10

Carcinogenic Effect of Military Fuel Vapors

The carcinogenicity of military fuels has been investigated in human epidemiological studies as well as in experimental animals. The findings of the investigations are discussed in this chapter.

EPIDEMIOLOGICAL STUDIES

Exposure to Jet Fuel Vapors

Selden and Ahlborg (1986, 1987) followed a cohort of 2,182 men exposed to jet fuel vapor in the Swedish armed forces. Air Force personnel constituted 86% of the cohort potentially exposed to jet fuel vapor, as well as to aviation kerosene, isopropyl nitrate, and aviation gasoline. Air monitoring for jet fuel vapor in selected work sites showed concentrations exceeding 350 mg/m3



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Permissible Exposure Levels for Selected Military Fuel Vapors 10 Carcinogenic Effect of Military Fuel Vapors The carcinogenicity of military fuels has been investigated in human epidemiological studies as well as in experimental animals. The findings of the investigations are discussed in this chapter. EPIDEMIOLOGICAL STUDIES Exposure to Jet Fuel Vapors Selden and Ahlborg (1986, 1987) followed a cohort of 2,182 men exposed to jet fuel vapor in the Swedish armed forces. Air Force personnel constituted 86% of the cohort potentially exposed to jet fuel vapor, as well as to aviation kerosene, isopropyl nitrate, and aviation gasoline. Air monitoring for jet fuel vapor in selected work sites showed concentrations exceeding 350 mg/m3

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Permissible Exposure Levels for Selected Military Fuel Vapors (43.75 ppm) in 1975 and 1976. The cohort was followed from 1974 to 1981 or 1982 with loss to followup of less than 0.2%. Analysis of cancer incidence and mortality revealed no significant increases in total neoplasms (25 observed vs. 29.4 expected) or increases in cancers at specific sites. IARC (1989) concludes, however, that this study was able to detect only large increased cancer rates because of a short followup period and low expected numbers of cancer deaths in a relatively young population. In 1991, Selden and Ahlborg reported further results of a historical cohort study undertaken to investigate a cluster of malignant tumors reported among workers on a military base in southeastern Sweden. The cohort, numbering 2,176 men, was established by the medical board of the Swedish armed forces. The cohort included those with normal and appreciable exposure to MC77 (equivalent to JP-4) and MC25 (a leaded synthetic fuel introduced in the 1950s for the starter motors of certain aircraft models) from 1972 to 1974. Classification of persons by job title from which estimates of exposure might be made was based on information retained in military records. Based on the reassessment of exposure, 94.3% of the Air Force personnel in the cohort were considered to have been exposed to aircraft fuel, specifically to MC77 or MC75 (equivalent to JP-1 or Jet A-1) or both, 80% (n = 1,741) to MC25, and 38% (n = 827) to MC55. MC55 was reported to contain 0.08% tetraethyl lead by volume. In addition, exposure to other organic solvents, such as paints and lacquers, might have occurred in the workplace (Selden and Ahlborg, 1991). The vital status of each individual was confirmed as of January 1, 1985, and for deceased individuals, the causes of death were determined for all persons who had died during 1975-1983. The National Cancer Registry was also searched for cases of cancer diagnosed during 1975-1983. The overall standardized mortality rate (SMR) in the cohort was 0.53 (confidence interval (CI), 0.40–0.68). The overall SMR

