8

Effects of Military Fuel Vapors on the Liver

The toxic effects of JP-5, JP-8, DFM, and JP-4 on the liver have been studied in experimental animals. The results of the studies are summarized and discussed in this chapter. No studies are available that report the effects on the liver of human exposure to JP-5, JP-8, or DFM fuel vapors.

HEPATIC EFFECTS OF JP-5 FUEL VAPORS

In an acute-exposure study involving male Sprague-Dawley rats, petroleum-derived and three samples of shale-derived JP-5 fuel were administered in single oral doses of 60, 48, 38, 30, or 24 mL/kg of body weight (assuming an average density of 816 kg/m3; 49, 39, 31, 24, or 20 g/kg, respectively) (Parker et al., 1981). The animals were observed for toxic effects for 14 days before they



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Permissible Exposure Levels for Selected Military Fuel Vapors 8 Effects of Military Fuel Vapors on the Liver The toxic effects of JP-5, JP-8, DFM, and JP-4 on the liver have been studied in experimental animals. The results of the studies are summarized and discussed in this chapter. No studies are available that report the effects on the liver of human exposure to JP-5, JP-8, or DFM fuel vapors. HEPATIC EFFECTS OF JP-5 FUEL VAPORS In an acute-exposure study involving male Sprague-Dawley rats, petroleum-derived and three samples of shale-derived JP-5 fuel were administered in single oral doses of 60, 48, 38, 30, or 24 mL/kg of body weight (assuming an average density of 816 kg/m3; 49, 39, 31, 24, or 20 g/kg, respectively) (Parker et al., 1981). The animals were observed for toxic effects for 14 days before they

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Permissible Exposure Levels for Selected Military Fuel Vapors were killed. The 14-day single-dose LD50 values were >60 mL/kg for petroleum JP-5, 39 mL/kg for shale-1 JP-5, 26 mL/kg for shale-2 JP-5, and >60 mL/kg for shale-3 JP-5. The animals that died during the 14-day observation had swollen and mottled livers with accentuated lobular patterns. Histopathological investigation of survivors showed hepatic periportal fatty changes. In similar studies, rats were administered JP-5 in single oral doses of 24 mL/kg (20 g/kg), and groups were killed 1, 2, and 3 days later (Parker et al., 1981; Bogo et al., 1983, 1984). The results show a clear pattern of liver injury. By day 2, the livers were swollen and mottled, and histopathological examinations showed vacuolization and degeneration of periportal hepatocytes. In most samples, lactate dehydrogenase (LDH), serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamic-pyruvic transaminase (SGPT) levels increased. The time course of the liver changes was examined over a period of 3 hr to 15 days. For petroleum JP-5, SGOT levels increased 9 hr to 2 days after administration and SGPT levels increased 6 hr to 2 days after administration; for shale JP-5, SGPT levels increased 9 hr to 2 days after administration. Small cytoplasmic vacuoles in the periportal region of hepatocytes were observed after 12 hr to 4 days. Bogo and co-workers (1984) also examined the livers of male Sprague-Dawley rats in a subacute-exposure study in which petroleum JP-5 vapor at a concentration of 1,100 mg/m3 and shale JP-5 vapor at a concentration of 1,600 mg/m3 were administered by inhalation for 6 hr per day, 5 days per week for 6 weeks. No significant pathological or serum enzyme (SGOT and SGPT) changes were observed at the end of the exposure period. In a set of subchronic inhalation studies, male and female beagles (three of each), male and female F344 rats (75 of each), and 111 female C57BL/6 mice were continuously exposed to petroleum or shale JP-5 vapor at concentrations of 150 mg/m3 or 750 mg/m3 for 90 days (MacEwen and Vernot, 1978, 1980, 1981, 1982, 1983, 1985; Gaworski et al., 1984). Some animals were killed immediately after the 90-day exposure and others were held

