values for PBPK Models. International Life Sciences Institute and Risk Science Institute, Washington, DC. Burbacher, T. M. (1993). Neurotoxic effects of gasoline and gasoline constituents. Enviro. Health Perspect. Suppl. 101, 133–141. DeJongh, J., and Blaauboer, B. J. (1996). Simulation of toluene kinetics in the rat by a physiologically based pharmacokinetic model with application of biotranformation parameters derived independently in vitro and in vivo. Fundam. Appl. Toxicol. 32, 260 –268. Fiserova-Bergerova, V., and Diaz, M. L. (1986). Determination and prediction of tissue-gas partition coefficients. Int. Arch. Occup. Environ. Health 58, 75– 87. Franks, N. P., and Lieb, W. R. (1994). Molecular and cellular mechanisms of general anaesthesia. Nature 367, 607– 614. Gargas, M. L., and Andersen, M. E. (1989). Determining kinetic constants of chlorinated ethane metabolism in the rat from rates of exhalation. Toxicol. Appl. Pharmacol. 99, 344 –353. 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. Gargas, M. L., Clewell, H. J., and Andersen, M. E. (1990). Gas uptake inhalation techniques and the rats of metabolism of chloromethanes, chloroethanes, and chloroethylenes in the rat. Inhal. Toxicol. 2, 295–319. Horton, V. L., Higuchi, M. A., and Rickert, D. E. (1992). Physiologically based pharmacokinetic model for methanol in rats, monkeys and humans. Toxicol. and Appl. Pharmacol. 117, 26 –36. Jean, P. A., and Reed, D. J. (1992). Utilization of glutathione during 1,2dihaloethane metabolism in rat hepatocytes. Chem. Res. Toxicol. 5, 386 –91. Kaneko, T., Wang, P. Y., and Sato, A. (1994). Partition coefficients of some acetate esters and alcohols in water, blood, olive oil and tissues. Occup. Environ. Med. 51, 68 –72. Kumagai, S., and Matsunaga, I. (1995). Physiologically based pharmacokinetic model for acetone. Occup. Environ. Med. 52, 344 –352. Longo, V., Citti, L., and Gervasi, P. G. (1985). Hepatic microsomal metbolism of isoprene in various rodents. Toxicol. Lett. 29, 33–37. McCarthy, L. S., Mackay, D., Smith, A. D., Ozburn, G. W., and Dixon, D. G. (1991). Interpreting aquatic toxicity QSARs: The significance of toxicant
body residues at the pharmacologic endpoint. In QSAR in Environmental Toxicology: Proceedings of the 4th International Workshop, Veldhoven The Netherlands, September 16 –20, 1991 (J. L. M. Hermens and A. Opperhuizen, Eds.), pp. 515–25. Elsevier, Amsterdam. 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. 14, 299 –308. Medinski, M. A., Leavens, T. L., Csanady, G. A., Gargas, M. L., and Bond, J. A. (1994). In vivo metabolism of butadiene by mice and rats: A comparison of physiological model predictions and experimental data. Carcinogenesis 15, 1329 –1340. Meylan, W. M., and Howard, P. H. (1995). Atom/fragment contribution method for estimating octanol–water partition coefficients. J. Pharm. Sci. 84, 83–92. Nakajima, T., and Sato, A. (1979). Enhanced activity of liver drug-metabolizing enzymes for aromatic and chlorinated hydrocarbons following food deprivation. Toxicol. Appl. Pharmacol. 50, 549 –556. Purcell, K. J., Cason, G. H., Gargas, M. L., Andersen, M. E., and Travis, C. C. (1990). In vivo metabolic interactions of benzene and toluene. Toxicol. Lett. 52, 141–152. 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, 159 –175. Raucy, J. L., Kraner, J. C., and Lasker, J. M. (1993). Bioactivation of halogenated hydrocarbons by cytochrome P4502E1. Crit. Rev. Toxicol. 23, 1–20. Sikkema, J., de Bont, J. A. M., and Poolman, B. (1995). Mechanisms of membrane toxicity of hydrocarbons. Microbiol. Rev. 59, 201–222. Tardif, R., Lapare, S., Krishnan, K., and Brodeur, J. (1993). Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat. Toxicol. Appl. Pharmacol. 120, 266 –273. Van Vliet, P. J., and DeJongh, J. (1996). Biokinetics and biokinetic models in risk assessment. Hum. Exp. Toxicol. 15, 799 – 809. van Wezel, A. P., and Opperhuizen, A. (1995). Narcosis due to environmental pollutants in aquatic organisms: Residue based toxicity, mechanisms, and membrane burdens. Crit. Rev. Toxicol. 25, 255–279. WHO (1983–1995).Environmental Health Criteria, Vols. 26, 31, 50, 52, 122, 128, 136, 150, 163, 164. World Health Organization, Geneva, Switzerland. Widdowson, E. M., and Dickerson, J. W. (1981). Composition of the body. In Geigi Scientific Tables (Lentner, C., Ed. ), Vol. 1, pp. 217–225. Ciba-Geigy, Basel, Switzerland.