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Permissible Exposure Levels for Selected Military Fuel Vapors for all malignant tumors was 0.70 (CI, 0.41–1.11 ). The investigators attributed the low SMR to the "healthy worker effect." No cases of lymphoma or leukemia were observed. Other results reported without further detail include no significant differences in mortality with regard to time of recruitment (before 1956 or later) or type of fuel exposure (jet fuel only or in combination with MC55). The total cancer morbidity among Air Force personnel in the cohort was somewhat lower than expected; the standardized incidence ratio (SIR) was 0.87 (CI, 0.61–1.20) regardless of the latency period (10, 20, or 30 years), time of recruitment, job title, and type of fuel exposure. Three cases of lymphatic cancers were observed versus 2.67 expected. Selden and Ahlborg (1991) concluded that the results from this study indicated that there was no increased risk of lymphatic cancer due to aircraft-fuel exposure. Possible limitations in the study include short followup (9 years for cancer incidence and 10 years for cancer mortality) and possible bias due to selection of persons in the cohort (only 4 of the original 10 men of the cancer cluster were included in this study). Rushton (1993a) conducted a followup from 1976 to 1989 of a cohort of approximately 22,000 workers employed for a least 1 year between January 1950 and January 1976 at eight oil refineries in Britain. The status of over 99% of the workers was successfully determined. The mortality of the refinery workers was compared with that of all the male population of England, Wales, and Scotland. Mortality from all neoplasms was lower in the workers than expected overall, largely because deaths from malignant neoplasms of the lung were lower than expected. Mortality from all neoplasms and particularly malignant neoplasms of the esophagus, stomach, and lung was higher in the workers than in the male population of England, Wales, and Scotland, although the mortality was also high in all the men in this social class in the male population. Regional variations might have accounted for some of the high mortality. Mortality was also increased for malignant neoplasms of the intestine, rectum, larynx, and prostate, but the

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Permissible Exposure Levels for Selected Military Fuel Vapors cases tended to be isolated and not consistent across refineries and other subgroups. Mortality from melanoma was increased in several job groups. Rushton (1993b) also conducted a followup from 1976 to 1989 of a cohort of approximately 14,000 workers employed for at least 1 year between January 1950 and January 1976 at oil distribution centers in Britain. The status of over 99% of the workers was successfully determined. Their mortality was compared with that of all the male population of England and Wales. Mortality from all neoplasms was lower than expected in the distribution workers, again because of fewer deaths than expected from malignant neoplasms of the lung. Mortality from all neoplasms, malignant neoplasms of the lung, and several nonmalignant disease groups was increased in general manual workers in comparison to craftsmen and managerial staff, although the mortality from many of these diseases is also high in this social class in the male population of England and Wales. Mortality from malignant neoplasms of the larynx and prostate was increased in the workers, but the cases tended to be in isolated subgroups. Mortality from malignant neoplasms of the kidney was increased in distribution workers overall and in drivers in particular. Mortality from leukemia was high at one company and in drivers in particular. Siemiatycki et al. (1987) conducted a case-control study in Montreal, Quebec, where they examined the possible association between cancer and exposure to any of 12 petroleum-derived liquids. Of 3,726 persons followed (representing an 82% response rate), 43 reported exposure to jet fuel. Twelve of the 43 were aircraft mechanics and repairmen, 26 had high confidence of exposure, 11 had high frequency of exposure, 15 had relatively high concentration of exposure, and 22 had more than 20 years of exposure. Among those exposed to jet fuel, there was a significantly increased risk only to kidney cancer (odds ratio (OR), 2.5; CI, 1.1–5.4), which occurred in 7 of the 43 exposure cases. Adjustments were made for age, socioeconomic status, ethnic group, cigarette smoking, and blue- or white-collar job history. Additional stratified analysis of cumulative exposure of two groups ("nonsub

