Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
7 Effects of Jet-Propulsion Fuel 8 on the Liver This chapter summarizes the findings on potential hepatic toxicity of jet-pro- pulsion fuel 8 (JP-8) and related fuels presented in the National Research Council report Perm issible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) and reviews additional stud ies, 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 hum an liver. SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT The National Research Council Subcommittee on Perm issible Exposure Levels for M ilitary Fuel V apors reviewed studies concerning potential hepatic changes associated with exposure to the vapors of JP-8, JP-4, JP5, or diesel fuel m arine (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/m 3 for a mean of 6.4 years had a significantly faster antipyrine clear- ance (68 mL/min) than an referent population of office workers (58 m L/m in). 86
Effects of Jet-Propulsion Fuel 8 on the L iver 87 No marked differences were found in serum aspartate aminotransferase and alkaline phosphatase activity between the two groups. No studies were avail- able that report the effects of JP-8, JP-5, or DFM vapors on the liver in hu- mans. 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/m 3 for 90 days. Som e 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/m 3, decreases in serum glutamic- pyruvic transaminase (SGPT) activity at 500 and 1,000 mg/m 3, and decreases in alkaline phosphatase activity at 1,000 mg/m 3; and female rats showed in- creases in liver weights and liver:body weight ratios at 500 and 1,000 mg/m 3, increases in alkaline phosphatase activity at 1,000 mg/m 3, and decreases in SGPT activity at 500 and 1,000 mg/m 3. Nine months after exposure, male rats showed decreases in SGPT activity at 500 and 1,000 mg/m 3. Twenty-one months after exposure, male rats show ed concentration-related increases in liver:body weight ratios at 500 and 1,000 mg/m 3; and female rats showed decreases in serum glutamic oxaloacetic transaminase (SGOT) activity at 500 mg/m 3 and decreases in SGPT activity at 500 and 1,000 mg/m 3. 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 examina- tions 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 inhala- tion 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/m 3 for 90 days (MacEwen and Vernot 1978, 1980, 1981, 1982, 1983, 198 5; 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/m 3 for 90 days (MacEw en and
88 Toxicologic A ssessment of Jet-Propulsion F uel 8 Vernot 1984); in F344 rats and C57BL/6 mice exposed to JP-4 vapor at 1,000 or 5,000 mg/m 3 for 6 hr/day, 5 days/wk for 12 mo (Bruner et al. 1993; W all 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/m 3 for 6 hr/day, 5 days/wk for 8 mo (M acNau ghton 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 exam- ined in a study recently com pleted by the U.S. Air Force. The preliminary results of that study are described below and sum marized 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 A FB, Arkansas; and Hurlbert Field, Florida. The exposed workers were fuel tank-entry personnel with at least 9 mo of persis- tent exposure to jet fuel (defined as 1-hr entry, twice a week). The unexposed group consisted of Air Force personnel w ho routinely had no significant expo- sure to solvents or fuels. The participants completed questionnaires on job category, exposure, and medical and dem ographic 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 com mercial imm unoassay 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 nor- mally 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 ben- zene metabolism to benzene oxide and phenol. Phenol via cytochrome P2E1
TABLE 7-1 Effects of JP-8 Exposure on the Liver in Humansa Reference Exposure Concentration Exposure Duration Resu lts Snawder and Measurements taken in breathing zones of High-exposure group had Concentrations of serum Butler 2001 subjects; median concentration of persistent exposure to JP-8 hepatic alpha-G ST activity naphthalene, 1.9 :g/m 3 (low-exposure grou p), (defined as at least 1 hr twice in study subjects were 447 :g/m 3 (high-exposure group); median per wk for 9 mo); low-exposure within normal range concentration of benzene, 3.1 :g/m 3 (low- group had no significant exposure group), 242 :g/m 3 (high-exposure exposure to jet fuel or solvents group) Butler