45, 26 –32 (1998)
TX982496
Role of Kinetics in Acute Lethality of Nonreactive Volatile Organic Compounds (VOCs) J. DeJongh,1 H. J. M. Verhaar, and J. L. M. Hermens Research Institute of Toxicology (RITOX), P.O. Box 80.176, 3508 TD Utrecht, The Netherlands Received July 21, 1997; accepted May 19, 1998
lation of compounds in lipoid membranes of nerve cells plays a key role in narcosis-related toxicity (McCarthy et al., 1991; Sikkema et al., 1995). However, as both lipophilic and hydrophilic solvents can induce narcotic toxicity, the existence of (semi)specific receptor proteins for small organic compounds in the CNS has also been suggested (Franks and Lieb, 1994). Most VOCs are rapidly cleared from the mammalian body and accumulation is usually not observed. However, marked differences exist in absorption, metabolism, and especially body distribution, due to differences in biochemical and physicochemical properties among the compounds within this group. It may reasonably be expected that differences in kinetic behavior play a role in the observed differences in narcotic potency between these compounds. The present study investigates this possible relation between external inhalation exposure parameters for lethal narcosis such as exposure concentration and length and internal exposure parameters (dose surrogates) for the CNS. LC50 inhalation exposure values for a series of solvents, including lipophilic as well as hydrophilic compounds, are considered and several dose surrogates, including blood and brain concentrations, are compared. The rat was chosen as a mammalian model species. A physiologically based pharmacokinetic (PB-PK) model was applied to incorporate physiological, physicochemical, and biochemical aspects of VOC kinetics.
Role of Kinetics in Acute Lethality of Nonreactive Volatile Organic Compounds (VOCs). DeJongh, J., Verhaar, H. J. M., and Hermens, J. L. M. (1998). Toxicol. Sci. 45, 26 –32. The role of kinetics in the acute inhalation toxicity of nonreactive, volatile organic compounds (VOCs), including lipophilic and hydrophilic compounds, was analyzed with a physiologically based pharmacokinetic (PB-PK) model for the rat. For 15 VOCs, a total of 23 LC50 values were retrieved from the literature. It was observed that the external exposure parameter (LC50 z exposure length; in ppm z h), varied approximately 60-fold. Concentrations of compounds in the lipoid brain fraction were simulated using a kinetic model. This lead to a more than 10-fold reduction in the toxic range of the 15 VOCs. The average value for this simulated dose surrogate was 70 6 31 mM for all VOCs. These observations support the presumption that nonspecific, acute narcotic lethality is directly related to the extent of VOC distribution into lipoid brain constituents. The present results can be used for estimation of the acute lethality of nonreactive VOCs on the basis of kinetic simulations. In addition, the presently calculated dose surrogate for VOC lethality in rats is found to be very similar to the reported internal lethal concentrations of so-called “baseline toxicity compounds” in fish. This indicates a common mechanism of acute VOC toxicity among mammalian and aquatic species. © 1998 Society of Toxicology.
