7
Effects of Jet-Propulsion Fuel 8 on the Liver

This chapter summarizes the findings on potential hepatic toxicity of jet-propulsion fuel 8 (JP-8) and related fuels presented in the National Research Council report Permissible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) and reviews additional studies, most of which were completed after the 1996 report was published. The subcommittee uses that information to assess the potential toxic effects of JP-8 on the human liver.

SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT

The National Research Council Subcommittee on Permissible Exposure Levels for Military Fuel Vapors reviewed studies concerning potential hepatic changes associated with exposure to the vapors of JP-8, JP-4, JP5, or diesel fuel marine (DFM) on the liver (NRC 1996).

One study examined the effects of JP-4 on the liver in humans. Dossing et al. (1985) reported that fuel-filling attendants exposed to JP-4 at an average of 31 mg/m3 for a mean of 6.4 years had a significantly faster antipyrine clearance (68 mL/min) than an referent population of office workers (58 mL/min).



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7 Effects of Jet-Propulsion Fuel 8 on the Liver This chapter summarizes the findings on potential hepatic toxicity of jet-propulsion fuel 8 (JP-8) and related fuels presented in the National Research Council report Permissible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) and reviews additional studies, most of which were completed after the 1996 report was published. The subcommittee uses that information to assess the potential toxic effects of JP-8 on the human liver. SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT The National Research Council Subcommittee on Permissible Exposure Levels for Military Fuel Vapors reviewed studies concerning potential hepatic changes associated with exposure to the vapors of JP-8, JP-4, JP5, or diesel fuel marine (DFM) on the liver (NRC 1996). One study examined the effects of JP-4 on the liver in humans. Dossing et al. (1985) reported that fuel-filling attendants exposed to JP-4 at an average of 31 mg/m3 for a mean of 6.4 years had a significantly faster antipyrine clearance (68 mL/min) than an referent population of office workers (58 mL/min).

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No marked differences were found in serum aspartate aminotransferase and alkaline phosphatase activity between the two groups. No studies were available that report the effects of JP-8, JP-5, or DFM vapors on the liver in humans. Studies in rats and mice had examined the toxic effects of JP-8 on the liver (MacEwen and Vernot 1983, 1984,1985). In subchronic inhalation studies, male and female F344 rats (10 of each) and male and female C57BL/6 mice (10 of each) were continuously exposed to JP-8 vapor at 500 or 1,000 mg/m3 for 90 days. Some groups of animals were killed immediately after the 90-day exposure, and others 2 wk, 2 months (mo), 9 mo, or 21 mo after the exposure. Immediately after exposure ceased, male rats showed increases in liver weights and liver:body weight ratios at 1,000 mg/m3, decreases in serum glutamic-pyruvic transaminase (SGPT) activity at 500 and 1,000 mg/m3, and decreases in alkaline phosphatase activity at 1,000 mg/m3; and female rats showed increases in liver weights and liver:body weight ratios at 500 and 1,000 mg/m3, increases in alkaline phosphatase activity at 1,000 mg/m3, and decreases in SGPT activity at 500 and 1,000 mg/m3. Nine months after exposure, male rats showed decreases in SGPT activity at 500 and 1,000 mg/m3. Twenty-one months after exposure, male rats showed concentration-related increases in liver:body weight ratios at 500 and 1,000 mg/m3; and female rats showed decreases in serum glutamic oxaloacetic transaminase (SGOT) activity at 500 mg/m3 and decreases in SGPT activity at 500 and 1,000 mg/m3. It should be emphasized that despite the significant changes observed in SGOT and SGPT activities, the alterations were within the normal range and thus not clinically relevant. Support for relevant changes in liver function would necessitate the measurement of liver enzyme functions and histopathologic studies, which were not conducted. No data on mice were presented. The available data on potential hepatic toxicity associated with subchronic exposure to JP-8 vapor are not definitive, because histopathologic examinations were not performed. The liver weight changes observed in rats might indicate hyperplasia or hypertrophy. Alternatively, the increases in liver:body weight ratios might reflect a loss of body weight in the test animals during the study. It is also possible that JP-8 was offensive to the animals, nauseating them and decreasing their food intake. Animal studies had also examined the liver effects from dermal or inhalation exposure to JP-4 or JP-5. Mild liver changes were observed in male and female beagles, male and female F344 rats, and male and female C57BL/6 mice exposed to JP-5 vapor continuously at 150 or 750 mg/m3 for 90 days (MacEwen and Vernot 1978, 1980, 1981, 1982, 1983, 1985; Gaworski et al. 1984). Similar results were reported in beagles, F344 rats, and C57BL/6 mice exposed to JP-4 vapor at 500 or 1,000 mg/m3 for 90 days (MacEwen and

