8
Effects of Jet-Propulsion Fuel 8 on the Kidney

This chapter summarizes the findings on kidney 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 kidney in humans.

SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT

The National Research Council Subcommittee on Permissible Exposure Levels for Military Fuels reviewed studies on the toxic effects of the vapors of JP-5, JP-8, and diesel fuel marine (DFM) on the kidney (NRC 1996).

That subcommittee reported that data on potential adverse health effects of JP-8 on the kidney were sparse. No human studies had examined kidney toxicity of JP-8. An acute exposure to hydrocarbon-based solvents at high concentrations (doses not specified) has been reported in a case study to produce kidney failure (Beirne and Brennan 1972); the authors reported that a



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8 Effects of Jet-Propulsion Fuel 8 on the Kidney This chapter summarizes the findings on kidney 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 kidney in humans. SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT The National Research Council Subcommittee on Permissible Exposure Levels for Military Fuels reviewed studies on the toxic effects of the vapors of JP-5, JP-8, and diesel fuel marine (DFM) on the kidney (NRC 1996). That subcommittee reported that data on potential adverse health effects of JP-8 on the kidney were sparse. No human studies had examined kidney toxicity of JP-8. An acute exposure to hydrocarbon-based solvents at high concentrations (doses not specified) has been reported in a case study to produce kidney failure (Beirne and Brennan 1972); the authors reported that a

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person exposed to jet fuel (type and dose not specified) while fueling aircraft in the U.S. Air Force had mild, reversible focal glomerulonephritis. One animal study that examined potential adverse effects of JP-8 exposure on the kidney was identified. Mattie et al. (1991) showed that exposure to JP-8 causes kidney lesions in male rats. Male and female F344 rats and C57BL/6 mice were exposed to JP-8 vapor at 500 or 1,000 mg/m3 for 90 days. After the 90-day exposure, a triad of lesions were found in the kidneys of male rats: dramatically exacerbated hyalin droplet formation, granular casts in the outer medulla, and increased incidence and severity of lesions undifferentiable from those of chronic progressive nephrosis. No such lesions were observed in female rats. In the male and female mice, no histopathologic lesions related directly to JP-8 were found. The increased incidence and severity of chronic progressive nephrosis persisted throughout the remainder of the lifetimes of the male rats. The kidney changes observed after 90 days were not reversible and were progressive. The severity of lesions was greater after the higher exposure. No kidney tumors were found in the study. No other animal studies of the effects of JP-8 on kidneys were identified in the 1996 report. Several studies that examined kidney toxicity of jet fuels other than JP-8 were described in the 1996 report (Parker et al. 1981; Bogo et al. 1983; MacEwen and Vernot 1985; Bruner et al. 1993). The results of those studies were consistent with the results of the Mattie et al. (1991) study. Male rats exposed to JP-4, JP-5, or DFM vapors developed kidney lesions consistent with hyaline droplet degeneration and resembling what is known as alpha 2u-globulin nephropathy. The mechanisms that underlie the development of that lesion are believed to occur only to male rats. The 1996 subcommittee concluded that the lesion is not expected to occur in humans. EFFECTS OF EXPOSURE TO JP-8 IN HUMANS The effects of exposure to JP-8 on the human kidney 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 8-1. Snawder and Butler (2001) collected venous blood and urine from 107 people who worked at six U.S. Air Force bases (AFBs): 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 persistent exposure to jet fuel (defined as a 1-hr entry twice a week for at least 9 months). The unexposed group consisted of Air Force personnel who had no important occupational exposure to hydrocarbon solvents or fuels. The participants

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TABLE 8-1 Effects of JP-8 Exposure on the Kidney 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 a wk for 9 mo); low-exposure group had no significant exposure to jet fuel or solvents Concentrations of urinary neph-alpha GST and pi-GST in subjects in 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 Analysis of CYP2EI, GSTT1, and NQO1 genotype data showed no statistically significant interaction between those genotypes, alpha-GST or pi-GST, and JP-8 exposure 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

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Reference Exposure Concentration Exposure Duration Results   differences among groups in kidney-related conditions 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 kidney-related conditions 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; low-exposure group does not routinely come into contact with jet fuel or solvents. Data were collected in morning before subjects went to work and after they completed their work for the day. Reported results are from preliminary analysis of data. Additional background information about these studies can be found in Appendix B. Abbreviations: GST, glutathione-S-transferase; CYP2E1, cytochrome P 2E1; NQO1, NAD(P)H quinone oxidoreductase.