Volatile organic compounds (VOCs) are widely used as solvents in industrial and household applications. Various forms of toxicity have been reported resulting from both acute and chronic exposure to these compounds (Burbacher, 1993). One common form of toxicity observed after acute inhalation exposure to high VOC concentrations is general anesthesia, possibly followed by death. Such effects have been observed for all mammalian species, including humans. General anesthesia is considered to be a nonspecific toxic effect that is related to uptake of these compounds by the central nervous system (CNS). It has traditionally been assumed that accumu-
METHODS A physiologically based-pharmacokinetic (PB-PK) model was constructed for simulation of uptake, distribution, and elimination of VOCs in the rat. The model structure (Fig. 1) was similar to that of earlier published PB-PK models for styrene and toluene (DeJongh and Blaauboer, 1996; Ramsey and Andersen, 1984). Model compartments include: (1) localized fat tissue, (2) a lumped compartment representing all slowly perfused tissues except fat tissue, (3) liver tissue, (4) a lumped compartment representing all rapidly perfused tissues except liver and brain tissue, and (5) brain (CNS) tissue. Two CNS subcompartments were defined, representing aqueous and lipoid brain components. Anatomical and physiological parameters were taken from the literature (Table 1). Blood–air and tissue– blood partition coefficients (PCs) of 15 VOCs were also obtained from the literature (Table 2). Where experimental brain– blood PC were unavailable, an estimate was made from an empirical, linear relationship between experimental fat– blood and brain– blood PCs (Fig. 2). Concentrations of compounds in brain lipids were assumed to be a function of the concentration in whole brain and were derived from octanol–water PCs (Meylan and Howard, 1995) according to the formulas in the Appendix.
1
To whom correspondence should be addressed at Research Institute of Toxicology (RITOX), Utrecht University, P.O. Box 80.176, 3508 TD Utrecht, The Netherlands. Fax: 131 30 253 5077. E-mail: J.DEJONGH@ RITOX.DGK.RUU.NL. 1096-6080/98 $25.00 Copyright © 1998 by the Society of Toxicology. All rights of reproduction in any form reserved.
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ROLE OF KINETICS IN THE LETHALITY OF VOCs
biotransformation rates (KFC) were assigned for hepatic metabolism of each compound. Biotransformation parameter values were derived from various in vivo and in vitro studies (Table 3). To account for possible differences in metabolism (Vmax and KF), ventilation rate (QP), and cardiac output (QC) among individual studies due to varying body weights, these parameters were allometrically scaled to exponential functions of whole animal body weight: V max 5 V maxC z BW0.7
(1a)
K F 5 K FC z BW20.3
(1b)
Q P 5 Q PC z BW0.7
(1c)
Q C 5 Q CC z BW
(1d)
0.7
Mass balance differential equations for the model (see Appendix) were numerically solved using the Advanced Continuous Simulation Language (ACSL) developed by Mitchell and Gauthier Associates (Concord, MA). Twenty-three LC50 values for inhalation exposure of rats to 15 different VOCs (Table 4) at varying exposure lengths were derived from various sources (Anonymous, 1987; WHO, 1983–1995). As animal body weight (BW) in individual LC50 studies were mostly unavailable, body weight was arbitrarily set to 0.35 kg for all simulations.
RESULTS
FIG. 1. Structure of the PB-PK model applied for analysis of acute inhalation lethality of volatile organic compounds. VOCs were assumed to be eliminated either by exhalation of unchanged compound or saturable and/or first-order biotransformation in the liver. Maximum metabolic rates (VmaxC), affinity constants (Km), and/or first-order
LC50 values of the compounds considered in the present study are shown in Table 4 and range from 129,000 ppm for butadiene to 3000 ppm for chlorobenzene. Since steady state may not be reached within the specified exposure lengths, LC50 values are multiplied by exposure length (LC50 z t) as an alternative measure for external exposure under nonequilibrium conditions. Thus, a range from approximately 500,000, for butadiene, to 8500 ppm z h, for pentachloroethane, is obtained.