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Permissible Exposure Levels for Selected Military Fuel Vapors 19 or 21 months after cessation of exposure. (The investigators also reported a preliminary experiment in mice ostensibly exposed to inhalation products of petroleum JP-5 at 1,500 mg/m3 for 6 days. Half the female mice died during or shortly after the exposure period. It was determined that a respirable aerosol of the fuel, rather than a vapor, was produced in the exposure. Therefore, this experiment was not considered further by the subcommittee.) Immediately after ending the exposure of the dogs to petroleum JP-5 vapor, diffuse mild swelling and clouding of hepatocytes was observed in two dogs exposed to 150 mg/m3 and in all six dogs exposed to 750 mg/m3 (MacEwen and Vernot, 1978). (No such effects were seen in the controls.) In later reports, these hepatocyte changes were described as containing excess glycogen (Gaworski et al., 1984; MacEwen and Vernot, 1985). After exposure to shale JP-5 vapor at 750 mg/m3, the dogs showed increased liver weights, increased liver-weight/body-weight ratios, and decreased SGPT levels as compared with controls. In rats exposed for 90 days to petroleum JP-5 vapor at 150 or 750 mg/m3, there were no liver histopathological changes or serum enzyme changes immediately after the exposure. Mild hepatic hyperplasia was observed at both concentrations in animals that died after the 90-day exposure or were held 19 or 21 months after exposure. In rats exposed to shale JP-5 vapor, more complex findings were observed. Immediately after exposure to 750 mg/m3, male rats had higher liver-weight/body-weight ratios and female rats had lower liver weights but higher liver-weight/body-weight ratios than controls. Histopathological results showed an increase in hepatocyte cytoplasmic vacuolization at 750 mg/m3 in male rats and at both concentrations in female rats. The histopathological changes in the female rats were dependent on chemical exposure but were not dose-dependent at the doses given. The only serum enzyme change that was noted in rats was a decrease in SGPT levels in male rats immediately after exposure to either concentration of the shale JP-5.

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Permissible Exposure Levels for Selected Military Fuel Vapors In mice exposed to petroleum JP-5 vapor, the females showed focal fatty changes in the hepatocytes that stained positive for fat at 150 and 750 mg/m3 and mild diffuse cytoplasmic vacuolization that was negative for fat and glycogen at 750 mg/m3. Both changes were seen at the end of the 90-day exposure but not at the end of the 19- and 21-month followup periods. In mice exposed to shale JP-5 vapor, an increase in hepatocyte cytoplasmic vacuolization was observed immediately after the 90-day exposure at both concentrations —3% in controls, 73% at 150 mg/m3, and 24% at 750 mg/m3—but the increase was not dose-related. After the 90-day exposure, an increase in damaged cell foci was observed for the low dose and an increase in liver adenomas was observed for the high dose. Liver-function indexes were normal 19 months after exposure. Liver histopathological changes were not observed in a study involving intermittent exposures. Bogo et al. (1984) reported that exposure of rats to JP-5 vapor at 1,100 or 1,600 mg/m3 for 6 hr per day, 5 days per week for 6 weeks did not result in any adverse effects in the liver, and there was no change in serum enzyme levels. HEPATIC EFFECTS OF JP-8 FUEL VAPORS 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 concentrations of 500 mg/m3 or 1,000 mg/m3 for 90 days (MacEwen and Vernot, 1983, 1984, 1985). Some groups of animals were killed immediately after the 90-day exposure and others were held for 2 weeks, 2 months, 9 months, or 21 months after cessation of exposure. Immediately after exposure ceased, male rats showed increases in liver weights and liver-weight/body-weight ratios at 1,000 mg/m3, decreases in SGPT at 500 and 1,000 mg/m3, and decreases in al

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Permissible Exposure Levels for Selected Military Fuel Vapors kaline phosphatase at 1,000 mg/m3. Immediately after exposure ceased, female rats showed increases in liver weights and liver-weight/body-weight ratios at 500 and 1,000 mg/m3, increases in alkaline phosphatase at 1,000 mg/m3, and decreases in SGPT at 500 and 1,000 mg/m3. Nine months after exposure, male rats showed decreases in SGPT at 500 and 1,000 mg/m3. Twenty-one months after exposure, male rats showed dose-related increases in liver-weight/body-weight ratios at 500 and 1,000 mg/m 3. Female rats showed decreases in SGOT at 500 mg/m3 and decreases in SGPT at 500 and 1,000 mg/m3. No data on mice were presented. The data available on the liver effects of JP-8 vapor are not definitive because histopathological examinations were not performed. The liver-weight changes observed in rats might be indicative of hyperplasia or hypertrophy. Alternatively, the increases in liver-weight/body-weight ratios might reflect a loss of body weight in the test animals during the study. HEPATIC EFFECTS OF DFM FUEL VAPORS In subchronic inhalation studies (MacEwen and Vernot, 1978, 1980, 1982, 1983, 1985), male and female beagles (three of each), male and female F344 rats (150 of each) and 150 female C57BL/6 mice were continuously exposed to petroleum-derived or shale-derived DFM vapor at concentrations of 50 mg/m3 or 300 mg/m3 for 90 days. Some animals were killed immediately after the 90-day exposure and others were held 19 or 21 months after exposure. MacEwen and Vernot (1983) also reported that five male rats were exposed to 2,600 mg/m3 for 8 hr per day for 5 days without any deaths. For dogs exposed to petroleum DFM vapor, increases in liver weights and liver-weight/body-weight ratios were observed at the end of the 90-day exposure to 300 mg/m3, and an increased incidence of cytoplasmic vacuolization of hepatocytes was seen at