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completed questionnaires providing job category, exposure level, and medical and demographic features. The exclusion criteria for participants were the presence of autoimmune disease, cancer, or diabetes and the use of immune-system altering drugs. Blood and urinary samples were collected before and after the shift at the AFB and shipped to a National Institute for Occupational Safety and Health laboratory in Cincinnati, Ohio, for analysis. The markers of renal damage included urinary neph-alpha glutathione S-transferase (GST), an index of proximal epithelial cell function; pi-GST, an index of distal tubule epithelial cell function; and creatinine, a marker of renal function. With commercial immunoassay kits, the concentrations of urinary neph-alpha GST and pi-GST in control and exposed subjects were within the normal range. Butler et al. (2001) further categorized exposed workers into three groups. The high-exposure group comprised subjects routinely performing tasks associated with repair of aircraft fuel systems; the moderate-exposure group comprised subjects involved in fuel handling, distribution, recovery, and testing; and the low-exposure group does not normally come into contact with jet fuel. There was no statistically significant change in urinary alpha-GST or pi-GST concentrations among any of the groups. Genotype was not considered a factor in renal response to JP-8 exposure in humans. The creatinine concentrations in urine of exposed personnel after the shift were higher than the creatinine concentrations in urine of unexposed subjects. However, even the highest urinary creatinine concentrations were within the normal clinical range; they were often indicative of mild dehydration. Data indicated that those sensitive measures of risk did not detect any adverse effect of acute JP-8 exposure on human renal function. Gibson et al. (2001a) examined the medical records of Air Force personnel occupationally exposed to JP-8 (5,706 people—242 women, 5,464 men) and compared them with records of unexposed personnel (5,706 people randomly selected from a population of 20,244 unexposed people). All were active-duty members of the Air Force. A preliminary assessment of data showed that the total number of medical visits and the types of specific diseases—including circulatory, cardiovascular, and urogenital—were not markedly different between groups. Gibson et al. (2001b) also conducted a self-assessment questionnaire survey of 328 exposed people, categorized into high-, moderate-, and low-exposure groups (as described above). A preliminary assessment of data showed that, in both men and women, the incidences of genitourinary, circulatory, and cardiovascular illnesses were not different between the groups.

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EFFECTS OF EXPOSURE TO JP-8 IN EXPERIMENTAL ANIMALS In addition to the studies summarized above, experimental-animal studies have been conducted to examine the effects of JP-8 exposure on renal function; they are described below and summarized in Table 8-2. Parton (1994) subjected male F344 rats to nose-only exposure to JP-8 aerosol (average particle size was 1.1054 ± 0.2918 mm) for 1 hr/day for 7 or 28 days at 500 mg/m3 (low-dose group) or 1,000 mg/m3 (high-dose group). Body weight gain in the 28-day groups was significantly reduced compared to controls, but the final body weights of the exposed groups were not markedly different from those of the concurrent control group. Kidney weights were not significantly different between exposed and control groups. However, the relative kidney weight was increased in the low- and high-dose groups exposed for 7 days and in the high-dose group exposed for 28 days. There was no significant change in renal weight for the low-dose group exposed for 28 days. Histologic examination showed that the changes in relative kidney weight were accompanied by an increase in hyalin droplet formation and in alpha 2u-globulin levels. There was no significant effect of JP-8 exposure on blood urea nitrogen measurements between exposed and concurrent control groups. The increase in relative kidney weight reflects the increase in alpha 2u-globulin, but renal function was not compromised. The hyalin droplet formation associated with alpha 2u-microglobulin is gender- and species-specific with no relevance to humans (Flamm and Lehman-McKeeman 1991). Mattie et al. (1995) administered JP-8 to Sprague-Dawley rats by oral intubation at 750, 1,500, or 3,000 mg/kg/day for 90 consecutive days. Urine simples were collected 24 hr before sacrifice. Blood and tissue samples were obtained at sacrifice. With respect to renal function, serum sodium and chloride concentrations increased only in the high-dose group. Serum creatinine concentrations increased in the low- and middle-dose groups but not in the high-dose group; however, urinary creatinine and protein concentrations were not significantly altered by JP-8. Urinary pH was significantly lower in the middle- and high-dose groups. The absolute renal weights were not altered in the exposed groups, but a significant increase in kidney:body weight ratio was found in the middle- and high-dose groups. The increase in renal weight was associated histopathologically with the accumulation of hyalin droplets in the cytoplasm of epithelial cells in the proximal convoluted tubules. The renal-function test result changes were not dose-related, and the histopathologic