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Permissible Exposure Levels for Selected Military Fuel Vapors stantial" and "substantial") produced an adjusted OR of 3.1 (CI, 1.5–6.6). The group with substantial exposure had an OR of 3.4 (CI, 1.5–7.6), compared with an OR of 2.1 (not statistically significant) for the nonsubstantial-exposure group (one exposed case), a finding the investigators offered as evidence of a possible dose-response relationship. Six of the cancer patients exposed to jet fuel were also exposed to aviation gasoline, which was associated with kidney cancer at similar risk levels. When both jet fuel and aviation gasoline were included in a regression model, the risk of kidney cancer ascribable to jet-fuel exposure was lower, whereas the risk associated with aviation gasoline was unaffected. Siemiatycki et al. (1987) suggested that this result indicated a "greater role for aviation gasoline than for jet fuel." The investigators also noted that exposures to jet fuels have been associated with development of kidney cancers in male rats; however, these exposures were not reported in this study. The investigators concluded that the results of this study supports the hypothesis that the development of kidney cancer is more likely to be due to exposure to aviation gasoline than to exposure to jet fuel. The only hematopoietic cancers reported in this study were non-Hodgkin's lymphoma (NHL). No associations were observed between exposures and NHL after adjustment for possible confounding factors. Direct Exposure to Diesel Fuel Siemiatycki et al. (1987) also reported an increased risk of squamous-cell lung cancer and possibly prostate cancer among workers exposed to diesel fuel. For squamous-cell lung cancer, the adjusted relative risk (RR) was 1.6 (CI, 1.0–2.6). A positive dose-response relationship was suggested by the difference in risks between the nonsubstantial-exposure group (RR, 1.0; CI, 0.4–2.0) and the substantial-exposure group (RR, 2.5; CI, 1.3–4.7). The authors conducted a separate analysis for all types of lung

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Permissible Exposure Levels for Selected Military Fuel Vapors cancer, excluding adenocarcinoma because increases in other lung-cancer types associated with diesel fuel were nonsignificant. The RR for any exposure was 1.6 (CI, 1.1–2.4), based on 39 exposure cases. Whether exposure in these cases was predominantly to diesel exhaust or to diesel-fuel fumes is not clear. For prostate cancer, the adjusted RR was 1.9 (CI, 1.2–3.0), but the risk was higher among those considered to have nonsubstantial exposure than among those considered to have substantial exposure, suggesting the absence of a dose-response relationship. Although the IARC (1989) working group appears to have discounted the prostate-cancer finding because of a lack of dose-response evidence, Siemiatycki et al. (1987) considered the data to provide a hypothesis worthy of followup. Exposure to Petroleum Petroleum-refinery workers have been the subject of a large number of epidemiological studies. Wong and Raabe (1989) conducted an extensive review and meta-analysis, which included published and available unpublished epidemiological studies of petroleum-industry employees from several countries. Although mortality from cancer at most sites was similar or lower than that experienced by the general population, data suggested that certain groups within the industry might have higher leukemia and kidney-cancer mortality. Studies of petroleum refineries are able to provide little evidence of risk from exposure to jet fuels or analogous products because the exposed groups are very small. The findings of excess leukemia in petroleum workers are consistent with low exposure to benzene from various products. The findings of excess kidney cancer, though not consistent, are pertinent to the weight of evidence of adverse health effects resulting from exposure to jet fuels. The results of studies examining kidney cancer among employees of the petrochemical industry are summarized in Table 10-1. A cohort mortality study of petroleum-industry employees with

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Permissible Exposure Levels for Selected Military Fuel Vapors TABLE 10-1 Kidney Cancer in Employees of the Petrochemical Industry Nature of Exposure Findings         Exposure No. OR (CI) SMR (CI) Comment Case-series and case-control study in Montreala Exposure levels based on job history; chemists and industrial hygienists translated job into potential exposures. Unadjusted ratios       Possible misclassification bias. Low power.   Auto gas 24 1.2 (0.8-1.6) —     Mineral spirits 39 1.1 (0.8-1.4) —     Kerosene 12 1.3 (0.8-2.1) —     Diesel fuel 10 1.4(0.8-2.3) —     Heating oil 8 1.1 (0.6-2.1) —     Cutting fluids 16 1.0 (0.7-1.5) —     Hydraulic fluids 9 1.1 (0.6-2.0) —     Lubricating oils 63 1.2 (0.9-1.5) —     Crude oil 2 1.2 (0.2-6.3) —     Other mineral oil 9 1.3 (0.7-2.2) —     Aviation gas 7 2.6 (1.2-5.8) —     Jet fuel 7 2.5 (1.1-5.4) —     Adjusted ratios           Aviation gas           All 7 3.1 (1.5-6.5) —     Substantial exposure 6 3.9 (1.7-8.8) —     Nonsubstantial exposure 1 1.5 (0.3-8.6) —     Jet fuel           All 7 3.1 (1.5-6.6) —     Substantial exposure 6 3.4 (1.5-7.6) —     Nonsubstantial exposure 1 2.1(0.3-12.7) —  