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Permissible Exposure Levels for Selected Military Fuel Vapors both the 50 and 300 mg/m3 concentrations. For dogs exposed to shale DFM, increases in liver weights were observed after exposure to 300 mg/m3. For rats exposed to petroleum DFM vapor, increases in liver-weight/body-weight ratios were observed in males after the 90-day exposure to 300 mg/m 3, and decreases in SGPT were observed at 50 and 300 mg/m3. When male rats were examined 19 months after the exposure ceased, decreases in liver weights, compared with controls, were observed at 300 mg/m3. For female rats exposed to petroleum DFM, decreases in liver weights were measured at the end of the 90-day exposure to 50 mg/m3 only; 19 months after the exposure ceased, decreases in liver weights were found at both concentrations. No liver enzyme changes were observed at the end of the 19- or 21-month period. For rats exposed to shale DFM, increases in liver-weight/body-weight ratios were observed in both males and females after exposure to 300 mg/m3. No changes in serum chemistry were noted for male rats, but decreases in SGOT and SGPT and increases in alkaline phosphatase were observed immediately after exposure to 300 mg/m3, and decreases in SGPT were also seen after exposure to 50 mg/m3. No changes in liver weights or serum-enzyme levels were observed 19 months after cessation of exposure. For mice exposed to petroleum DFM vapor at 300 mg/m3, an increased number of inflammatory cells were observed in the liver at the time that exposure ceased. Nineteen to 21 months after exposure, there were no important liver changes or increased tumor incidence. For mice exposed to shale DFM, increased numbers of fatty changes and vacuolization in hepatocytes were seen after exposure to both 50 and 300 mg/m3. The fatty changes were the same at both concentrations, that is, not dose-related. Nineteen or 21 months after exposure, liver changes or increases in tumor incidence were not significant. In a study performed by Cowan et al. (1979), rats were exposed continuously by inhalation to petroleum DFM vapor at concentrations of 14 mg/m 3 for 90 days or 167 mg/m3 for 120 days. No

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Permissible Exposure Levels for Selected Military Fuel Vapors changes in histopathology or tumor incidence were reported after 90 days of exposure to 14 mg/m3. No changes in histopathology were reported after 120 days of exposure to 167 mg/m3; however, an increased tumor incidence of 60%, compared with 26% in the control group, was reported. The effects seen with DFM are similar to those seen with JP-5 and JP-8, but they appear at lower concentrations. The increased tumor incidence described in the study of Cowan et al. (1979) is of concern, but without additional information, its importance relative to the other studies described should be discounted. HEPATIC EFFECTS OF JP-4 FUEL VAPORS Due to the similarities between JP-4 and other jet fuels, JP-4-induced liver changes are discussed in this section. Fuel-filling attendants who were exposed to JP-4 at an average of 31 mg/m3 for a mean of 6.4 years had a significantly faster anti-pyrine clearance (68 mL/min) than did an equivalent population of office workers (58 mL/min). No differences were found in serum aspartate aminotransferase and alkaline phosphatase levels in the two groups (Dossing et al., 1985). In subchronic inhalation studies (MacEwen and Vernot, 1984, 1985), male and female F344 rats, female C57BL/6 mice, and beagle dogs were continuously exposed to JP-4 vapor at concentrations of 500 mg/m 3 or 1,000 mg/m3 for 90 days. Some groups of animals were killed immediately after the 90-day exposure and others were held 2 weeks, 2 months, 9 months, or 21 months after exposure. The beagle dogs used in the studies were normal with regard to liver function and histology; male rats showed increases in liver-weight/body-weight ratios at both concentrations at the end of the 90-day exposure. Nine months after exposure, male rats showed decreases in SGOT and SGPT at both dose concentrations and decreases in serum alkaline phosphatase at the