et al. Measurements taken in breathing zones of High- and mod erate-exposure Frequency of CYP2E1 2001 subjects; median concentration of groups had persistent exposure and NQO I genotypes was naphthalene, 1.9 :g/m 3 (low-exposure grou p), to JP-8; low exposure group similar in su bjects in all 10.4 :g/m 3 (moderate-exposure group), 447 had no significant expo sure to exposure groups; no :g/m 3 (high-exposure group); median jet fuel or so lvents change in enzym atic concentration of benzene, 3.1 :g/m 3 (low- activity exposure group), 7.45 :g/m 3 (moderate- exposure group), 242 :g/m 3 (high-exposure group) Gibson et al. Exposed group (5,706 people) had potential Not reported Analysis of medical 2001a occupational exposure to JP-8. Control group records showed that (5,706 people) did not w ork in occup ations in subjects in all groups had which exposure to JP-8 would occur similar health-care visit rates; no differences were noted am ong grou ps in digestive ailments (Continued) 89
90 TABLE 7-1 Continued Reference Exposure Concentration Exposure Duration Resu lts Gibson et al. Measurements taken in breathing zones of High- and mod erate-exposure Analysis of self- 2001b subjects; median concentration of naphthalene, groups had persistent exposure assessment 1.9 :g/m 3 (low-exposure group), 10.4 :g/m 3 to JP-8; low-exposure group had questionnaire did not (moderate-exposure group), 447 :g/m 3 (high- no significant exposure to jet report differences exposure group); median concentration of fuel or so lvents am ong grou ps in benzene, 3.1 :g/m 3 (low-exposure group), 7.45 digestive ailments :g/m 3 (moderate-exposure group), 242 :g/m 3 (high-exposure grou p) a Data co llected from volunteers (male and fem ale active-duty A ir Force person nel) at six Air Force bases in U nited 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. Ad dition al background information can be fo und in Appendix B. Abbreviations: GST, glutathione-S-transferase; CYP2E1, cytochrome P2E1; NQO1, NAD (P)H quinone oxidoreductase.
Effects of Jet-Propulsion Fuel 8 on the L iver 91 is oxidized to hydroquinone and other quinines, including benzoquinones. NA D(P)H quinone oxidoreductase (NQOI) then catalyzes conversion of benzoquinones to less-reactive metabolites. The frequency of the cytochrome P2E1 and N QO I genotypes w as 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 expo- sures 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 unex- posed population. The d ata used were from a population of 5,706 (242 wom en and 5,464 men) in the exposed group and a population of 5,706 (2,853 men and 2,853 wom en) randomly chosen from a cohort of 20,244 Air Force per- sonnel 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 w omen, the incidence of diges- tive ailments was not markedly different between the exposed and referent groups. EFFECT S OF EXPO SURE 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 sum- marized 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 m icrons) at 500 or 1,000 mg/m 3 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 signifi- cantly different. There were no significant alterations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, indica- tors of hepatic function, and there were no marked changes in the liver histopathologic findings and cytochrome P450 content, a measure of xenobi- otic metabolism. Mattie et al. (1991) exposed male and female F344 rats and male and female C57BL/6 m ice to JP-8 vapor at 500 or 1,000 mg/m 3 for 90 days. Only
92 TABLE 7-2 Effects of Jet Fuel Exposure on the Liver in Experimental Animals Exposu re Exposu re Fuel Type Species Concentration Duration Effec ts Reference JP-8 Male, female 500 or 1,000 90 days Increased in liver weight and liver:body MacEwen and F344 rats mg/m 3 (vapor) continuo usly weight ratio, decreased in SG PT activity in Vernot 1983, males and females at 500 or 1,000 mg/m 3; 1984, 1985 decreased alkaline phosp hatase activity in males, increased alkaline phosphastase activity in females at 1,000 mg/m 3 JP-8 Male F344 500 or 1,000 1 hr/day for 7 Body weight gain in rats exposed for 28 days Parton 1994 rats mg/m 3 or 28 days was significantly decreased; final body (aerosol, nose- weigh ts of exposed anim als were similar to only) those of control animals; liver weights not significantly different between grou ps; relative liver weight increased in high-do se groups; no significant alterations in AST and ALT activity; no marked changes in liver histopathologic findings and CYP450 content JP-8 Male, female 500 or 1,000 90 days Male rats had a statistically significant Mattie et al. F344 rats, mg/m 3 (vapor) continuo usly increase in hepatic basophilic foci. T heir 1991 C57Bl/6 mice 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
