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Toxicologic Assessment of Jet-Propulsion Fuel 8 (2003)

Chapter:12 Carcinogenic Effects of Jet-Propulsion Fuel 8

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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"12 Carcinogenic Effects of Jet-Propulsion Fuel 8." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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12 Carcinogenic Effects of Jet-Propulsion Fuel 8 This chapter summarizes the findings on carcinogenicity of jet-propulsion fuel 8 (JP-8) presented in the N ational Research C ouncil report Perm issible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) and reviews additional studies on JP-8 and related mixtures, some of which were completed after the 1996 report was published. The studies are sum marized in Table 12-1. Because the available data on JP-8 are sparse, the subcommittee also reviewed carcinogenic- ity and genotoxicity data on som e individual components of JP-8 that are identified as major components (by weight percent) or as carcinogens. The subcomm ittee used the body of available information to assess the carcino- genic potential of JP-8 in hum ans. SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT The National Research Council (NRC ) Subcomm ittee on Permissible Exposure Levels for Military Fuels reviewed studies relevant to the evaluation of the carcinogenicity of JP-5, JP-8, and diesel fuel marine (DFM ) (NRC 1996). The review included epidemiologic studies of exposures to jet fuels and other 141

TABLE 12-1 Carcinogenic Effects of Fuels in Humans and Experimental Animals 142 Species or Exposu re Exposu re Fuel Type Cell Line Concentration Duration Effec ts Reference Jet fuel Hum an Not reported Not reported No evidence o f association between e xposure Selden and (historical to jet fuel and lymphatic malignancies Ahlborg prospective 1991 as cohort study of cited in 2,176 m en in ATSDR Swedish armed 1998 forces) Jet fuel Hum an Not reported Not reported Screening-level analyses suggested association Siemaitycki (population- between kerosene exposure and stomach et al. 1987 based case- cancer, but result was not confirmed by in- referent study of depth analyses; screening analyses indicated cohort of 3,726 that subjects with prior exposure to jet fuel (n cancer patients) = 43) had O R of 2.1 for colon can cer (n = 7), 2.1 for rectal cancer (n = 4), and 2.5 for kidney cancer (n = 7); in-depth analyses indicated association between jet-fuel exposure and kidney cancer (OR = 3.4) for workers exposed at substantial level (n = 6); dose-response relation observed for jet-fuel exposure and increased risk of kidney cancer Jet fuel Hum an Not reported Not reported Indication of excess risk of renal-cell Parent et al. (population- carcinoma among aircraft mechanics and 2000 based case- others with workplace exposures to jet fuel control study;

142 male patients w ith renal cancer, 1,900 controls with other types of cancers, 533 population- based controls) JP-8 F344 rat, 500, 1,000 90 days No treatm ent-related tumors w ere obse rved in Mattie et al. C57B /6 m ouse mg/m 3 continuously, rats or mice of either sex; male rats had 1991 (inhalation) then non- treatment-related accumulation of hyaline exposure droplets in proximal convoluted tubular period u ntil epithelium of kid ney consistent with male 24 mo of age alpha-2u -globulin nephropathy, a con dition is specific to male rats JP-8 F344 rat 750, 1,500, 90 days No treatm ent-related tum ors observed in rats; Mattie et al. 3,000 mg/kg alpha-2u-globulin nephropathy, a condition 1995 per day (oral specific to male rats, was observed gavage) JP-5 F344 rat, 150, 750 90 days No increase in tumors was observed in JP-5- Gaworski et C57Bl/6 mouse, mg/m 3 continuo usly treated mice al. 1984, Beagle dog (inhalation) 1985 JP-5 B6C3F 1 mou se 250 or 500 5 times/wk, No increase in skin tumors was observed in JP- NTP 1986 mg/kg 103 wk 5-treated mice (dermal) (males), 90 wk (fem ales) (Continued) 143

TABLE 12-1 Continued 144 Species or Exposu re Exposu re Fuel Type Cell Line Concentration Duration Effec ts Reference JP-4 F344 rat 1,000, 5,000 6 hr/day, 5 Males in the high-d ose group had statistically Bru ner et al. mg/m 3 days/wk for nonsignificant increase in renal cell tumo rs; 1993 (inhalation) 12 mo, authors concluded that increase in tumors was followed by a due to alpha-2u-globulin accumulation and non- associated nephropathy exposure period of 12 mo Jet fuel A, C3H mou se Jet fuel A, Neat 2 Skin tumors found in 44% of mice treated with Freeman et lightly undiluted; times/wk for jet fuel A 2 times/wk and no tumors in control al. 1993 refined middle 2 yr or on a animals; skin tumors found in 2% of mice paraffinic distillates, intermittent treated with jet fuel A interm ittently; skin oil undiluted or schedule tumors found in 8% of mice treated with neat 25% or 50% paraffinic oil and no tumors in mice treated dilution in with diluted material mineral oil or toluene; chemicals applied dermally Jet fuel A, C3H/H eN 25 m g/dose 3 times/wk Skin tumors found in 28% of mice treated with Clark et al. JP-4 mou se (dermal) for up to 105 shale-derived jet fuel A, 26% of mice treated 1988 wk with petroleum-derived jet fuel A, and skin- tum or late ncy was 79 w k; skin tum ors fo und in