TABLE 1 Physiological and Anatomical Parameters for the PB-PK Model
a b
Parameter
Abbreviation
Alveolar ventilation rate (liters/h*kg)a Cardiac output (liters/h*kg)a Blood flow fractionsa Liver Fat Richly perfused tissue (RPT) Slowly perfused tissue (SPT) Brain Tissue group volume fractionsa Liver Fat Richly perfused tissue (RPT) Slowly perfused tissue (SPT) Brain Target tissue volume fractionsb Brain water Brain lipids
QPC QCC
Brown et al., 1994. Widdowson and Dickerson, 1981.
Value 14 14
Scaling factor BW0.7 BW0.7
QLC QFC QRC QSC QBrC
0.25 0.09 0.52 0.11 0.03
— — — — —
VLC VFC VRC VSC VBrC
0.04 0.07 0.09-VLC-VBrC 0.82-VFC 0.006
— — — — —
Fab Flb
0.85 0.15
— —
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DEJONGH, VERHAAR, AND HERMENS
TABLE 2 Partition Coefficients of the Compounds Partition coefficients tissue–body Compound
Reference
Kowa
Blood–air
Liver
Muscle
Fat
Brain
Brain–brain lipids
Hexane Butadiene Isoprene Methanol Acetone Dichloromethane Chloroethane 1,2-Dichloroethane 1,1,1-Trichloroethane Pentachloroethane Tetrachloroethene Benzene Toluene p-Xylene Styrene Chlorobenzene
Gargas et al., 1989 Medinski et al., 1994 Gargas et al., 1989 Kaneko et al., 1994 Kumagai and Matsunaga, 1995 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989 Gargas et al., 1989
3.87 1.99 2.42 20.77 20.24 0.94 1.43 1.46 2.48 3.22 3.40 2.14 2.64 3.15 2.95 2.86
2.29 1.49 1.87 31342 208 9.4 4.08 30.4 5.76 104 18.9 17.8 18 41.3 40.2 59.4
2.27 0.8 1.67 0.9 1.15 0.73 0.88 1.17 1.49 2.5 3.72 0.96 4.64 2.18 3.46 1.45
1.27 0.99 1.09 1.16 0.82 0.41 0.79 0.77 0.55 0.7 1.06 0.58 1.54 0.93 1.16 0.57
69.43 14.89 38.5 0.06 0.38 6.19 9.46 11.32 45.66 39.6 86.67 28.03 56.72 42.32 86.47 21.5
3.25 1.28 2.13 1.01 0.76 0.97 1.08 1.15 2.39 2.17 3.87 1.75 2.79 2.27 3.86 1.52
21.65 8.07 13.90 0.20 0.47 3.90 5.95 6.40 15.64 14.42 25.74 11.21 18.36 15.07 25.57 10.05
a
Log octanol–water partition coefficient.
The three parameters for internal exposure (i.e., dose surrogates) in this study are the simulated concentrations in respectively venous blood (Cv), whole brain (Cwb) and brain lipids (Cbl). Cv and Cwb range from respectively 214 –2.0 and 218 – 5.3 mM with methanol at the upper and 1,1,1-trichloroethane and pentachloroethane at the lower limits of these ranges. Cbl
spans a substantially smaller range from 160 –35.5 mM with pentachloroethane and tetrachloroethylene at the lower and upper limits (Table 4). Steady state is indeed not reached within the length of exposure for all 23 LC50 studies (Table 4), and LC50 z t is considered as the preferred measure of external exposure. When comparing the range of LC50 z t values with the three simulated dose surrogates, it is observed that neither Cv nor Cwb reduces the variation in the range of LC50 z t values (Fig. 3). Only when Cbl is considered, the 60-fold difference in toxicity, expressed through the external exposure parameter LC50 z t, is reduced by more than a factor 10- to a 5-fold range (Fig. 3) with an average value of 70 6 31 mM. Simulation of five lethality studies reported on 1,1,1-trichloroethane (TCE) shows that a reduction of uncertainty may also be achieved when analyzing the acute lethality of a single compound under varying exposure lengths (Fig. 4). In this case, toxicity range of LC 50 values for TCE (100,000 –10,000 ppm z h), expressed on the basis of external exposure as LC50 z t, is substantially reduced after simulation of the corresponding dose surrogates (Cbl) for each exposure scenario (33–75 mM). The resulting average value of 52.3 6 15.3 mM of Cbl for TCE lethality also compares well with the previously calculated value of 70 6 31 mM for all 15 compounds of the present study. DISCUSSION
FIG. 2. Correlation between fat– blood (PF) and brain– blood (PBr) partition coefficients for VOCs. PBr 5 0.038 z PF 1 0.41 (n 5 50) data from Fiserova-Bergerova and Diaz (1986) and Kaneko et al. (1994).