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Permissible Exposure Levels for Selected Military Fuel Vapors Mortality study in Great Britainb Workers at oil distribution centers. Total cohort, 23,358 Marketing transportation 23 — 1.21, p = 0.21 No control for smoking. Mortality study in Canadac Oil industry workers; exposure segments assigned by industrial hygienist. Cohort, 34,597 All work segments 23 — 0.98 Possible misclassification bias; no control for smoking. Marketing transportation 9 — 1.34 (0.61-2.54) Marketing — — 1.53 (0.61-3.16) Refinery workers 9 — 0.92 (0.42-1.73) Case-control study in the United Statesd Male refinery workers from five petroleum companies (36 locations). Industrial hygienists assessed jobs and assigned exposures. Large cohort, ≈100,000. Workers in receipt, storage, and movements — 2.5 (0.9-6.6) — No association between renal-cancer mortality and exposure to nonaromatic liquid gasoline distillates at typical background. Three groups at risk compared with office workers, professionals, and technicians. Exposure misclassification possible. Laborers — 1.9 (1.0-3.9) — Unit cleaners — 2.3 (0.5-9.9) — Above refinery background exposure to nonaromatic liquid gasoline distillates 102 1.0 (0.5-1.9) —

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Permissible Exposure Levels for Selected Military Fuel Vapors Cohort mortality study in Californiae Based on employment history: Predominant work area or job assignment Total cohort, 4,585. — 8 — 1.33 (0.57-2.62) Nonsignificant increase in kidney cancer. No significant increases in any cause of death. Possible exposures to other chemicals. Average duration of employment, 20 yr. Meta-analysis study in the U.S., U.K., Canada, Europe, Australia, Japanf Occupational exposures; methods of determining exposure vary by study Texaco production and pipe-line workers 5 — 0.35, p < 0.05 Overall kidney cancer: SMR = 0.98, p = 0.85. Minimum detectable SMR = 1.21. Lymphopoietic cancer: SMR = 1.03, p = 0.58. Minimum detectable SMR = 1.12. Cancer risk among petroleum workers similar to general population. Workers at three Exxon refineries 22 1.43, p = 0.09 Gulf Port Arthur study 22 — 1.23, p = 0.33 By length of employment       9 yr   — 0.93 10-20 yr   — 1.25 >20 yr   — 1.38

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Permissible Exposure Levels for Selected Military Fuel Vapors Case-referent study in Finlandg Industrial hygienists assessed work histories, industry, and occupation and assigned exposures; 338 matched sets of cases and referents. Exposure of men and women       Gasoline exposure significantly associated with risk of renal cancer. Some hydrocarbon constituents or additives of gasoline are conducive to renal-cell cancer. Time period for the study, 1920-1968. Gasoline 39 1.72 (1.03-2.87) — Diesel, distilled fuel oils 21 1.20 (0.63-2.27) — Exposure of men only       Gasoline 23 2.05 (1.05-3.98) — Diesel or other distilled fuel oil only 6 0.68 (0.23-2.01) —   Both 13 1.29 (0.55-3.02) — a Siemiatycki et al., 1987. b Rushton and Alderson, 1983. c Schnatter et al., 1992. d Poole et al., 1993. RR determinations rather than OR. e Tsai et al., 1993; study in two California Shell refinery and petrochemical facilities. f Wong and Raabe, 1989. g Partanen et al., 1991. / 93