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TABLE 8-2 Effects of Jet Fuel Exposure on the Kidney in Experimental Animals Fuel Type Species Exposure Concentration Exposure Duration Effects Reference JP-8 Male and female F344 rats, male and female C57BL/6 mice 500 or 1,000 mg/m3 (vapors, whole-body) 90 days continuously Kidney lesions (hyalin droplets, granular casts in outer medulla, nephrosis) in male rats only; no kidney toxicity in female rats or male and female mice Mattie et al. 1991 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 significantly decreased; final body weights of exposed animals similar to those of control animals; relative kidney weight increased in animals exposed for 7 days and in animals exposed at high dose for 28 days; changes in relative kidney weight associated with increase in hyalin droplet formation and in alpha-2u-globulin; renal function not compromised Parton 1994 JP-8 Male Sprague-Dawley rats 750, 1,500, or 3,000 mg/kg (by gavage) 90 days consecutively Serum sodium and chloride concentrations increased in highest-dose group; serum creatinine concentrations increased in low-and middle-dose groups (but not in high-dose group); urinary creatinine and protein concentrations not significantly altered by exposure; urinary pH significantly lower in the middle- and high-dose groups; exposure did not alter absolute renal weights but produced Mattie et al. 1995

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Fuel Type Species Exposure Concentration Exposure Duration Effects Reference   significant increase in kidney: body weight ratio in the middle- and high-dose groups; increased renal weight caused by accumulation of hyalin droplets   JP-8 Male Swiss-Webster mice 1,000 mg/m3 (aerosol, nose-only) 1 hr/day for 5 days Exposure significantly altered abundance of 56 proteins; concentrations of 21 proteins increased, concentrations of 35 proteins decreased, compared with controls Witzmann et al. 2000a JP-8 Male Sprague-Dawley rats 1,000 mg/m3 (vapor, whole-body) 6 hr/day, 5 days/wk for 6 wk Renal GST homolog and 10-formyltetrahydrofate dehydrogenase increased in charge modification index; no change in abundance Witzmann et al. 2000b JP-8, JP-5 Male and female C3Hf/Bd mice Undiluted or 50% diluted in cyclohexane (dermal) 3 applications/ wk for 60 wk Exposure produced significant increase in water consumption; animals treated with undiluted fuels had significantly increased number of kidney lesions Easley et al. 1982 JP-5 Rats 24 mL/kg of body weight (by gavage) 1 dose LD50 about 60 mL/kg or higher; cytoplasmic droplets occurred in kidneys of male rats; serum creatinine and blood urea nitrogen increased in male rats Parker et al. 1981; Bogo et al. 1983

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JP-5 Rats, mice 150 or 750 mg/m3 (vapor) 90 days continuously More than 75% of male rats exposed at either concentration showed nephrosis and tubular damage; no kidney toxicity in mice MacEwen and Vernot 1985 JP-4 Male and female F344 rats, C57BL/6 mice 1,000 or 5,000 mg/m3 (vapor) 6 hr/day, 5 day/wk for 12 mo Alpha-2u-globulin nephropathy occurred in males rats only; no kidney toxicity in mice Bruner et al. 1993 Abbreviations: GST, glutathione-S-transferase; LD50, dose that is lethal to 50% of the test animals.