Nonspecific narcotic lethality is generally assumed to be related to accumulation of compounds in phospholipid
29
ROLE OF KINETICS IN THE LETHALITY OF VOCs
TABLE 3 Biotransformation Parameters Compound
Reference
VmaxC (mg/h/kg)
Km (mg/L)
KFC (h21 z kg21)
Hexane Butadiene Isoprene Methanol Acetone Dichloromethane Chloroethane 1,2-Dichloroethane 1,1,1-Trichloroethane Pentachloroethane Tetrachloroethylene Benzene Toluene p-Xylene Styrene Chlorobenzene
McDougal et al., 1990 Medinski et al., 1994 Longo et al., 1985 Horton et al., 1992 Kimagai and Matsunaga, 1995 Gargas et al., 1990 Gargas et al., 1990 Gargas et al., 1990 Gargas et al., 1990 Gargas and Anderson, 1989 Gargas et al., 1990 McDougal et al., 1990 Purcell et al., 1990 Tardiff et al., 1993 Ramsey and Andersen, 1984 Nakajima and Sato, 1979
6.0 3.35 1.8 15.4 18.6 4 4.0 3.25 — 9.71 — 3.3 7.5 8.4 8.4 2.22
0.4 0.2 5.44 3.91 48.4 0.4 0.1 0.25 — 0.9 — 0.6 0.3 0.2 0.4 —
3.4 — — — — 2.0 1.0 — 5.0 — 5.0 — — — — —
membrane bilayers of CNS cells. This accumulation in cell membranes is thought to induce alterations in the membrane structure that may influence the conformation of membrane-
bound proteins, like, e.g., ion channels, that are involved in the specific functions of the nerve cells (Sikkema et al., 1995).
TABLE 4 LC50 Values, Exposure Times (t), LC50 z t Products, and Simulated Concentrations in Blood (Cv), Whole Brain (Cwb), and Brain Lipids (Cbl) after Exposure at the LC50 Concentration during t Hours Compound Hexane Butadiene Isoprene Methanol Acetone Dichloromethane Dichloromethane Chloroethane 1,1,1-Trichloroethane 1,1,1-Trichloroethane 1,1,1-Trichloroethane 1,1,1-Trichloroethane 1,1,1-Trichloroethane Pentachloroethane Tetrachloroethylene Benzene Benzene Toluene Toluene Toluene p-Xylene Styrene Chlorobenzene Highest value Lowest value Mean Upper 95% confidence limit Lower 95% confidence limit
LC50 (ppm)
t (h)
LC50 z t (ppm*h)
Cv (mM)
Cwb (mM)
Cbl (mM)
Steady-State Level (%)
77000 129000 64721 64000 21874 95781 25181 59725 18000 14250 18400 10300 38000 4238 25700 3700 10000 12159 13022 8800 4550 5634 2965
1 4 4 4 8 0.25 6 2 3 7 4 6 0.25 2 1 4 7 6.5 4 4 6 2 6
77,000 516,168 258,884 256,000 174,992 23,945 151,086 119,450 54,000 99,750 73,600 61,800 9,500 8,476 25,700 54,800 70,000 79,033 52,088 35,200 27,300 11,268 17,790
5.4 7.8 4.7 213.9 11.6 22.9 17.7 9.5 3.2 2.9 3.4 2.0 4.2 2.3 5.6 7.2 6.3 5.7 5.0 3.6 3.5 2.0 3.9
19.2 10.0 10.2 218.1 85.0 24.3 17.3 10.3 8.0 7.1 8.5 5.0 11.4 5.3 24.0 12.9 11.1 16.4 14.6 9.8 8.2 8.3 6.0
127.7 63.3 66.8 42.3 52.3 97.6 69.5 56.9 52.1 46.2 55.6 32.8 74.9 35.5 159.8 82.4 70.8 107.7 96.0 64.5 54.7 55.2 39.4
84 100 97 0 62 37 100 97 85 95 89 93 58 14 40 74 87 66 55 55 50 24 55
516,168 8,476 98,167 348,933 9,142
213.9 2.0 15.4 89.8 2.0
218.1 5.0 24.0 131.6 5.2
159.8 32.8 70.0 138.9 34.6
30
DEJONGH, VERHAAR, AND HERMENS
FIG. 3. Box plots of the external exposure parameters LC50 and LC50 z t and three simulated dose surrogates for 15 compounds and 23 LC50 values. Horizontal markers indicate means 6 95% confidence limits.