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Permissible Exposure Levels for Selected Military Fuel Vapors potential exposure to gasoline for at least 1 year indicated no increased mortality from either kidney cancer or leukemia, when compared with the general population (ENSR Health Sciences, 1992). The study involved 9,026 land-based terminal workers (i.e., service-station workers) and 9,109 marine distribution workers. There was no association between mortality from kidney cancer or leukemia and various indexes of gasoline exposure, including duration of employment, duration of exposure, age at first exposure, year of first exposure, job category, cumulative exposure, frequency of peak exposures, and average intensity of exposure. Among land-based terminal employees, there was a nonsignificant increase in mortality from acute myeloid leukemia (SMR = 150.5), based on 13 deaths, but no association was found with the various indexes of gasoline exposure. The excess in acute myeloid leukemia was limited to land-based terminal employees hired before 1948, whereas a deficit for this cause of death was observed among marine employees (SMR = 74). The cohort study (ENSR Health Sciences, 1992) was prompted in part by two cohort studies and three case-control studies that reported associations between exposures in the petroleum industry and increased risk of kidney cancer. Rushton and Alderson (1983) observed an excess mortality from kidney and suprarenal cancer among drivers in a cohort study of British marketing employees (SMR, 171; borderline significant). A more recent mortality study of 34,597 Canadian petroleum employees observed a nonsignificant increase in kidney cancer among marketing transportation workers (SMR, 1.34; 95% CI, 0.61–2.54); the increase was slightly higher among marketing workers (SMR, 1.53; 95% CI, 0.61 –3.16) (Schnatter et al., 1992). Analyses of the entire cohort revealed a significant increase in malignant melanoma and a nonsignificant increase in multiple myeloma. A population-based case-control study of kidney cancer (495 cases of renal-cell carcinoma, 74 cases of cancer of the renal pelvis, and 679 controls) reported associations with petroleum, tar,

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Permissible Exposure Levels for Selected Military Fuel Vapors or pitch with no information specific to military fuels (McLaughlin, 1984). For renal-cell arcinoma, the OR risk was 1.7 (95% CI, 1.0 –2.9), and for cancer of the renal pelvis, the OR risk was 2.4 (95% CI, 0.9–6.1). A subsequent investigation on the same renal-cell-carcinoma study group, however, concluded that there was no difference between the cases and controls in the proportion of persons with petroleum-related employment (McLaughlin et al., 1985). Although the latter study does not discuss the discrepancy with the former study, few subjects (less than 2%) are noted as ever working in petroleum refineries, which precludes an evaluation of refinery workers. Steineck et al. (1990) reported results of a case-control study of 320 patients with urothelial cancer or squamous-cell carcinoma of the lower urinary tract. Exposure to benzene (any annual dose) was associated with a RR of 2.0 (95% CI, 1.0–3.8), and exposure to diesel and gasoline exhausts was associated with a nonsignificant increased risk. Poole et al. (1993) conducted a case-control study of 102 kidney-cancer deaths identified from previous U.S. refinery cohort studies. They found no association between kidney-cancer mortality and exposure to nonaromatic liquid gasoline distillates at concentrations typical of refinery background exposure. However, three groups appeared to be at an increased risk of kidney cancer when compared with office workers, professionals, and technicians. Increased risk appeared to be among workers in receipt, storage, and movements (RR, 2.5; 95% CI, 0.9–6.6), laborers (RR, 1.9; 95% CI, 1.0–3.9), and unit cleaners (RR, 2.3; 95% CI, 0.5–9.9). None of these risks is large (and two of the three are not statistically significant), but the possibility of exposure misclassification, which might have affected detection of modest positive associations, exists. A cohort mortality study conducted by Tsai et al. (1993) of two California refinery and petrochemical plants reported no significant excess of deaths due to kidney cancer (8 observed and 6.03

