5

Effects of Military Fuel Vapors on the Kidney

The kidney is a target tissue for petroleum-derived or shale-oil-derived military fuel vapors. However, kidney toxicity, at least under conditions of chronic exposure, appears to occur only in male rats. Pertinent data available on the kidney toxicities of JP-5 fuels, JP-8 fuels, and DFM in animals are summarized in this chapter.

EFFECTS OF ACUTE EXPOSURES TO FUEL VAPORS

Few studies have addressed the toxicity associated with exposure to diesel fuel. An acute exposure to high concentrations of hydrocarbon solvents and jet fuel has been reported in a case study to produce kidney failure. Beirne and Brennan (1972), as cited by Phillips (1984), reported rapidly progressive glomerulo



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Permissible Exposure Levels for Selected Military Fuel Vapors 5 Effects of Military Fuel Vapors on the Kidney The kidney is a target tissue for petroleum-derived or shale-oil-derived military fuel vapors. However, kidney toxicity, at least under conditions of chronic exposure, appears to occur only in male rats. Pertinent data available on the kidney toxicities of JP-5 fuels, JP-8 fuels, and DFM in animals are summarized in this chapter. EFFECTS OF ACUTE EXPOSURES TO FUEL VAPORS Few studies have addressed the toxicity associated with exposure to diesel fuel. An acute exposure to high concentrations of hydrocarbon solvents and jet fuel has been reported in a case study to produce kidney failure. Beirne and Brennan (1972), as cited by Phillips (1984), reported rapidly progressive glomerulo

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Permissible Exposure Levels for Selected Military Fuel Vapors nephritis in a 44-year-old worker who was exposed to an unspecified hydrocarbon-solvent and jet-fuel mixture. The acute toxicity of petroleum- or shale-derived JP-5 fuels has been examined in rats. In these studies, rats were administered JP-5 at a comparatively high dose of 24 mL/kg of body weight. (The exposure was to the total fuel and not to the vapors only.) The LD50 was estimated to be approximately 60 mL/kg or higher. Pathological changes observed in male rats 14 days after gavage included the appearance of cytoplasmic droplets in the kidneys. It was noted that these droplets were larger and more numerous in the kidneys of rats killed 2 or 3 days after gavage than in those killed later. At the base of some of the affected cells, small vacuoles were detectable. The presence of hyaline droplets in the kidneys correlated with an accompanying rise in serum creatinine and blood urea nitrogen (BUN), signs of functional kidney damage (Parker et al., 1981; Bogo et al., 1983). EFFECTS OF SUBCHRONIC EXPOSURES TO FUEL VAPORS The subchronic toxicity of JP-5, JP-8, and DFM vapors has been examined in several studies. Fischer 344 (F344) rats and C57BL/6 mice were exposed for 90 days to two different concentrations of airborne fuel vapors. After 90 days of exposure, one-third of the animals were killed, and tissues were analyzed by histopathology. The remaining animals were allowed to recover in air until approximately 2 years after initiation of the study. Male and female rats and female mice were exposed to petroleum-derived and shale-derived JP-5 vapors at concentrations of 150 or 750 mg/m 3for 90 days (MacEwen and Vernot, 1985). Immediately following exposure, the most significant histopathological changes—nephrosis and tubular damage—were found in more than 75% of the male rats exposed to either dose. The le

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Permissible Exposure Levels for Selected Military Fuel Vapors sions were described as being more severe in the high-dose exposure group. No such changes were found in female rats or in control rats of both sexes. In female mice, kidney lesions (casts and signs of glomerulonephritis) increased slightly but not significantly. Following exposure to shale-derived JP-5, male rats were found to have a high incidence of renal tubular necrosis. No such changes were observed in female rats. Tubular fatty changes were reported in some female mice exposed to the low dose but were not found in those exposed to the high dose. No male mice were used in this study. After cessation of exposure, most of the animals were allowed to survive for 19 or 24 months after the beginning of the study. The histopathological changes that had been observed at the end of the 90-day exposure were found to persist. Most striking were the kidney lesions seen in male rats. They included focal diffuse papillary hyperplasia of the pelvic urothelium and moderate-to-severe deposits of mineralized debris in the medullary tubules as well as degeneration of the tubules. Although similar changes were found in a high percentage (up to 84%) of control males, they clearly were more frequent in the fuel-exposed rats. No kidney tumors were found in rats exposed to JP-5. Signs of tubular degeneration and mineralization were found in only a few females, and the changes occurred with the same frequency in both controls and exposed rats. Mice did not show any signs of exposure-related kidney damage. Similar observations were made when JP-8 vapor was evaluated (Mattie et al., 1991). Male and female F344 rats and male and female C57BL/6 mice were exposed for 90 days to JP-8 vapor at airborne concentrations of 500 or 1,000 mg/m3. After the 90-day exposure, a "triad" of lesions was described in the kidneys of male rats: dramatically exacerbated hyaline droplet formation, granular casts in the outer medulla, and an 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 histopathological lesions were found that were related directly to exposure.