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Vernot 1984); in F344 rats and C57BL/6 mice exposed to JP-4 vapor at 1,000 or 5,000 mg/m3 for 6 hr/day, 5 days/wk for 12 mo (Bruner et al. 1993; Wall et al. 1990; MacEwen and Vernot 1981, 1982); and in monkeys, dogs, rats, and mice exposed to JP-4 vapor at 2,500 or 5,000 mg/m3 for 6 hr/day, 5 days/wk for 8 mo (MacNaughton and Uddin 1984). EFFECTS OF EXPOSURE TO JP-8 IN HUMANS The effects of acute exposure to JP-8 on the liver in humans were examined in a study recently completed by the U.S. Air Force. The preliminary results of that study are described below and summarized in Table 7-1. Snawder and Butler (2001) collected venous blood and urine from 107 people working at six Air Force bases (AFB): Davis Monthan AFB, Arizona; Seymour Johnson AFB, North Carolina; Langley AFB, Virginia; Pope, AFB, North Carolina; Little Rock AFB, Arkansas; and Hurlbert Field, Florida. The exposed workers were fuel tank-entry personnel with at least 9 mo of persistent exposure to jet fuel (defined as 1-hr entry, twice a week). The unexposed group consisted of Air Force personnel who routinely had no significant exposure to solvents or fuels. The participants completed questionnaires on job category, exposure, and medical and demographic items. The exclusion criteria for participants were the presence of autoimmune disease, cancer, or diabetes and the use of immune-system altering drugs. Blood samples were collected before and after shift at each AFB and sent to a National Institute for Occupational Safety and Health (NIOSH) laboratory in Cincinnati, Ohio, for analysis. The markers of liver damage included serum alpha-glutathione S-transferase (GST) activity, an index of liver toxicity. In measurement with commercial immunoassay kits, hepatic alpha-GST activity in control and exposed subjects fell within the normal range. Butler et al. (2001) further categorized hepatic alpha-GST in three exposure groups to assess correlation of JP-8 exposure with potential liver toxicity. The high-exposure group consisted of subjects who routinely performed tasks associated with repair of aircraft fuel systems; the moderate-exposure group consisted of subjects who were involved with fuel handling, distribution, recovery, and testing; and the low-exposure group consisted of subjects who did not normally come into contact with jet fuel or solvents. That hepatic alpha-GST activity was not significantly different among those groups indicated a lack of interaction between exposure concentration and genotype, and there was no enzymatic induction. In addition, Butler et al. (2001) measured serum cytochrome P2E1 activity; cytochrome P2E1 is an enzyme involved in benzene metabolism to benzene oxide and phenol. Phenol via cytochrome P2E1