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Permissible Exposure Levels for Selected Military Fuel Vapors expected; SMR, 1.33). No predominant pattern of job type existed among those individuals, and multiple chemical exposures were present. Wong and Raabe (1989) reported an overall SMR for kidney cancer of 0.98 in their meta-analysis. The SMR for lymphopoietic cancer was 1.03. They concluded that employees in the petroleum industry as a whole experienced similar risks of cancers as the general population. For skin cancer, analysis of the available epidemiological data suggests an increased incidence of skin cancer among workers who operate machinery that leads to exposure to lubricating oils derived from coal tar or petroleum (Bingham et al., 1979). EXPERIMENTAL ANIMAL STUDIES 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 tumorigenesis 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. Distinct JP-4-induced respiratory toxicity was not observed, and pulmonary neoplasms were not significantly increased in any treatment group. Benign hepatocellular adenomas were slightly increased in female mice exposed at high dosages, but the trend was reversed in male mice. The study did not demonstrate target-organ toxicity or carcinogenesis that could be extrapolated to other species. Mice and rats of both sexes have been exposed to various concentrations of unleaded gasoline. The toxicological properties of military fuels are likely to be similar to those of gasoline, which

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Permissible Exposure Levels for Selected Military Fuel Vapors has been studied extensively in chronic toxicity assays. Three concentrations of unleaded gasoline vapor (67, 292, and 2,056 ppm) were administered to mice and rats for 6 hr per day, 5 days per week over a lifetime, i.e., 103 to 113 weeks. Total exposure was thus considerably higher in the gasoline studies than in any of the military-fuel studies. In the gasoline experiments, the most prominent finding was pathological changes in the kidneys of male rats. Kidney carcinomas in male rats were observed at all dose concentrations, and there was some evidence of a dose-response relationship. The few kidney neoplasms found in female rats and in mice were considered unrelated to exposure. It was concluded that the occurrence of kidney cancer in male rats was related to the exposure to unleaded gasoline (MacFarland et al., 1984). In view of those results, the question must be asked whether longer exposure of male rats to JP-5, JP-8, or DFM might have resulted in the development of kidney tumors. However, the kidney lesions observed in male rats are not believed to be relevant to humans. It is now generally recognized that kidney lesions produced by hydrocarbons in male rats are likely to be a unique lesion confined to male rats. Briefly, the lesion, known as α2u-globulin nephropathy, is a toxicological syndrome that occurs in male rats. The livers of male rats secrete a unique protein, α2u-globulin, which binds reversibly to certain chemicals and their metabolites. The α2u-globulin protein complex subsequently accumulates in renal lysosomes but proves to be resistant to proteolytic hydrolysis. As a result, toxicity and death of individual cells occur in the proximal renal tubules. Cell death in the kidney is followed by cell proliferation and development of tubular hyperplasia in the convoluted proximal tubules; if exposure to the chemical continues, these effects can persist for prolonged periods. At the same time, granular casts formed from sloughed cell debris form in the tubular lumen, accompanied by tubular dilatation and papillary mineralization. Sustained cell proliferation then is thought to serve as a promoting stimulus, which allows initiated kidney cells to expand and develop into preneoplastic

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Permissible Exposure Levels for Selected Military Fuel Vapors foci and eventually into kidney tumors. So far, this process has been seen only in male rats. No evidence for a similar sequence of events has been found in species that do not form this specific protein, including humans, nor has it been observed in rats that lack the capability to synthesize α2u-globulin. A thorough analysis of the α2u-globulin neuropathy observed in male rats was conducted in 1991 by the U.S. Environmental Protection Agency (EPA, 1991). EPA concluded that the mechanism of kidney-tumor induction by certain chemicals in the male rat was unique. Therefore, the occurrence of kidney tumors in only male rats should not be used as an indicator of susceptibility in other species, including humans. An evaluation of the data on JP-5, JP-8, and DFM indicate that the reported kidney changes strongly resemble the α2u-globulin nephropathy. The histopathological changes described in male rats after exposure to JP-5, JP-8, or DFM are similar to the changes that were described in rats exposed to unleaded gasoline and other compounds known to produce this syndrome. Absence of similar changes in female rats, mice, and dogs exposed to the military fuels reinforce the conclusion. Because the α2u-globulin has been seen so far only in male rats, the kidney lesions in male rats after exposure to military fuels were not considered appropriate to use in evaluating the proposed exposure limits of the fuels. Skin tumors have been reported in experimental animals dermally exposed to petroleum hydrocarbons (Bingham et al., 1965, 1979). Analysis of several skin-painting studies done with petroleum derivatives reveal common features, the most prominent one being severe skin irritation. On occasion, skin irritation and ulceration develop after only a few weeks of treatment with the test fuels (Clark et al., 1988). Development of skin lesions interferes with interpretation of the histopathological data. Severe damage to the kidneys was observed in a chronic-exposure skin-painting study of JP-5 and DFM (Easley et al., 1982). It was not clear whether the lesions were caused directly by the fuels or whether they were the result of dehydration caused by excessive water loss from damaged skin.

