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Toxicokinetics and Toxicodynamics of Jet-Propulsion Fuel 8

This chapter contains a review of toxicokinetics and toxicodynamics data for jet-propulsion fuel 8 (JP-8). Given the presence of hundreds of hydrocarbons in JP-8, it is impractical to describe here the toxicokinetics and disposition of each component hydrocarbon. In the previous National Research Council (NRC) report, Permissible Exposure Levels for Selected Military Fuel Vapors, the toxicokinetics of some toxic components of JP-8—including benzene and alkylbenzenes (such as xylenes and toluene)—were discussed in detail (NRC 1996).

The following general principles were applied to describe the toxicokinetics of JP-8. The major determinants of hydrocarbon toxicokinetics following systemic uptake are disposition-related physiologic measures, such as alveolar ventilation, cardiac output and blood flow to organs, partition coefficients, and organ volume. Hydrocarbons with high blood:air partition coefficients will be absorbed to a greater extent than chemicals with poor blood solubility. Given that most hydrocarbons have fairly high fat:air and fat:blood partition coefficients, it is not surprising that fat or adipose tissue is a major storage depot for many of these JP-8 components. For hydrocarbons with high fat:blood partition coefficients, metabolic clearance following cessation of exposure is more important than that during exposure. Given the accumulation of hydrocarbons or their metabolites in lipid-rich tissues, the absence



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3 Toxicokinetics and Toxicodynamics of Jet-Propulsion Fuel 8 This chapter contains a review of toxicokinetics and toxicodynamics data for jet-propulsion fuel 8 (JP-8). Given the presence of hundreds of hydrocarbons in JP-8, it is impractical to describe here the toxicokinetics and disposition of each component hydrocarbon. In the previous National Research Council (NRC) report, Permissible Exposure Levels for Selected Military Fuel Vapors, the toxicokinetics of some toxic components of JP-8—including benzene and alkylbenzenes (such as xylenes and toluene)—were discussed in detail (NRC 1996). The following general principles were applied to describe the toxicokinetics of JP-8. The major determinants of hydrocarbon toxicokinetics following systemic uptake are disposition-related physiologic measures, such as alveolar ventilation, cardiac output and blood flow to organs, partition coefficients, and organ volume. Hydrocarbons with high blood:air partition coefficients will be absorbed to a greater extent than chemicals with poor blood solubility. Given that most hydrocarbons have fairly high fat:air and fat:blood partition coefficients, it is not surprising that fat or adipose tissue is a major storage depot for many of these JP-8 components. For hydrocarbons with high fat:blood partition coefficients, metabolic clearance following cessation of exposure is more important than that during exposure. Given the accumulation of hydrocarbons or their metabolites in lipid-rich tissues, the absence

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of hydrocarbons and their metabolites in exhaled air, blood, or urine does not necessarily mean the absence of systemic exposure. With regard to metabolism, cytochrome P450 (CYP450) enzymes metabolize most hydrocarbons by such reactions as aliphatic hydroxylation, aromatic hydroxylation, and epoxidation. For many hydrocarbons, alcohol and aldehyde dehydrogenases play an important role in metabolizing alcohols to their corresponding keto acids. Phase II reactions, including conjugation with glutathione, glucuronic acid, sulfate, and glycine, are important in formation of water-soluble metabolites. The following discussion of toxicokinetics will be limited to a brief summary of disposition of only toxicologically relevant components of JP-8. BENZENE Benzene is a minor component of JP-8 (<1%), but its high volatility, its flammability, and its moderate water solubility make it an important component of JP-8 exposure (ACGIH 1996; Paustenbach 2000). Benzene is a potent genotoxicant and a recognized human carcinogen. Dose-dependent bone-marrow suppression, pancytopenia (e.g., aplastic anemia), and neurologic toxicities can occur after high-dose benzene exposure (Evans et al. 1981; McConnell 1993). The metabolism of benzene has been discussed in a previous NRC report (NRC 1996) and by ACGIH (1996). Benzene is metabolized primarily via the hepatic CYP450 system to benzene oxide, which is biotransformed to 1,2-dihydrodiol, which leads to catechol formation. Benzene oxide can also rearrange nonenzymatically to phenol, which is biotransformed to hydroquinone and benzoquinone. The water-soluble metabolites of benzene (phase II conjugative metabolism) are readily excreted (Paustenbach et al. 1993). Combined exposure to catechol and hydroquinone metabolites has been implicated in benzene’s genotoxicity (Robertson et al. 1991). Benzene and its metabolites have been shown to accumulate in humans (e.g., they appear in exhaled air and urine) after repeated exposure to benzene. ALKYLBENZENES The alkylbenzenes (single-ring aromatic compounds with single or multiple aliphatic side chains) are constituents of JP-8. Toluene (methylbenzene) and mixed xylenes (o-, m-, and p-) are present in JP-8 and have been identified as potential neurotoxic chemicals after sufficiently high intentional, accidental, or occupational exposures (Gamberale and Hultengren 1972; Boor and Hurtig 1977; Klaucke et al. 1982; Hipolito 1980).