JP-8 Male Sprague- 750, 1,500, or 90 days Serum ALT and A ST activity increased Mattie et al. Dawley rats 3,000 mg/kg consecutively significantly in all groups, but increase was 1995 (gavage) not d ose-relate d; liver weight sim ilar in all grou ps; increased relativ e tissue weight in high-exp osure group ; liver histologic findings similar in all groups (including control group) JP-8 Male Sprague- 1,000 mg/m 3 6 hr/day, 5 He patic lamin L83 abun dan ce significantly Witzman et al. Dawley Rats (vapor, whole- days/w k for 6 decreased; lamin L603 abundance increased; 2000 body) wk total lamin A abundance not signific antly altered by JP-8 exposure JP-8 Female 1 or 2 g/kg per 7 days Significantly increased body weights of Dudley et al. B6C3F1, day (oral B6C3F1 m ice, but not DBA/ 2 mice; 2001 DBA /2 mice gavage) increased liver:body weight ratios in both strains; no marked change in expression of CYP1A1 JP-5 Beagles, F344 150 or 750 90 days Reversible diffuse mild swelling of MacEwen and rats, mg/m 3 (vapor) continuo usly hepatocytes, decreased SGPT activity, Vernot 1978, C57BL/6 increase d liver weight in dogs; mild hepatic 1980, 1981, mice hyperplasia, increased hepatocyte 1982, 1983, vacuolization in rats; fatty changes in 1985; Gaworski hepatocytes, increased hepatocytic et al. 1984 vacuolization, increased liver adenom as in mice (Continued) 93
94 TABLE 7-2 Continued Exposu re Exposu re Fuel Type Species Concentration Duration Effec ts Reference JP-4 Male, female 1,000 or 5,000 6 hr/day, 5 Decreased liver weights, liver:body weight MacEwen and F344 rats, mg/m 3 (vapor) day/wk for 12 ratio, SGPT activity in male rats; decreased Vernot 1981, C57BL/6 mo SGPT activity, presence of liver nodular 1982; W all et al. mice hyperplasia in high-dose female rats; 1990; Bruner et decreased incidence of adenom as in m ale al. 1993 high-dose m ice; increased liver inflamm atory infiltrates, incidence of hepatocellular adenomas in high-dose female mice JP-4 Beagle dogs, 500 or 1,000 90 days No effects in d ogs; increased liver weight, MacEwen and F344 rats, and mg/m 3 (vapor) continuo usly decreased SG OT and SG PT ac tivity in rats; Vernot 1984 C57BL/6 increase d he patocellular fatty changes in mice mice JP-4 Monkeys, 2,500 or 5,000 6 hr/day, 5 Increase d liver weights; no histo pathologic MacNaughton dogs, rats, mg/m 3 (vapor) days/w k for 8 changes and Ud din mice mo 1984 Kerosene Rat 58 mg/m 3 or Subchronic Decreased blood glucose at 58 mg/m 3; Starek and 231 mg/m 3 (duration not increased blood lactate, pyruvate at 231 Vojtisek 1986 (vapor, specified) mg/m 3 as cited in possibly some ATSD R 1998 aerosol)
Kerosene Dogs, rats 100 mg/m 3 6 hr/day, 5 No histopathological changes in the livers of Carpenter et al. (deodorized) days/wk, 13 dogs and rats; no liver weight changes in 1976 wk dogs Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CYP, cytochrome P; GST, glutathione-S-transferase; SG OT, serum glutamic oxaloacetic transam inase; SG PT , serum glutamic pyruvic tran sam inase. 95
96 Toxicologic A ssessment of Jet-Propulsion F uel 8 in male rats were hepatic basophilic foci foundâin 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 m ale rats is of uncertain biological significance. This find ing 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 w ere found in male rats and that no alterations w ere found in hepatic tissue of female rats or of mice diminish the biologic meaning of hepatic foci changes in m ale rat liver for hum ans. 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 A LT and AST activity increased significantly in all three groups, but the change was not dose-related. Liver weight w as 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 in- creased relative liver weight in both strains of mice. Measurement of hepatic cytochrome P1A1 with W estern blot analyses revealed no m arked 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 rele- vance to occupationally-exposed humans. Witzmann et al. (2000) exposed male Sprague-Dawley rats to JP-8 aerosol with a m ass m edian aerodynamic diameter of 1.7-1.9 mm (M. Witten, University of A rizona, personal com mu ni- cation, 2002) by inhalation for 6 hr/day, 5 days/wk for 6 wk. The concentra- tion of JP-8 in the chamber was 1,000 mg/m 3. 