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TABLE 7-1 Effects of JP-8 Exposure on the Liver in Humansa Reference Exposure Concentration Exposure Duration Results Snawder and Butler 2001 Measurements taken in breathing zones of subjects; median concentration of naphthalene, 1.9 μg/m3 (low-exposure group), 447 μg/m3 (high-exposure group); median concentration of benzene, 3.1 μg/m3 (low-exposure group), 242 μg/m3 (high-exposure group) High-exposure group had persistent exposure to JP-8 (defined as at least 1 hr twice per wk for 9 mo); low-exposure group had no significant exposure to jet fuel or solvents Concentrations of serum hepatic alpha-GST activity in study subjects were within normal range Butler et al. 2001 Measurements taken in breathing zones of subjects; median concentration of naphthalene, 1.9 μg/m3 (low-exposure group), 10.4 μg/m3 (moderate-exposure group), 447 μg/m3 (high-exposure group); median concentration of benzene, 3.1 μg/m3 (low-exposure group), 7.45 μg/m3 (moderate-exposure group), 242 μg/m3 (high-exposure group) High- and moderate-exposure groups had persistent exposure to JP-8; low exposure group had no significant exposure to jet fuel or solvents Frequency of CYP2E1 and NQOI genotypes was similar in subjects in all exposure groups; no change in enzymatic activity Gibson et al. 2001a Exposed group (5,706 people) had potential occupational exposure to JP-8. Control group (5,706 people) did not work in occupations in which exposure to JP-8 would occur Not reported Analysis of medical records showed that subjects in all groups had similar health-care visit rates; no differences were noted among groups in digestive ailments

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Reference Exposure Concentration Exposure Duration Results Gibson et al. 2001b Measurements taken in breathing zones of subjects; median concentration of naphthalene, 1.9 μg/m3 (low-exposure group), 10.4 μg/m3 (moderate-exposure group), 447 μg/m3 (high-exposure group); median concentration of benzene, 3.1 μg/m3 (low-exposure group), 7.45 μg/m3 (moderate-exposure group), 242 μg/m3 (high-exposure group) High- and moderate-exposure groups had persistent exposure to JP-8; low-exposure group had no significant exposure to jet fuel or solvents Analysis of self-assessment questionnaire did not report differences among groups in digestive ailments aData collected from volunteers (male and female active-duty Air Force personnel) at six Air Force bases in United States. Volunteers were divided into three exposure groups: high, moderate, and low. High-exposure group performed tasks associated with repairing aircraft fuel systems; moderate-exposure group performed tasks associated with fuel handling, distribution, recovery, and testing; and low-exposure group did not routinely come into contact with jet fuel or solvents. Data were collected in morning before subjects went to work and again after they completed their work for that day. Reported results are from preliminary analysis of data. Work referred to in table is part of larger study examining potential human health effects of acute exposure to JP-8. Additional background information can be found in Appendix B. Abbreviations: GST, glutathione-S-transferase; CYP2E1, cytochrome P2E1; NQO1, NAD(P)H quinone oxidoreductase.

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is oxidized to hydroquinone and other quinines, including benzoquinones. NAD(P)H quinone oxidoreductase (NQOI) then catalyzes conversion of benzoquinones to less-reactive metabolites. The frequency of the cytochrome P2E1 and NQOI genotypes was similar in subjects regardless of exposure concentration, and there was no change in enzymatic activity, so there was probably no hepatic metabolic induction. Data indicated that those sensitive measures of risk did not detect adverse effects of JP-8 at the assumed exposures on human liver function. Gibson et al. (2001a) examined the medical records of Air Force personnel occupationally exposed to JP-8 and compared them with records of an unexposed population. The data used were from a population of 5,706 (242 women and 5,464 men) in the exposed group and a population of 5,706 (2,853 men and 2,853 women) randomly chosen from a cohort of 20,244 Air Force personnel who were not occupationally exposed to JP-8. The total number of health-event visits was not markedly different between groups. There was no association between JP-8 exposure and specific neoplasia or digestive ailments. Furthermore, Gibson et al. (2001b) conducted a self-assessment questionnaire on 328 exposed people, categorized into high-, moderate-, and low-exposure groups (as described above). In both men and women, the incidence of digestive ailments was not markedly different between the exposed and referent groups. EFFECTS OF EXPOSURE TO JP-8 IN EXPERIMENTAL ANIMALS Several studies have been conducted to examine the potential adverse effects of JP-8 on liver function. Those studies are described below and summarized in Table 7-2. Parton (1994) subjected male F344 rats to nose-only inhalation exposure to JP-8 aerosols (average particle size was 1.1054 ± 0.2918 microns) at 500 or 1,000 mg/m3 for 1 hr/day for 7 or 28 days. Weight gain in the 28-day low-and high-dose groups was significantly decreased, but the final body weight was not markedly different between groups. Liver weights were not significantly different. There were no significant alterations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, indicators of hepatic function, and there were no marked changes in the liver histopathologic findings and cytochrome P450 content, a measure of xenobiotic metabolism. Mattie et al. (1991) exposed male and female F344 rats and male and female C57BL/6 mice to JP-8 vapor at 500 or 1,000 mg/m3 for 90 days. Only