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Permissible Exposure Levels for Selected Military Fuel Vapors The increased incidence and severity of chronic progressive nephrosis persisted throughout the remainder of the lifetimes of the male rats. The kidney changes seen after 90 days were not reversible and were progressive. The severity of lesions was greater at the high-dose exposure, as was the case for JP-5. No kidney tumors were found in this study. Bruner et al. (1993) divided 300 F344 rats and 300 C57BL/6 mice of each sex into three treatment groups and exposed them intermittently (6 hr per day, 5 days per week) to JP-4 fuel vapors at concentrations of 0, 1,000, and 5,000 mg/m3 for 12 months. At exposure termination, 10% of the animals were killed, and those remaining were held for a 12-month observation period. Pathological findings in male rats revealed treatment-related kidney toxicity and kidney neoplasia consistent with the α2u-globulin nephropathy syndrome, which is unique to male rats and has no relevance to humans. Studies with DFM vapors gave similar results (MacEwen and Vernot, 1985). Male and female F344 rats and female C57BL/6 mice were exposed to DFM, petroleum- or shale-derived, at concentrations of 50 or 300 mg/m3. After 90 days, renal tubular degeneration was found in a high proportion of the male rats exposed to petroleum- or shale-derived DFM. The severity of the lesions was dose-related and characterized as minimal to mild in the low-dose groups and mild to moderate in the high-dose groups. At 50 mg/m3, shale-derived DFM appeared to produce a slightly higher incidence of hyaline degeneration lesions than petroleum-derived DFM, but at 300 mg/m3, no difference between the two fuels was found. Renal epithelial tubular cell necrosis appeared to occur at the same incidence with the two fuels. Female rats were free of any significant kidney injuries, as were female mice. No male mice were used in this study. After 19 or 24 months, no substantial mineralization or papillary hyperplasia was found in rats exposed for 90 days to 50 mg/m3of petroleum-derived DFM vapors. However, such changes were seen in rats exposed to shale-derived DFM at the same concentration. At 300 mg/m3, papillary hyperplasia and mineraliza

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Permissible Exposure Levels for Selected Military Fuel Vapors tion were present for petroleum- and shale-derived DFM. Again, no kidney toxicity was observed in female rats or female mice. In summary, kidney effects in experimental animals exposed by the inhalation to JP-5, DFM, or JP-8 were remarkably similar: immediately following a 90-day exposure, dose-related severe nephropathy occurred in male rats but not in female rats or female mice. After a recovery period of almost 2 years, the lesions still were present. Age-related nephropathy now was also visible in controls. However, in the exposed animals, there was a general increase in occurrence of papillary hyperplasia and mineralization. In none of these studies was there evidence that fuel exposure produced kidney tumors. The histopathological changes in the male rats exposed to the different fuel vapors were similar in all experiments. A summary description was provided by Bruner (1984). Briefly, upon microscopic inspection of the slightly tan discolored kidneys, cystic tubules were noted at the corticomedullary junction that were filled with granular eosinophilic debris. Tubules were dilated and the lining epithelium was markedly flattened. The lesions appeared to be located before the pars recta of the proximal tubules descended into Henle's loop. There was a marked increase in cytoplasmic hyaline droplets in the proximal tubular cells throughout the renal cortex. Individual cells in the proximal tubules were dying, exfoliating, and being replaced by mitotically active epithelial cells. Thus, a consistent pattern with regard to kidney lesions is observed in subchronic-exposure studies in which experimental animals are exposed to vapors from JP-5, JP-8, and DFM. Histopathological signs of kidney damage are essentially seen only in male rats. Female rats and mice do not show kidney lesions comparable to the ones found in male rats. In none of the reported studies on JP-5, JP-8, and DFM was there evidence of any of the three fuels producing kidney tumors. Evidence of potential kidney carcinogenicity was reported in a study that examined the chronic toxicity of JP-4 vapors in rats exposed intermittently for 12

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Permissible Exposure Levels for Selected Military Fuel Vapors months (Brunner et al., 1993). The incidence of kidney neoplasms in male rats increased, although the increase was not statistically significant. Nevertheless, the increase was considered to have biological relevance and plausibility. Military fuels in general appear to have the potential to produce kidney tumors in male rats, although no direct evidence is available for JP-5, JP-8, or DFM. Table 5-1 summarizes the kidney toxicity of these military fuels. CONCLUSIONS The kidney lesions seen in male rats exposed to JP-5, JP-8, and DFM vapors resemble a lesion known as α2u-globulin nephropathy. The mechanisms that underlie the development of this particular lesion are believed to be unique to male rats. Accordingly, these lesions are not expected to occur in other species, including humans.

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Permissible Exposure Levels for Selected Military Fuel Vapors TABLE 5.1 Kidney Toxicity of Military Fuel Vapors in Experimental Animals Fuel Type Animal Species Exposure Concentration, mg/m3 Exposure Duration Adverse Effects Reference JP-5 Rats, mice 150 or 750 90 days continuously Nephrosis and tubular damage in rats; slight but not significant increase in glomerulonephritis in mice MacEwen and Vernot, 1985 JP-8 F344rats, C57BL/6 mice 500 or 1,000 90 days continuously Kidney lesions: hyaline droplets, granular casts in outer medula, nephrosis in male rats only; no kidney toxicity in mice Mattie et al., 1991 JP-4 F344 rats, C57BL/6 mice 1,000 or 5,000 6 hr/day, 5 days/wk for 12 months α2u-Globulin nephropathy in male rats only; no kidney toxicity in mice Brunner et al., 1993 DFM F344rats, C57BL/6 female mice 50 or 300 90 days continuously Tubular degeneration in male rats; no kidney toxicity in mice MacEwen and Vernot, 1985