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The toxicokinetics of toluene have been well characterized in laboratory animals (Benignus et al. 1981; Benignus 1982). In rats, after inhalation exposure, toluene was quickly absorbed and distributed in lipoidal and highly vascularized tissues. Within an hour of inhalation exposure at 2,167 mg/m3, about 95% of maximal concentrations in blood and brain were achieved. Toluene is metabolized principally by series of oxidation reactions that lead to benzoic acid, which is conjugated with glycine to form hippuric acid. Un-changed toluene is readily removed in exhaled air. Xylene vapor is rapidly absorbed from the lungs, and xylene liquid and vapor are absorbed slowly through skin. More than 90% of the absorbed xylene is metabolized to methylhippuric acid, which is readily excreted in urine. On repeated administration, xylene auto-induces some P450 enzymes, which metabolize the methyl side chain to toluic acid (methylbenzoic acid), which is also rapidly excreted. Additional metabolites of xylenes are dimethylphenol and methylbenzyl alcohol (Langman 1994). Exposures to toluene appear to have an initial central nervous system (CNS) stimulatory effect; intentional or accidental high exposures are associated with CNS depression (Gamberale and Hultengren 1972; Boor and Hurtig 1977). In humans, accidental exposures to xylene at up to 10,000 ppm resulted in epileptic seizure, complete amnesia, cerebral hemorrhage, unconsciousness, and ventricular fibrillation (Low et al. 1989). There are no relevant studies on low-level chronic exposure to toluene or mixed xylenes in JP-8. C9-C13 ALIPHATIC AND AROMATIC HYDROCARBONS Long-chain and branched hydrocarbons that are primary components of JP-8, include n-nonane, n-decane, n-dodecane, n-tridecane, isopropylbenzene, n-propylbenzene, trimethylbenzene, n-dimethylbenzene, naphthalene, n-pentylbenzene, and n-triethylbenzene. Inhaled long-chain aliphatic hydrocarbons generally show poor blood uptake because of lower blood solubility. They have relatively high lipid:blood partition coefficients; this can result in accumulation in lipid-rich tissues, such as brain and fat. In laboratory studies, brain concentrations of hydrocarbons and their metabolites greatly exceed their plasma concentrations. Zahlsen et al. (1993) found that C8-C10 hydrocarbons were extremely well absorbed and their tissue distribution in brain and fat were largely dependent on the number of carbon atoms. n-Nonane is one component of JP-8 and it is metabolized at relatively high rates to hydroxyl derivatives, which are converted to the corresponding ketone. Other important hydrocarbons (from a