Studies on narcotic effects in fish that were exposed to contaminated water have reported on the residues of nonreactive compounds in individual organisms that were measured directly after the onset of death. These so-called “internal lethal doses” (ILDs) or “critical body residues” (CBRs) were found to be equal for all nonreactive compounds, when expressed on a molar basis, and are basically independent of exposure time and concentration. They reflect a threshold of internal exposure above which acute lethality occurs. In aquatic toxicology, this phenomenon is also referred to as the baseline toxicity of compounds, i.e., the minimum toxicity of compounds due to their nonspecific action on the CNS (McCarthy et al., 1991; van Wezel and Opperhuizen, 1995). For cross-species comparisons, ILDs are normalized to lipid content and they may be considered equivalent to some of the dose-surrogates used in risk assessment of mammalian species (Van Vliet and DeJongh, 1996). PB-PK modeling allows for simulation of the ILD concept for inhalation exposure of mammalian species. In the present study, simulated concentrations in venous blood (Cv) and whole brain (Cwb) were examined as a refined application of the ILD concept for mammals. In addition, the possible use of the concentration in the brain’s lipid constituents (Cbl) as a dose surrogate was considered from information on the mechanisms of narcotic action. A more then 10-fold reduction of the variation in acute inhalation toxicity of the 15 compounds is achieved by application of the dose surrogate Cbl instead of a traditional external ex-
posure parameter C z t (Table 4 and Fig. 3). This clearly supports the previously discussed mechanism of narcotic action by accumulation of compounds in phospholipid bilayers in the nerve cell membrane. Comparison of the simulated values of Cbl in rats (33–160 mM; avg. 70 6 31 mM) with the ILDs (40 –160 mM, on lipid basis) reported for several fish species (van Wezel and Opperhuizen, 1995) suggest that the mechanism of lethal narcosis may be similar across species. When examining the feasibility of the studied dose surrogates, it is a prerequisite that any LC50 value that is included, results from narcosis only and does not represent other forms of acute toxicity. In addition to transformation to more polar metabolites (Jean and Reed, 1992) many VOCs may be bioactivated by, e.g., cytochrome P450IIE1 (Raucy et al., 1993). When these metabolites are not conjugated with, e.g., glutathione (Jean and Reed, 1992), they bind directly with cellular proteins leading to acute hepatic, renal, or myocardial damage. Thus, compounds like 1,1dichloro- or dibromoethane are not included in the present study. It should be realized that the Cbl values for the rat considered in the present study are simulated values. In contrast, the ILDs reported for fish are experimental values. There are some possible reasons for uncertainty in the simulated values for Cbl. (I) Strain, age, weight and sex of the rats used in the LC50 studies are not taken into account in the present model since these data were often not specified in the original study reports. All of these factors can influence the kinetics of a compound, like, e.g., the age- and sex-dependent sizes of body fat depots that may alter the
FIG. 4. Box plots of the external exposure parameter LC50 z t and the simulated dose surrogate Cbl for 1,1,1-trichloroethane (n 5 5). Horizontal markers indicate means 6 95% confidence limits.