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TABLE 7-2 Effects of Jet Fuel Exposure on the Liver in Experimental Animals Fuel Type Species Exposure Concentration Exposure Duration Effects Reference JP-8 Male, female F344 rats 500 or 1,000 mg/m3 (vapor) 90 days continuously Increased in liver weight and liver:body weight ratio, decreased in SGPT activity in males and females at 500 or 1,000 mg/m3; decreased alkaline phosphatase activity in males, increased alkaline phosphastase activity in females at 1,000 mg/m3 MacEwen and Vernot 1983, 1984, 1985 JP-8 Male F344 rats 500 or 1,000 mg/m3 (aerosol, nose-only) 1 hr/day for 7 or 28 days Body weight gain in rats exposed for 28 days was significantly decreased; final body weights of exposed animals were similar to those of control animals; liver weights not significantly different between groups; relative liver weight increased in high-dose groups; no significant alterations in AST and ALT activity; no marked changes in liver histopathologic findings and CYP450 content Parton 1994 JP-8 Male, female F344 rats, C57Bl/6 mice 500 or 1,000 mg/m3 (vapor) 90 days continuously Male rats had a statistically significant increase in hepatic basophilic foci. Their presence in the livers of male rats is of uncertain biological significance. No alterations were found in hepatic tissue of female rats or in mice Mattie et al. 1991

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JP-8 Male Sprague-Dawley rats 750, 1,500, or 3,000 mg/kg (gavage) 90 days consecutively Serum ALT and AST activity increased significantly in all groups, but increase was not dose-related; liver weight similar in all groups; increased relative tissue weight in high-exposure group; liver histologic findings similar in all groups (including control group) Mattie et al. 1995 JP-8 Male Sprague-Dawley Rats 1,000 mg/m3 (vapor, whole-body) 6 hr/day, 5 days/wk for 6 wk Hepatic lamin L83 abundance significantly decreased; lamin L603 abundance increased; total lamin A abundance not significantly altered by JP-8 exposure Witzman et al. 2000 JP-8 Female B6C3F1, DBA/2 mice 1 or 2 g/kg per day (oral gavage) 7 days Significantly increased body weights of B6C3F1 mice, but not DBA/2 mice; increased liver:body weight ratios in both strains; no marked change in expression of CYP1A1 Dudley et al. 2001 JP-5 Beagles, F344 rats, C57BL/6 mice 150 or 750 mg/m3 (vapor) 90 days continuously Reversible diffuse mild swelling of hepatocytes, decreased SGPT activity, increased liver weight in dogs; mild hepatic hyperplasia, increased hepatocyte vacuolization in rats; fatty changes in hepatocytes, increased hepatocytic vacuolization, increased liver adenomas in mice MacEwen and Vernot 1978, 1980, 1981, 1982, 1983, 1985; Gaworski et al. 1984

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Fuel Type Species Exposure Concentration Exposure Duration Effects Reference JP-4 Male, female F344 rats, C57BL/6 mice 1,000 or 5,000 mg/m3 (vapor) 6 hr/day, 5 day/wk for 12 mo Decreased liver weights, liver:body weight ratio, SGPT activity in male rats; decreased SGPT activity, presence of liver nodular hyperplasia in high-dose female rats; decreased incidence of adenomas in male high-dose mice; increased liver inflammatory infiltrates, incidence of hepatocellular adenomas in high-dose female mice MacEwen and Vernot 1981, 1982; Wall et al. 1990; Bruner et al. 1993 JP-4 Beagle dogs, F344 rats, and C57BL/6 mice 500 or 1,000 mg/m3 (vapor) 90 days continuously No effects in dogs; increased liver weight, decreased SGOT and SGPT activity in rats; increased hepatocellular fatty changes in mice MacEwen and Vernot 1984 JP-4 Monkeys, dogs, rats, mice 2,500 or 5,000 mg/m3 (vapor) 6 hr/day, 5 days/wk for 8 mo Increased liver weights; no histopathologic changes MacNaughton and Uddin 1984 Kerosene Rat 58 mg/m3 or 231 mg/m3 (vapor, possibly some aerosol) Subchronic (duration not specified) Decreased blood glucose at 58 mg/m3; increased blood lactate, pyruvate at 231 mg/m3 Starek and Vojtisek 1986 as cited in ATSDR 1998