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quantitative perspective) are decane, dodecane, tetradecane, and hexadecane; they are each present at concentrations of over 10% in the liquid form of JP-8. Decane has immunotoxic potential, and its lipophilicity is similar to that of hexane and octane. Decane metabolism is similar to that of nonane: it is metabolized to the corresponding ketone though an intermediate hydroxylation step. Dodecane, tetradecane, and hexadecane are likely to be metabolized similarly, but their metabolism is not well characterized. Microorganisms also metabolize these hydrocarbons extensively. Because aliphatic fractions above C13 have relatively low volatility, they are unlikely to be present at toxicologically significant concentrations in JP-8 vapor (Sandmeyer 1981). The presence of the very-long-chain aliphatics (i.e., above C13) in JP-8 aerosol is not known. Sufficiently high exposures to alkylbenzenes—such as n-diethylbenzene, n-triethylbenzene, n-trimethylbenzene, and isopropylbenzene—can produce adverse motor and sensory effects in rats after inhalation. Gagnaire et al. (1990) reported decreased motor and sensory conduction velocities and decreased amplitude of the sensory action potential of the tail nerve in rats exposed repeatedly to a mixture of diethylbenzene and its major metabolite, 1,2-diacetylbenzene (DAB). In the rat, 1,2-diethylbenzene was about 5 times more potent a neurotoxicant than n-hexane (Gagnaire et al. 1990). Spinal-cord axonal swelling with partial demyelination has been associated with DAB exposure in rats (Kim et al. 2001). The neurotoxicity of 1,2-diethylbenzene appears to be related to formation of protein complexes: reaction with amino acids of proteins to form pyrolated polymers that lead to protein cross links. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS OF BENZENE, NONANE, AND C9-C12 OR C9-C17 ALIPHATIC HYDROCARBONS Physiologically based pharmacokinetic (PB-PK) models for some JP-8 components have been developed to understand the relationship between vapor concentrations and accumulation in tissue and blood compartments. When appropriately developed and validated, PB-PK models can provide a time course of distribution of a chemical or its metabolites in tissues and show the effect of changing physiologic characteristics on plasma and tissue concentrations. PB-PK models have been applied to predict toxicokinetic parameters and to scale dose in different species. Kinetic studies have been done with representative compounds, including benzene, short-chain alkanes and iso-alkanes, and naphthalene. There is kinetic information about the higher-molecular-weight compounds that become

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less volatile and less water- and blood-soluble and more lipid-soluble. PK studies provide information on those components of JP-8, which might assist in biomonitoring for components that are found in JP-8 at higher percentages and in beginning to assess their metabolites. PB-PK models have been applied to evaluate the behavior of benzene and alkylbenzenes alone and in combination (Medinsky et al. 1989, 1995; Purcell et al. 1990). Some of the published models examine human populations exposed at concentrations found in the environment (Sherwood and Sinclair 1999) or at occupationally relevant concentrations in volunteers (Beningnus et al. 1998). The models all use flow-limited uptake of chemicals by tissues and metabolic clearance from the liver compartment. Interaction models rely on competition of the various substrates for enzymatic clearance in liver (Haddad et al. 2000). Another similarity in all the kinetic models is the representation of the relationship of circulating concentrations of those aromatic hydrocarbons to exhaled air. In the model, all compounds in venous blood are available for gas exchange in the lungs; this leads to simple relationships in which concentration in exhaled air is a straightforward function of concentration in blood, blood:air partition coefficient, total cardiac output, and alveolar ventilation. The models have proved successful for low-molecular-weight hydrocarbons; their application has not been established for the longer-chain n-alkanes. Robinson (2000) described a PB-PK model of JP-8 constituents that used nonane as a marker. Nonane has been considered a surrogate biomarker for JP-8 aliphatic hydrocarbons (e.g., C9-C12 or C9-C17 aliphatic hydrocarbons) in breath, and it distributes preferentially to brain. Nonane disposition was described in a PB-PK model that includes its distribution in blood, lungs, liver, muscle, and fat. The model was developed with “inhouse” F-344 rat inhalation data, including blood concentrations, and was validated with published data on Sprague-Dawley rats. The model was used to predict the body burden of nonane after known occupational JP-8 exposures. There was generally good agreement between the PB-PK model based on inhouse data and published data. Overall, blood and brain nonane concentrations were well predicted over a 10-fold range of concentrations in inhaled air. Limitations of the model include the lack of empirical data on metabolic measures such as Vmax and Km; the information on metabolic rates (hydroxylation followed by metabolism to corresponding keto form); and the lack of data on alveolar ventilation rates. Given those limitations, the model overpredicted blood concentrations and underpredicted the slope of terminal elimination. The incorrect predictions appear related to oversimplifications of several tissue compartments and the use of only a small number of homogeneous compartments. Efforts were made to extrapolate the rat PB-PK model of nonane to predict