31
ROLE OF KINETICS IN THE LETHALITY OF VOCs
body distribution of lipophilic compounds. (II) In addition, the value of some model parameters, like, e.g., ventilation and perfusion rate, may be changed as a result of the exposure and form another possible source of parameter uncertainty. (III) In contrast with ILDs for fish, simulated Cbl values do not necessarily represent the concentration after the onset of death but rather after the termination of exposure. As most LC50 studies do not specify the onset of death of the individual animals, this may be a justifiable approximation at the cost of some uncertainty. In summary, it is concluded that a dose surrogate for acute lethal toxicity by nonspecific narcosis has been identified in the rat. Quantitative comparison with previously reported data on narcosis in fish suggest that the mechanism for general narcosis may be similar across species. Studies on cellular and molecular aspects of narcotic toxicity are needed to refine the understanding of these mechanisms.
Rate of Amount (AM) Metabolized dA M /dT 5 ~V MAX z C VL!/~K M 1 C VL! 1 K F z C VL z V L Mixed Venous Blood Concentration (CV) C V 5 ~Q F z C VF 1 Q L z C VL 1 Q S z C VS 1 Q R z C VR 1 Q Br z C VBr!/Q C Rate of Change of Amount in Exhaled (AX) Air dA X/dt 5 Q P z C X C X 5 C A/P B C Xppm 5 ~0.7 z C X 1 0.3 z C I! z 24450/MW Abbreviations
APPENDIX
Mass Balance Differential Equations of the PB-PK Model Arterial Blood Concentration (CA) C A 5 ~Q C z C V 1 Q P z C I!/~Q C 1 ~Q P/P B!! Rate of Change of Amount (AT) in Noneliminating Tissues: Fat (T 5 F), Slowly (T 5 S), and Rapidly Perfused (T 5 R) Tissues dA T /dt 5 Q T z ~C A 2 C VT! C VT 5 A T /~V T z P T! C T 5 A T /V T
CA CV CVT CT Cbl Fab Flb Kow QC QT
Rate of Change of Amount (ABr) in Brain (Target) Tissues
QP CI PB PT
dA Br /dt 5 Q Br z ~C A 2 C VBr!
VT
C VBr 5 A Br /~V Br z P Br! C wb 5 A Br /V Br C bl 5 C wb /~~F ab /K ow! 1 F lb!
VMAX Km KF CX CXppm Cwb, CBr
Concentration (mg/L) in arterial blood Concentration (mg/L) in mixed venous blood Concentration (mg/L) in venous blood of noneliminating tissue (T 5 F, Br, S, R) or liver (T 5 L) Concentration (mg/L) in noneliminating tissue (T 5 F, Br, S, R) or liver (T 5 L) Concentration (mg/L) in lipid brain fraction Fraction of aquatic brain constituents Fraction of lipid brain constituents Octanol–water partition coefficient Cardiac output (L/h) Perfusion rate (L/h) of noneliminating tissue (T 5 F, Br, S, R) or liver (T 5 L) Ventilation rate (L/h) Concentration in inhaled air (mg/L) Blood–air partition coefficient Partition coefficient for noneliminating tissues (T 5 F, Br, S, R) or liver (T 5 L) Tissue volume (L) for noneliminating tissues (T 5 F, Br, S, R) or liver (T 5 L) Maximum metabolism rate (mg/h) Affinity constant (mg/L) First-order elimination rate (h21) Concentration in air released from alveoli Concentration (ppm) in air released from lung Concentration (mg/L) in (whole) brain
Rate of Change of Amount (AL) in Liver Tissue dA L /dt 5 Q L z ~C A 2 C VL! 2 dA M/dT C VL 5 A L /~V L z P L! C L 5 A L /V L
ACKNOWLEDGMENTS This study was supported by grants from the Dutch Platform for Alternatives to Laboratory Animals (PAD), Grant 94-31, and from the European Center for Validation of Alternative Methods (ECVAM), Contract 11277-95-10 F1 ED ISP NL.
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