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Kerosene Dogs, rats 100 mg/m3 (deodorized) 6 hr/day, 5 days/wk, 13 wk No histopathological changes in the livers of dogs and rats; no liver weight changes in dogs Carpenter et al. 1976 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CYP, cytochrome P; GST, glutathione-S-transferase; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase.

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in male rats were hepatic basophilic foci found—in livers of 11, 35, and 31% of control, low-dose, and high-dose groups, respectively. The increase in basophilic foci was statistically significant. Basophilic foci are not reliable predictors of potential hepatic carcinogenicity and their presence in the livers of the male rats is of uncertain biological significance. This finding is similar to the specific hyaline nephropathy found in male rats, which does not have biological relevance for humans (see Chapter 8). The observations that no other hepatic alterations were found in male rats and that no alterations were found in hepatic tissue of female rats or of mice diminish the biologic meaning of hepatic foci changes in male rat liver for humans. In a study by Mattie et al. (1995), Sprague-Dawley rats were given JP-8 daily for 90 days at 750, 1,500, or 3,000 mg/kg by oral gavage. Serum samples were collected 24 hr before sacrifice. Blood and tissue samples were obtained at sacrifice. With respect to hepatic function, serum ALT and AST activity increased significantly in all three groups, but the change was not dose-related. Liver weight was similar in all groups, and relative tissue weight increased only in high-exposure group. Liver histopathologic findings were similar in all dose groups, and not different from the control group. Dudley et al. (2001) administered JP-8 to female B6C3F1 and DBA/2 mice by oral gavage at 1 or 2 g/kg per day JP-8 for 7 days. Oral JP-8 was associated with a significant increase in body weight in the 1- and 2-g/kg groups of B6C3F1 mice but did not markedly affect body weight gain in DBA/2 mice. Liver weights were not reported, but both doses of JP-8 increased relative liver weight in both strains of mice. Measurement of hepatic cytochrome P1A1 with Western blot analyses revealed no marked change in expression. Reported tissue and body weight changes were not dose-related, and the doses used and the route of administration are of questionable relevance to occupationally-exposed humans. Witzmann et al. (2000) exposed male Sprague-Dawley rats to JP-8 aerosol with a mass median aerodynamic diameter of 1.7-1.9 mm (M. Witten, University of Arizona, personal communication, 2002) by inhalation for 6 hr/day, 5 days/wk for 6 wk. The concentration of JP-8 in the chamber was 1,000 mg/m3. Eighty-two days after exposure, there was no significant change in body weight, and the general health of the rats appeared normal. According to results of electrophoresis, protein mass “fingerprinting,” and sequence tag analysis, hepatic lamin L83 abundance was significantly decreased and lamin L603 abundance was increased. However, total lamin A abundance was not markedly altered by JP-8. Only one measurement time (82 hr after exposure) and one concentration were studied. The relevance of the Witzmann et al. (2000) findings for human risk assessment is not known.