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Permissible Exposure Levels for Selected Military Fuel Vapors high concentration. In female mice, there was an increased incidence of centrilobular hepatocellular fatty changes at both concentrations at the end exposure. The increases in liver weights and liver-weight/body-weight ratios were examined in male rats to determine if the effect was related to strain. F344, Sprague-Dawley, Wistar, and Osborne Mendel rats all showed similar effects. Similar studies (Bruner et al., 1993; Wall et al., 1990; MacEwen and Vernot, 1981, 1982) were performed in which the exposure protocol was altered: male and female F344 rats (300 of each) and C57BL/6 mice (300 of each) were exposed to JP-4 vapors at concentrations of 1,000 or 5,000 mg/m3 6 hr per day, 5 days per week for 12 months. Animals were killed either immediately after exposure or 1 year after exposure. Male rats examined immediately after exposure ended showed decreased liver weights at both concentrations and decreased liver-weight/body-weight ratios at the high concentration only; those held for a year after exposure had decreased liver weights and liver-weight/body-weight ratios at both concentrations. Male rats also displayed decreased SGPT levels at the high concentration—5,000 mg/m3. Immediately after exposure, female rats had decreased SGPT levels at both concentrations and, after 1 year, had liver nodular hyperplasia at 5,000 mg/m3 but no primary liver neoplasms. Female mice had an increase in liver inflammatory infiltrates immediately after exposure to 5,000 mg/m 3 and an increased incidence of hepatocellular adenoma at 5,000 mg/m 3. Male mice had a decreased incidence of adenomas at that concentration. In this study, hepatocellular fatty changes were not observed; however, 6 days elapsed between exposure termination and euthanasia and necropsy. A third inhalation study was briefly described (MacNaughton and Uddin, 1984) in which dogs, rats, mice, and monkeys were exposed to JP-4 vapor at concentrations of 2,500 or 5,000 mg/m3 for 6 hr day, 5 days per week for 8 months. The only results reported were increases in liver weights and liver-weight/body-weight ratios in male rats. Histopathology did not show any exposure-related effects.

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Permissible Exposure Levels for Selected Military Fuel Vapors The mild liver effects observed in animals following exposure to JP-4 vapor are consistent with those reported following exposure to other fuel mixtures. If cumulative exposures are calculated, the concentrations of JP-4 tested are the highest used in any study: 5,000 mg/m3 and 1,000 mg/m3 (counts = 8 × 106 and 2 × 106 mg·hr/m3, respectively) in the 1-year study, and 1,000 and 500 mg/m3 (counts = 2 × 10 6 and 1 × 10 6 mg·hr/m 3, respectively) in the 90-day study. The human-exposure study involving JP-4 is comparable: counts = 4 × 105 mg·hr/m3. Similar to the animal studies, the effect observed in humans—increased antipyrine clearance—is a mild effect. It appears that the same effects are seen with all the fuels; however, the effects might be observed at lower concentrations as the fuel boiling point increases. Because the reported liver changes are effects for which there is no defined no-observed-adverse-effect level (NOAEL), the subcommittee commissioned a further review of the liver histology slides of rodents exposed to JP-4 (Bruner et al., 1993) to address specific questions. This review found that the hepatocellular hypertrophy was minimal to mild for all exposures. No dose response was seen in the animals exposed for 12 months. The lesions disappeared after exposure ceased. Little evidence of necrosis was observed. If necrosis was an important outcome of these exposures, there should have been evidence of long-term sequelae, such as fibrosis, in the 12-month-exposed animals. None was seen. Table 8-1 summarizes the liver toxicity of these military fuels. CONCLUSIONS The liver was found to be a target organ of orally administered jet fuels (total fuel) in rats. However, that finding cannot be used to set exposure limits for workers exposed to vapors while fueling or servicing military vehicles for several reasons: (1) the major potential for worker exposure is via the inhalation route, not the