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alterations are not relevant for human health risk assessment (Flamm and Lehman-McKeeman 1991). Easley et al. (1982) dermally exposed male and female C3Hf/Bd mice to undiluted or diluted (50% weight/volume dilution in cyclohexane) JP-8 or JP-5 three times per week for 60 wk. After 30 wk, the mice exposed to JP-8 and JP-5 had significantly increased water consumption. After 60 wk, the animals treated with undiluted JP-8 and JP-5 had a significant increase in number of kidney lesions, compared with the control animals. Witzmann et al. (2000a) exposed male Swiss-Webster mice to JP-8 aerosol with a median mass aerodynamic diameter (MMAD) of 1.7-1.9 μm (M. Witten, University of Arizona, personnel communication, 2002) by nose-only inhalation. The total daily exposure time was 1 hr for a total of 5 days at an average JP-8 concentration of 1,000 mg/m3. Control mice were subjected to ambient air. By means of various techniques—including electrophoresis, protein digestion, matrix-assisted laser desorption and ionization mass spectrometric protein identification, and sequence tagging with electrospray mass spectrometry—JP-8 exposure was shown to alter the abundance of 56 proteins. The concentrations of 21 proteins increased, and the concentrations of 35 proteins decreased; these 56 proteins accounted for 6% of all total resolved proteins. Only a single time-point and only one concentration were used, and the relevance of the findings to human health risk is not established. In a later study, Witzmann et al. (2000b) exposed male Sprague-Dawley rats to JP-8 for 6 hr/day, 5 days/wk for 6 wk. The concentration of JP-8 in the exposure chamber was 1,000 mg/m3. Eighty-two days after exposure, there was no change in body weights, and the general health of the rats appeared normal. By means of electrophoresis, protein mass “fingerprinting,” and sequence tag analysis, renal GST homolog and 10-formyltetrahydrofate dehydrogenase showed an increase in charge modification index but not in abundance. Only a single measurement time (82 hr after exposure) and a single concentration of JP-8 were used. The relevance of these findings to human health risk is not established. CONCLUSIONS AND RECOMMENDATIONS F344 rats and C57BL/6 mice exposed on a continuous basis by inhalation to JP-8 vapors at concentrations of 500 or 1,000 mg/m3 for 90 days showed induction of alpha 2u-globulin nephropathy in male rats but not in female rats or in male or female animals of other species. Alpha-2u-globulin-induced nephropathy occurs only in male rats and is not relevant to humans.

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The subcommittee recommends that kidney toxicity be evaluated in experimental animals exposed to JP-8 vapors and mixtures of vapors and aerosols by the inhalation route. REFERENCES Beirne, G.J., and J.T. Brennan. 1972. Glomerulonephritis associated with hydrocarbon solvents. Arch. Environ. Health. 25(5):365-369. Bogo, V., R.W. Young, T.A. Hill, C.L. Feser, J. Nold, G.A. Parker, and R.M. Cartledge. 1983. Pp. 46-66 in The Toxicity of Petroleum and Shale JP5. AFRRI SR83-26. Armed Forces Radiobiology Research Institute, Bethesda, MD. 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. Easley, J.R., J.M. Holland, L.C. Gipson, and M.J. Whitaker. 1982. Renal toxicity of middle distillates of shale oil and petroleum in mice. Toxicol. Appl. Pharmacol. 65(1):84-91. Flamm, W.G., and L.D. Lehman-McKeeman. 1991. The human relevance of the renal tumor-inducing potential of d-limonene in male rats: Implications for risk assessment. Regul. Toxicol. Pharmacol. 13(1):70-86. 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. MacEwen, J.D., and E.H. Vernot. 1985. Investigation of the 1-hour emergency exposure limit of JP-5. Pp. 137-144 in Toxic Hazards Research Unit Annual Technical Report: 1985. AAMRL-TR-85-058. Aerospace Medical Research Laboratory, Wright-Patterson AFB, OH. 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. NRC (National Research Council). 1996. Permissible Exposure Levels for Selected Military Fuel Vapors. Washington, DC: National Academy Press.

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Parker, G.A., V. Bogo, and R.W. Young. 1981. Acute toxicity of conventional versus shale-derived JP5 jet fuel: Light microscopic, hematologic, and serum chemistry studies. Toxicol. Appl. Pharmacol. 57(3):302-317. 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. Witzmann, F. A., M.D. Bauer, A.M. Fieno, R.A. Grant, T.W. Keough, M.P. Lacey, Y. Sun, M.L. Whiten, and R.S. Young. 2000a. Proteomic analysis of the renal effects of simulated occupational jet fuel exposure. Electrophoresis 21(5):976-984. Witzmann, F.A., R.L. Carpenter, G.D. Ritchie, C.L. Wilson, A.F. Nordholm, and J. Rossi III. 2000b. 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.