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Several animal studies have examined the effect of kerosene, the primary substance in JP-8, on liver function. Reductions in blood glucose concentrations were noted in rats after subchronic inhalation of kerosene vapor (and possibly some aerosol) at a mean of 58 mg/m3 (Starek and Vojtisek 1986 as cited in ATSDR 1998). Increased blood lactate and pyruvate concentrations were observed in rats exposed to kerosene at a mean of 231 mg/m3, but not at a mean of 58 mg/m3. The authors speculate that decreased circulating glucose concentrations were associated with increased glycolysis and the inhibition of gluconeogenesis. The effect of kerosene on glycolysis is supported by the findings of increased concentrations of lactate and pyruvate in the blood and liver and increased lactate dehydrogenase activity in the liver. The authors suggested that increased glycolysis was a result of inhibition of cellular respiration by kerosene. In another study, rats and dogs were exposed to deodorized kerosene at 100 mg/m3 for 6 hr/day, 5 days/wk for 13 wk (Carpenter et al. 1976). No histopathologic changes were observed in the livers of the rats or dogs, and no liver weight changes were noted in the dogs. EFFECTS OF IN VITRO EXPOSURE TO JP-8 Grant et al. (2000) examined the in vitro cytotoxic potential of JP-8 in an H4IIE liver cell line. The H4IIE cell line is an established model used to assess hepatic function and responds to polycyclic aromatic hydrocarbons. In 72-hr viability assays, the concentration of JP-8 producing 50% inhibition (IC50) of growth in H4IIE cells was 12.6 ± 0.4 μg/mL. The relevance of the in vitro findings for humans is not known. CONCLUSIONS AND RECOMMENDATIONS In one experimental animal study, F344 rats and C57BL/6 mice continuously exposed to JP-8 vapors at concentrations up to 1,000 mg/m3 for up to 90 days did not show significant changes in hepatic function or structure. In another study, liver weights in male F344 rats exposed to JP-8 aerosols at up to 1,000 mg/m3 for 1 hr per day for 28 days were not significantly different from liver weights in control animals. There were no significant alterations in serum aspartate aminotransferase and alanine aminotransferase activities, indicators of hepatic function, and there were no marked changes in the liver histopathologic findings and cytochrome P450 content, a measure of xenobiotic metabolism. No liver toxicity was observed in rats and mice exposed to JP-4 vapors at up to 5,000 mg/m3 for 6 hr/day, 5 days/wk for 12 mo.

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The Subcommittee on Permissible Exposure Levels for Military Fuels, which wrote the 1996 National Research Council report Permissible Exposure Levels for Selected Military Fuel Vapors, used the latter study as a basis for derivation of the interim PEL. On the basis of a no-observed-adverse-effect level of 5,000 mg/m3 identified in rats given JP-4 and applying an uncertainty factor of 10 for interspecies extrapolation, the PEL was 500 mg/m3 (no intraspecies uncertainty factor was used). The subcommittee recommends that liver toxicity be evaluated in experimental animals exposed to JP-8 vapors and mixtures of vapors and aerosols by the inhalation route. Because inhalation exposures greater than approximately 1,000 mg/m3 for pure JP-8 vapors are difficult to achieve, the Air Force should consider conducting studies with saturated vapor atmospheres on larger numbers of animals or employ longer exposure durations (i.e., longer than 90 days) to increase the power of the studies for observing adverse responses in various organ systems. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 1998. Toxicological Profile for Jet Fuels (JP-5 and JP-8). U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. Bruner, R.H., E.R. Kinkead, T.P. O’Neill, C.D. Fleming, D.R. Mattie, C.A. Russell, and H.G. Wall. 1993. The toxicologic and oncogenic potential of JP-4 jet fuel vapors in rats and mice: 12-month intermittent inhalation exposures. Fundam. Appl. Toxicol. 20(1):97-110. 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. Carpenter, C.P., D.L. Geary Jr., R.C. Myers, D.J. Nachreiner, L.J. Sullivan, and J.M. King. 1976. Petroleum hydrocarbon toxicity studies. XI. Animal and human response to vapors of deodorized kerosene. Toxicol. Appl. Pharmacol. 36(3):443-456. Dosing, M., S. Loft, and E. Schroeder. 1985. Jet fuel and liver function. Scand. J. Work Environ. Health. 11(6):433-437. Dudley, A.C., M.M. Peden-Adams, J. EuDaly, R.S. Pollenz, and D.E. Keil. 2001. An aryl hydrocarbon receptor independent mechanism of JP-8 jet fuel immunotoxicity in Ah-responsive and Ah-nonresponsive mice. Toxicol. Sci. 59(2):251-259. Gaworski, C.L., J.D. MacEwen, E.H. Vernot, R.H. Bruner, and M.J. Cowan Jr. 1984. Comparison of the subchronic inhalation toxicity of petroleum and oil shale JP-5 jet fuels. Pp. 33-48 in Advances in Modern Environmental Toxicology, Vol. 6.