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Permissible Exposure Levels for Selected Military Fuel Vapors TABLE 8-1 Liver Toxicity of Military Fuel Vapors in Experimental Animals Fuel Type Animal Species Exposure Concentration, mg/m3 Exposure Duration Adverse Effects Reference JP-5 Sprague-Dawley rats 1,100 or 1,600 6 hr/day, 5 days/wk for 6 wk None Bogo et al., 1984 JP-5 Beagles, F344 rats, C57BL/6 mice 150 or 750 90 days continuously Reversible diffuse mild swelling of hepatocytes, decreased SGPT levels, and increased liver weight in dogs; mild hepatic hyperplasia and increased hepatocytic vacuolization in rats; fatty changes in hepatocytes, increased hepatocytic vacuolization, and increased liver adenomes in mice MacEwen and Vernot, 1978, 1980, 1981, 1982, 1983, 1985; Gaworski et al., 1984 JP-8 F344 rats 500 or 1,000 90 days continuously Increased liver weight, increased alkaline phosphatase, and decreased SGPT levels MacEwen and Vernot, 1983, 1984, 1985 DFM Beagles, F344 rats, C57BL/6 mice 50 or 300 90 days continuously Increased liver weight and hepatic vacuolization in dogs and rats; increased number of inflammatory cells in livers of mice MacEwen and Vernot, 1978, 1980, 1982, 1983, 1985

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Permissible Exposure Levels for Selected Military Fuel Vapors DFM Rats 14 or 167 90 days continuously or 120 days continuously None for 90-day exposure; increased liver tumors (60% vs. 26%)for 120-day exposure Cowan et al., 1979 JP-4 Rats, mice, dogs, and monkeys 2,500 or 5,000 6 hr/day, 5 days/wk for 8 months Increased liver weight; no histopathological changes MacNaughton and Uddin, 1984 JP-4 Rats and mice 1,000 or 5,000 6 hr/day, 5 days/wk for 12 months No histopathological effects Brunner et al., 1993 JP-4 Beagles, F344 rats, C57BL/6 mice 500 or 1,000 90 days continuously No effects in dogs; increased liver weight and decreased SGOT and SGPT levels in rats; increased fatty changes in livers of mice MacEwen and Vernot, 1984, 1985

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Permissible Exposure Levels for Selected Military Fuel Vapors oral route; (2) use of the oral data is complicated by the fact that some of the ingested petroleum products will be regurgitated and subsequently aspirated into the lung, thus causing pneumonia; and (3) the results of oral exposure in rats cannot be correlated easily with inhalation results because of the large difference in the doses and because of the difference in the composition of the total fuel and the inhaled vapors. Data from inhalation studies in which animals were exposed continuously for 90 days also cannot be used to set exposure limits. The meaning of the liver changes observed in dogs, rats, and mice exposed continuously to JP-5 vapors for 90 days is unclear. Results from a series of subchronic inhalation studies are relevant. MacNaughton and Uddin (1984) reported that dogs, rats, mice, and monkeys exposed to JP-4 at 2,500 or 5,000 mg/m3 for 6 hr per day, 5 days per week for 8 months exhibited no exposure-related effects other than a slight increase in liver weights in female rats. In a recent report, Bruner et al. (1993) did not observe any target-organ toxicity or carcinogenicity in rats and mice exposed to JP-4 vapor at 0, 1,000, or 5,000 mg/m3 for 6 hr per day, 5 days per week for 12 months. A review of the slides from livers of rats exposed to JP-4 vapor was conducted at Wright-Patterson Air Force Base by a member of the Committee on Toxicology (E.E. McConnell, Consultant, Raleigh, N.C., personal communication, 1994) to determine the nature of the liver lesions. The liver changes observed were reported to be a reversible lesion of questionable toxicological importance. Because the vapors from the various fuels are expected to be similar in composition, the subcommittee elected to use the MacNaughton study for calculating the PEL. Based on the NOAEL of 5,000 mg/m3 identified in rats administered JP-4 and dividing by an uncertainty factor of 10 for interspecies extrapolation, the PEL would be 500 mg/m3. No uncertainty factor for intraspecies variation was applied because the potentially exposed Navy personnel are considered to be healthy.

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Permissible Exposure Levels for Selected Military Fuel Vapors The subcommittee recommends that further research be conducted to evaluate the effect of military fuel vapors on hepatotoxicity in experimental animals; this research would help to identify the NOAEL with greater confidence.