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results of exposures of fuel-tank entry workers and attendants. The rat PB-PK model overpredicted the blood concentrations of nonane determined in a JP-8 acute-exposure human study (Pleil et al. 2000), possibly because of the higher affinity of nonane to rat red blood cells than to human red blood cells and the lack of information on human metabolic measures and partition coefficients. Dixon et al. (2001) described a preliminary PB-PK model to predict JP-8 concentrations in Air Force fuel-cell maintenance workers. The model used data from PB-PK models of naphthalene inhalation in mice and rats and nonane inhalation in rats. In addition to inhalation, a pathway of dermal exposure and a skin compartment were included. For highly exposed people, the PB-PK model was generally in agreement with exhaled-air naphthalene concentrations; however, predictions for the low-exposure scenarios were grossly underestimated, especially in female workers, by a factor of 10. The model did not predict blood and urinary concentrations. The major limitation of the Dixon et al. (2001) study was the lack of appropriate human data (e.g., metabolic measures, blood and tissue partition coefficients, and diffusion rates). The Dixon et al. (2001) model predicted a rapid decline in naphthalene concentrations in all compartments after exposure except liver, fat, and brain. The model predicted accumulation in liver, brain, and fat tissues for a 7-day period that included 4-hr exposures on 5 days. Competition for enzyme does not occur only from interactions of different inhaled compounds. Interactions can also occur between inhaled compounds and metabolites formed in the body that require similar enzymes for biotransformation. Detailed kinetic studies with both benzene and n-hexane show inhibition of later metabolic steps, phenol to hydroquinone or methyl n-butyl ketone to 2,5-hexane dione, by high concentrations of inhaled benzene or hexane, respectively (Medinsky et al. 1989; Andersen and Clewell 1984). Recent work with another highly lipophilic compound with low blood:air partitioning and high fat solubility may be instructive for developing predictive PB-PK models for higher-molecular-weight n-alkanes found in JP-8 (Andersen et al. 2001). Octamethylcyclotetrasiloxane (D4) has a Pb value of about 2.0 and a fat:blood partition coefficient of 500-600. A set of detailed studies was conducted to measure behavior of D4 in blood, exhaled air, and tissues during and after 6-hr exposures in rats. The data could not be described with a conventional PB-PK model, because there were discrepancies between blood and exhaled-air concentrations. By focusing on the exhaled-air concentrations as a measure of free D4 in plasma, a PB-PK model was developed that included a pool of blood D4 that was not available for exhalation and was probably sequestered in blood lipids (Andersen et al. 2001). The ability to discern deviations from conventional models and a model with

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sequestered blood D4 depended on the availability of a robust, quality-controlled study with multiple collections of blood and exhaled-air concentrations. No such data are available on any of the long-chain alkanes found in JP-8 in laboratory animals or human volunteers. Overall, almost all recently developed PB-PK models of various JP-8 components based on nonane or naphthalene do not predict accurately the JP-8 or component concentrations in blood, breath, or tissue. Given that most JP-8 components have a propensity to accumulate in lipid-rich tissues, there is a need for more accurate PB-PK models that can predict tissue concentrations of important classes of JP-8 components. Such data are critical in assessing the long-term safety of JP-8 occupational exposure. TOXICOKINETICS-RELATED INTERACTIONS AMONG HYDROCARBON FUEL COMPONENTS With over 200 hydrocarbons present in JP-8, there is the possibility of toxicokinetics- and toxicodynamics-related antagonistic, additive, and synergistic interactions among various hydrocarbon components. The toxicokinetic parameters of individual chemicals in a complex mixture such as JP-8 are very different from the toxicokinetic profiles of individual chemicals. Chemical-chemical interactions may be related to mutual induction of competing metabolic and elimination pathways or mutual inhibition of absorption, distribution, metabolism, and excretion. Similar CYP450 enzymes and phase II conjugative metabolic pathways metabolize many alkane hydrocarbons (NRC 1996). Depending on the Km and Vmax for the metabolism of individual chemicals, competitive metabolic interactions can result in lower or higher concentrations of chemicals and their metabolites. For example, toluene inhibits the oxidative metabolism of benzene and reduces blood and bone marrow toxicity of benzene (Purcell et al. 1990). Tardif et al. (1992) evaluated dose-dependent interactions between toluene and xylene. The combined exposure to toluene and xylene resulted in lower amounts of urinary hippuric acid (20-30%) and methylhippuric acid (4-40%) than exposure to the individual agents. The greatest reductions were observed in the group exposed to both toluene and xylene at 150 ppm. The blood and brain concentrations of both toluene and xylene were 230-500% higher than the concentrations following equivalent exposures to the individual chemicals alone. A similar interaction was observed after repeated exposure. Those interactions were probably related to competitive and mutual inhibition of oxidative and conjugative metabolism by both xylene and toluene inasmuch as the two compounds use similar metabolic pathways.