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 âfingerprinting,â and sequence tag analysis, hepatic lamin L83 abundance was significantly decreased and lam in L603 abundance was increased. However, total lamin A abundance was not markedly altered by JP-8. Only one measure- ment time (82 hr after exposure) and one concentration were studied. The relevance of the W itzm ann et al. (2000) findings for hum an risk assessment is not known.
Effects of Jet-Propulsion Fuel 8 on the L iver 97 Several animal studies have examined the effect of kerosene, the primary substance in JP-8, on liver function. Red uctions in blood glucose concentra- tions were noted in rats after subchronic inhalation of kerosene vapor (and possibly some aerosol) at a mean of 58 mg/m 3 (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/m 3, but not at a mean of 58 mg/m 3. The authors speculate that decreased circulating glucose concentrations were associated with increased glycolysis and the inhibi- tion 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 respira- tion by kerosene. In another study, rats and dogs were exposed to deodorized kerosene at 100 mg/m 3 for 6 hr/day, 5 days/wk for 13 w k (Carpenter et al. 1976). No histopathologic changes were observed in the livers of the rats or dogs, and no liver w eight changes were noted in the dogs. EFF ECTS O F IN VIT RO EXPOSUR E 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 arom atic hydrocarbons. In 72-hr viability assays, the concentration of JP-8 producing 50% inhibition (IC 50) of growth in H4IIE cells was 12.6 ± 0.4 :g/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 continu- ously exposed to JP-8 vapors at concentrations up to 1,000 mg/m 3 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/m 3 for 1 hr per day for 28 days were not significantly different from liver weights in control anim als. There were no significant alterations in serum aspartate aminotransferase and alanine am inotransferase activities, indicators of hepatic function, and there were no marked changes in the liver histopathologic findings and cytochrome P450 content, a measure of xenobi- otic metabolism. No liver toxicity was observed in rats and mice exposed to JP-4 vapors at up to 5,000 mg/m 3 for 6 hr/day, 5 days/wk for 12 mo.
98 Toxicologic A ssessment of Jet-Propulsion F uel 8 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 deriva- tion of the interim P EL . On the basis of a no-observed-adverse-effect level of 5,000 mg/m 3 identified in rats given JP-4 and applying an uncertainty factor of 10 for interspecies extrapolation, the PEL was 500 mg/m 3 (no intraspecies uncertainty factor was used). The subcom mittee recom mends that liver toxicity be evaluated in experi- mental animals exposed to JP-8 vapors and mixtures of vapors and aerosols by the inhalation route. Because inhalation exposures greater than approxi- mately 1,000 mg/m 3 for pure JP-8 vapors are difficult to achieve, the Air Force shou ld consider conducting studies with saturated vapor atmospheres on larger num bers 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 system s. 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 Su bstances and Disease R egis- try, Atlanta, GA. Brune r, R.H ., E.R. Kinkead, T.P. OâNeill, C.D. Fleming, D.R. Mattie, C.A. Russell, and H.G. Wall. 199 3. The toxicologic and oncogenic potential of JP-4 jet fuel vapors in rats and mice: 12-month interm ittent inhalation exposure s. 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 intera ctions and exposure to JP8 jet fuel. Pp. 76-80 in JP8 Final Risk Assessme nt. The Institute of Environmental and Hu man Health (TIEH H), Lubbock, TX. August 2001. Carpenter, C.P., D.L. Geary Jr., R.C. Myers, D.J. Nachreiner, L.J. S ullivan, and J.M. King. 1976. Petroleum hyd rocarbon 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. Scan d. 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 imm unotoxicity in Ah-respon sive and Ah-non responsiv e m ice. Toxicol. Sci. 59(2):251-259. Gaworski, C.L., J.D. MacEw en, 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.