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Permissible Exposure Levels for Selected Military Fuel Vapors A second common feature of many skin-painting studies is that the various fuels often show widely different carcinogenic potential. For example, in a study on the comparative carcinogenicity of several shale- and petroleum-derived distillates, it was found that tumors appeared in 87% of mice exposed to crude petroleum distillate. In mice exposed to shale- and petroleum-derived diesel fuel, only 7% developed skin neoplasms (Clark et al., 1988). Water treatment of the fuels usually greatly diminished or even completely abolished the carcinogenic activity of the fuels (Clark et al., 1988; Witschi et al., 1987). The National Toxicology Program (NTP) conducted a skin-painting study of DFM and JP-5 (NTP, 1986). Male and female B6C3F1 mice were painted on the back five times a week with JP-5 or DFM at 250 mg/kg or 500 mg/kg. The test agents were supplied by Wright-Patterson Air Force Base and were assumed to be identical to the agents used in inhalation bioassays (see Chapter 5 on kidney lesions). Severe skin lesions (dermatitis and ulcerations) led to termination of the experiment at 84 weeks for male and female mice treated with DFM and at 90 weeks for female mice treated with JP-5. The experiment was terminated after 103 weeks (as planned) for all the other groups. Few skin tumors were found in mice exposed to DFM. However, a statistically significant positive trend was found for squamous-cell papillomas and carcinomas. (Total numbers of tumors at the site of application and the adjacent inguinal skin were 1/50 (vehicle), 2/49 (low dose), and 3/50 (high dose) in males and 0/50 (vehicle), 1/45 (low dose), and 2/48 (high dose) in females.) In mice exposed to JP-5 fuel, there was a marked increase in the incidence of chronic dermatitis; the increase was dose-related. Only two skin tumors were found in the 300 mice exposed to JP-5, and both were in the high-dose group (one male and one female). Following review, the NTP concluded that, under the conditions of the experiment, there was equivocal evidence of carcinogenicity of DFM because the study showed only a marginal increase in skin tumors attributable to exposure to DFM. There was no evidence for carcinogenicity of JP-5 fuel. After review of

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Permissible Exposure Levels for Selected Military Fuel Vapors all the data, the IARC concluded that there is inadequate evidence for carcinogenicity of JP-5, whereas DFM is considered possibly carcinogenic to humans. CONCLUSIONS An analysis of the available human data on occupational exposure to military fuel vapor suggests a weak association with kidney cancer or other cancers. However, the data do not provide a consistent body of evidence needed to support the conclusion that exposure to military fuels carries a risk of kidney cancer, hematopoietic cancer, or other cancer. 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 unique to male rats. Accordingly, occurrence of these lesions, including development of kidney tumors in male rats, is not an appropriate indicator of toxicity that might be expected to occur in other species, including humans. There appears to be no reason to assume that the three fuels of concern in this report constitute a carcinogenic hazard with regard to development of kidney tumors. There is also only tenuous evidence that these fuels pose a carcinogenic hazard to the skin. Exposure conditions in the animal studies that resulted in excessive skin damage are unlikely to occur in humans. There is some evidence that the appearance of skin tumors might depend on skin irritation and accompanying cell proliferation (McKee et al., 1989; Skisak, 1991). However, the subcommittee recommends that appropriate protective clothing be worn to avoid dermal exposures to the fuels.