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Morata et al. (1995) reported metabolic and toxic interactions between toluene and several components of jet fuels. In rats exposed to toluene and hexane for 18 hr/day for 61 days, a synergistic reduction in auditory sensitivity occurred in the toluene-plus-hexane group that persisted for 365 days. Pryor and Rebert (1992) evaluated possible interactions between toluene and n-hexane exposures (individual vs. mixture protocols). Generally, the addition of toluene to the n-hexane exposure reduced n-hexane-induced neuropathy. Perbellini et al. (1992) showed that inhibition of n-hexane-induced neuropathy by toluene was related to inhibition of n-hexane metabolism to its neurotoxic metabolite, 2,5-hexanedione. n-Hexane and toluene use similar oxidative pathways for their primary metabolism. Although most chemical-chemical interactions related to JP-8 tend to result from competitive inhibition of oxidative metabolism, induction of metabolism can result in increased toxicity of some components of JP-8, such as benzene, hexane, and naphthalene. Dosing et al. (1985, 1988) reported increased oxidative metabolism (antipyrene clearance) in personnel exposed to the jet fuel by vapor inhalation. The effect of metabolic induction by JP-8 hydrocarbons on the toxicity of chemicals that produce toxicity through metabolite(s) has not been evaluated. Ethanol is an inducer of hepatic CYP2E, which also metabolizes benzene. Ethanol ingestion might lead to increased metabolic activation of benzene, which might lead to bone marrow toxicity, hematotoxicity, and possibly leukemia (ACGIH 1996). The metabolic and toxicologic interactions between ethanol consumption and the various hydrocarbon components in JP-8 have not been carefully studied. Coupling of validated PB-PK models with a better grasp of the constituents or metabolites associated with target organ toxicity makes it possible to assess the effects of phenotypic variants and other forms of variation on tissue doses of inhaled compounds and their metabolites. Such assessments are becoming routine, but in the absence of a model for calculating the consequences of the variants in relation to tissue dose, the presence of the phenotypic variations is impossible to assess quantitatively in a rigorous manner. TOXICOKINETIC-RELATED INDIVIDUAL SUSCEPTIBILITY FACTORS Toxicokinetic-related individual susceptibility factors may include individual differences in rates of absorption, concentration at target sites, metabolic activation, and detoxification of individual chemicals. In addition, people can differ in the induction of adaptive protective responses. Genetics, pregnancy, lifestyle factors (such as smoking, alcohol-drinking, and recreational drug

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abuse), age, health status, ethnicity, and prior and concurrent occupational exposures to multiple chemicals contribute to a person’s susceptibility to chemical toxicity. Genetic polymorphism in drug-metabolizing enzymes has been shown to be a major contributing factor of individual susceptibility to chemical toxicity (Wiencke et al. 1997; Snyder and Hedli 1996). Of particular interest is a recent, preliminary study (Butler et al. 2001; Frame and Dickerson 2001) that evaluated allelic variants in three polymorphic genes: CYP2E1 (for activation of benzene), GST M1 (for inactivation of bioactivated metabolites), and NAD(P)H quinone reductase (NQO1, involved in inactivation of benzoquinones). A minor DraI allele C in the CYP2E1 gene contributing to high activity is present in about 10-14% of the population and was correlated with formation of DNA adducts after low-level exposure (Kato et al. 1995). The C-to-T transition at base pair 609 of exon 6 in the NQO1 gene leads to about a 3-fold decrease in activity and is present in about 50% of the population (Rothman et al. 1997; Wiencke et al. 1997). Because of a homozygous deletion of GST T1 gene, about 30% of the population does not express an active GST T1 enzyme (Ketterer et al. 1992). Overall, this preliminary study did not identify any important influence of genetic polymorphism in the above three genes on individual toxicokinetics (body burden of JP-8) or on adverse effects following brief exposure to JP-8 (Butler et al. 2001; Frame and Dickerson 2001). In a study by Soderkvist et al. (1996), a significant correlation was found with the GST M1 null genotype and the risk of chronic toxic encephalopathy in patients with a history of long-term exposure to industrial hydrocarbon solvents. GST M1 is a polymorphic enzyme; about 50% of the population expresses a null GST M1 genotype. Frame and Dickerson (2001) found a significant increase in GST M1 null phenotype distribution in naphthalene-exposed people (60.6% GST 1 null phenotype) compared with unexposed people (45.4% GST null phenotype). Despite that trend, there was no relationship between GST M1 null distribution and high or low exposure to naphthalene on the basis of exhaled-air concentration. That suggests that environmental and lifestyle factors contributed to an increase in GST M1 null genotype independently of JP-8 exposure. The presence of GST M1 null genotype after low or moderate exposure may predispose people to adverse health effects compared to people with normal GST M1 activities. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1996. Threshold Limit Values for Chemical Substances and Physical Agents and Bio-