Effects of Jet-Propulsion Fuel 8 on the L iver 99 Applied Toxicology of Petroleum Hydrocarbons, H.N. MacFarland, C .E. Holdworth, J.A. M acG rego r, R.W . Call, and M.L. Lane, eds. Princeton, NJ: Princeton Scientific Publishers. Gibson, R.L., S. Sha nklin, and R.L. Wa rner. 2001a. H ealth effects co mparisons. Pp. 125-129 in JP-8 Final Risk Assessment Report. The Institute of Environmental and Human H ealth (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 H ealth (TIEHH), Lubbock, TX. August 2001. Gra nt, G.M ., K.M. Shaffer, W.Y. Kao, D.A. Stenge r, and J.J. Pancrazio. 2000. Inves- tigation of in vitro toxicity of jet fuels JP-8 and jet A. Drug C hem . Tox icol. 23(1):279-291. MacEwen, J.D., and E.H . Vernot. 1978. Toxic Hazards Research Unit Annual Tech- nical 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 Tech- nical Report. AM RL-T R-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 Tech- nical Report. AM RL-T R-81-126. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H. Vernot. 1982. To xic H azards R esea rch Unit Annual Tech- nical Report. AMR L-TR-82-62. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H. Vernot. 1983. Tox ic Hazards R esea rch Unit Annual Tech- nical Report. AMR L-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 Tech- nical Report. AM RL-T R-84-001. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacEwen, J.D., and E.H . Vernot. 1985. To xic Hazards Research Unit Annual Tech- nical Report. AM RL-T R-85-058. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. MacNaughton, M.G., and D.E . Ud din. 1984. Toxicology of mixed distillate and high- energy synth etic fuels. Pp. 121-132 in A dvances in M odern Environm ental Toxi- cology, 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. Flemm ing. 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 m ice. Toxicol. Pathol. 19(2 ):77-8 7. 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.
100 Toxicologic A ssessment of Jet-Propulsion F uel 8 NRC (National Research Council). 1996. Permissible Exposure Levels for Selected Military Fuel V apors. Washington, DC: National Acad emy Press. Parton, K.H. 1994. The Effects of JP-8 Jet Fuel Inhalation on Liver and Kidney Function in M ale F -344 Rats. M .S. Th esis, University of Arizona. 76pp. Snawder, J.E., and M.A. Bu tler. 2001. Sensitive early indicators of he patic and kidney damage in workers expose d to jet fuel. Pp. 81-86 in JP-8 Final Risk Assessment Rep ort. The Institute of Environmental and Hum an Health (TIEHH), Lubbock, TX. August 2001. Starek, A., and M. Vojtisek. 1986. Effects of kerosene hydrocarbons on tissue metab- olism 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 E xposed to JP-4 Vapor for One Y ear. Toxic H azards R esea rch Unit Annual Technical Report. AMR L-TR-90-063. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, OH. Witzmann, F.A., R.L. Carpenter, G.D . Ritch ie, C.L. W ilson, A.F. Nordh olm, and J. Rossi III. 2000. Toxicity of chemical mixtures: Proteom ic analysis of persisting liver and kidney protein alterations induced by re peated exposure of rats to JP-8 jet fuel vapor. Electrophoresis 21(11):2138-2147.