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Applied Toxicology of Petroleum Hydrocarbons, H.N. MacFarland, C.E. Holdworth, J.A. MacGregor, R.W. Call, and M.L. Lane, eds. Princeton, NJ: Princeton Scientific Publishers. Gibson, R.L., S. Shanklin, and R.L. Warner. 2001a. Health effects comparisons. Pp. 125-129 in JP-8 Final Risk Assessment Report. The Institute of Environmental and Human Health (TIEHH), Lubbock, TX. August 2001. Gibson, R.L., S. Shanklin, and R.L. Warner. 2001b. Self-reported health status. Pp. 132-139 in JP-8 Final Risk Assessment Report. The Institute of Environmental and Human Health (TIEHH), Lubbock, TX. August 2001. Grant, G.M., K.M. Shaffer, W.Y. Kao, D.A. Stenger, and J.J. Pancrazio. 2000. Investigation of in vitro toxicity of jet fuels JP-8 and jet A. Drug Chem. Toxicol. 23(1):279-291. MacEwen, J.D., and E.H. Vernot. 1978. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-78-55. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H. Vernot. 1980. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-80-79. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H. Vernot. 1981. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-81-126. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H. Vernot. 1982. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-82-62. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H. Vernot. 1983. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-83-64. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H. Vernot. 1984. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-84-001. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H. Vernot. 1985. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-85-058. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacNaughton, M.G., and D.E. Uddin. 1984. Toxicology of mixed distillate and high-energy synthetic fuels. Pp. 121-132 in Advances in Modern Environmental Toxicology, Vol. 7. Renal Effects of Petroleum Hydrocarbons, M.A. Mehlman, G.P. Hemstreet III, J.J. Thorpe, and N.K. Weaver, eds. Princeton, NJ: Princeton Scientific Publishers. Mattie, D.R., C.L. Alden, T.K. Newell, C.L. Gaworski, and C.D. Flemming. 1991. A 90-day continuous vapor inhalation toxicity study of JP-8 jet fuel followed by 20 or 21 months of recovery in Fischer 344 rats and C57BL/6 mice. Toxicol. Pathol. 19(2):77-87. Mattie, D.R., G.B. Marit, C.D. Flemming, and J.R. Cooper. 1995. The effects of JP-8 jet fuel on male Sprague-Dawley rats after a 90-day exposure by oral gavage. Toxicol. Ind. Health 11(4):423-435.

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NRC (National Research Council). 1996. Permissible Exposure Levels for Selected Military Fuel Vapors. Washington, DC: National Academy Press. Parton, K.H. 1994. The Effects of JP-8 Jet Fuel Inhalation on Liver and Kidney Function in Male F-344 Rats. M.S. Thesis, University of Arizona. 76pp. Snawder, J.E., and M.A. Butler. 2001. Sensitive early indicators of hepatic and kidney damage in workers exposed to jet fuel. Pp. 81-86 in JP-8 Final Risk Assessment Report. The Institute of Environmental and Human Health (TIEHH), Lubbock, TX . August 2001. Starek, A., and M. Vojtisek. 1986. Effects of kerosene hydrocarbons on tissue metabolism in rats. Pol. J. Pharmacol. Pharm. 38(5-6):461-469. Wall, H.G., A. Vingegar, and E.R. Kinkead. 1990. Evaluation of Toxic Effects in Rats and Mice Exposed to JP-4 Vapor for One Year. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-90-063. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. Witzmann, F.A., R.L. Carpenter, G.D. Ritchie, C.L. Wilson, A.F. Nordholm, and J. Rossi III. 2000. Toxicity of chemical mixtures: Proteomic analysis of persisting liver and kidney protein alterations induced by repeated exposure of rats to JP-8 jet fuel vapor. Electrophoresis 21(11):2138-2147.