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logical Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Andersen, M.E., and H.J. Clewell III. 1984. Pharmacokinetic interactions of mixtures. Pp. 226-238 in Proceedings of the 14th Annual Conference on Environmental Toxicology, 15-17 Nov. 1983, Dayton, OH. AFAMRL-TR-83-099. AD-A146 400. Air Force Aerospace Medical Division, Wright-Patterson AFB, OH. August. Andersen, M.E., R. Sarangapani, R.H. Reitz, R.H. Gallavan, I.D. Dobrev, and K.P. Plotzke. 2001. Physiological modeling reveals novel pharmacokinetic behavior of inhaled octamethylcyclotetrasiloxane in rats. Toxicol. Sci. 60(2):214-231. Benignus, V.A., K.E. Mueller, C.N. Barton, and J.A. Bittikoffer. 1981. Toluene levels in blood and brain of rats during and after respiratory exposure. Toxicol. Appl. Pharmacol. 61(3):326-334. Benignus, V.A. 1982. Neurobehavioral effects of toluene: A review. Neurobehav. Toxicol. Teratol. 3(4):407-416. Benignus, V.A., W.K. Boyes, and P.J. Bushnell. 1998. A dosimetric analysis of behavioral effects of acute toluene exposure in rats and humans. Toxicol. Sci. 43(2):186-195. Boor, J.W., and H.I. Hurtig. 1977. Persistent cerebellar ataxia after exposure to toluene. Ann. Neurol. 2(5):440-442. Butler, M.A., C.A. Flugel, E.F. Krieg, J.E. Snawder, and J.S. Kesner. 2001. Gene-environment interactions and exposure to JP8 jet fuel. Pp. 76-80 in JP8 Final Risk Assessment . The Institute of Environmental and Human Health (TIEHH), Lubbock, TX. August 2001. Dixon, K.R, E.P. Albers, and C. Chappell. 2001. A model for predicting health risk to exposure to JP8 jet fuel. Pp. 140-151 in JP8 Final Risk Assessment. The Institute of Environmental and Human Health (TIEHH), Lubbock, TX. August 2001. Dosing, M., S. Loft, and E. Schroeder. 1985. Jet fuel and liver function. Scand. J. Work Environ. Health. 11(6):433-437. Dosing, M., S. Loft, J. Sonne, and E. Schroeder. 1988. Antipyrene and metronidazole metabolism during occupational exposure to gasoline. Int. Arch. Occup. Environ. Health. 60(2):115-118. Evans, H.L., A.M. Dempster, and C.A. Snyder. 1981. Behavioral changes in mice following benzene inhalation. Neurobehav. Toxicol. Teratol. 3(4):481-485. Frame, L.T., and R.L. Dickerson. 2001. The human glutathione-S-transferase M1 (GSTM1) polymorphism as a risk factor for acute toxicity from jet fuel exposure. Pp. 87-90 in JP8 Final Risk Assessment. The Institute of Environmental and Human Health (TIEHH), Lubbock, TX. August 2001. Gagnaire, F., B. Marignac, and J. de Ceaurriz. 1990. Diethylbenzene-induced sensori-motor neuropathy in rats. J. Appl. Toxicol. 10(2):105-112. Gamberale, F., and M. Hultengren. 1972. Toluene exposure. II. Psychophysiological functions. Work Environ. Health 9(3):131-139. Haddad, S., G. Charest-Tardif, and K. Krishnan. 2000. Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures. J. Toxicol. Environ. Health A 61(3):209-223.

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