50% of mice treated with shale-derived JP-4, 26% of mice treated with petroleum-derived JP-4, and skin-tumor latency was 84 wk Several C3H , CD-1 Undiluted or 2 times/wk Mice exposed to undiluted materials had Nessel et al. middle mou se 50% or 28.6% (und iluted ), 7 significant inc reases in skin tum ors, with 1998; Nessel distillates, dilutions in times/wk incidence of 23-57%; exposure to diluted et al. 1999 including mineral oil (28.6%), and materials did not lead to increases in num bers kerosene 4 times/wk of skin tumors (50%) for 52 wk or 2 yr following initiation with DMBA Lightly CD -1 mou se Undiluted 6 times over Oil was not a tumor initiator; had weak tumor- Mckee et al. refined material a 2-wk promoting activity (17% skin-tumor response, 1989 paraffinic period com pared w ith 0% in controls) oil followed by promotion with TPA (initiation assay) or DMBA treatment followed by 28-wk exposure (promotion study) (Continued) 145

TABLE 12-1 Continued 146 Species or Exposu re Exposu re Fuel Type Cell Line Concentration Duration Effec ts Reference MD API CD -1 mou se Undiluted 2 times/wk MD API 81 -70 had tum or-prom oting effects; Skisak 1991 81-07 material for 25 wk induced tumors were squamous cell carcinoma (middle after and papillom a of skin; treatment with distillates) initiation dexamethasone inhibited tumor promotion Abbreviations: DM BA, dimethylbenzanthracene; TPA, 12-O-tetradecanoyl-p horbol-1 3-ac etate.

Carginogenic Effects of Jet-Propulsion Fuel 8 147 petroleum-based mixtures, such as gasoline; however, no studies of JP-5, JP-8, or DF M were located. Am ong the studies discussed in the 1996 report, the historical prospective cohort study of men in the Swedish armed forces (Selden and Ahlborg 1991) and the population-based case-referent study of Siemiatycki et al. (1987) appear to be the most relevant to the present assessment of JP-8. Selden and Ahlborg (1991) reported that total cancer incidences were generally lower than expected in the cohort of 2,176 men in the Swedish armed forces, and they observed no associations between aircraft fuel and cancer at any site. The 1996 report noted as possible limitations of that study the short followup period (9-10 years [yr]) and selection bias. Siemiatycki et al. (1987) investigated possible associations between exposures to 12 petroleum-derived liquids, including jet fuel and kerosene, and cancer am ong 3,726 subjects in M ontreal. Screening analyses suggested an association between kerosene exposure and stomach cancer, but it was not confirmed by more in-depth analyses. Screen- ing analyses indicated that people with exposure to jet fuel (e.g., aircraft me- chanics and repairmen) (n = 43) had odd s ratios (ORs) of 2.1 (90% CI, 0.9-5.1) for colon cancer (n = 7), 2.1 (0.6-7.4) for rectal cancer (n = 4), and 2.5 (1.1-5.4) for kidney cancer (n = 7). More in-depth analyses indicated an association between jet fuel and kidney cancer with an O R of 3.4 (1.5-7.6) for workers exposed at a substantial level (n = 6). A dose-response relation was observed for jet-fuel exposure and increased risk of kidney cancer, and the authors judged the strength of the evidence of this association as moderate to strong. On the basis of in-depth analyses, the authors also found a nonsignificant excess of colorectal cancers associated with jet-fuel exposure and noted a report of a slight excess of colorectal cancer (22 observed, 18 expected) among aircraft mechanics in Washington state. The subcommittee concluded that the data did not provide a consistent body of evidence sufficiently robust to sup- port the conclusion that exposure to military jet fuels carries an excess risk of cancer at any site. The Subcommittee on Permissible Exposure Levels for M ilitary Fuels also discussed animal studies of chronic inhalation exposures to JP-4 and unleaded- gasoline vapor; studies of subchronic inhalation exposures to JP-8, JP-5, and JP-4; and studies of dermal exposure (skin painting) to JP-5 and DFM (NRC 1996). No lifetime inhalation animal bioassays of JP-5, JP-8, or D FM were located. Among the studies discussed in the 1996 report, the subchronic inhalation studies of JP-8 (Mattie et al. 1991) and the studies of JP-5 (Gaworski et al. 1984, 1985; NTP 1986) and JP-4 (Bruner et al. 1993) are the most rele- vant to the present assessment. Those studies are discussed below with addi- tional studies included in the current assessm ent.

148 Toxicologic A ssessment of Jet-Propulsion F uel 8 CARCINOGENICITY STUDIES IN HUMANS No long-term studies of the chronic health effects, including cancer, of JP- 8 exposure have been conducted . With regard to epidemiologic studies of related jet fuels, one additional study published after the release of the 1996 NRC report was identified (Parent et al. 2000). Numerous studies of the carcinogenic potential of gasoline streams and related middle distillates have appeared in the open literature. Parent et al. (2000) conducted further analyses of the occupational infor- mation collected in association with the population-based case-control study reported by Siemiatycki et al. (1987), examining the association between occu- pational exposures and renal-cell cancer. Some 142 male patients with renal- cell carcinoma, 1,900 controls with cancer at other sites, and 533 population- based controls were interviewed for occupational histories and data on poten- tial confounders. Multivariate logistic-regression models based on population, cancer controls, or a pool of both groups were used to estimate OR s. With regard to aviation fuel, the authors reported indications of excess risks among aircraft mechanics (OR, 2.8; 95% CI,1.0-8.4) and among people employed in defense services for more than 10 yr (OR, 3.0; 95% CI,1.2-7.4). Excess risk of renal-cell cancer was associated with workplace exposures to jet fuel (OR, 3.5; 95% CI, 1.4-8.7) and aviation gasoline (OR, 3.5; 95% CI, 1.4-8.6). The latter analyses were adjusted for nonoccupational and occupational potential confounders. The authors noted that the high degree of correlation within the study population between exposures to jet fuel and aviation gasoline precluded assessment of the risks posed by each independently. The subcomm ittee is aware of a suspected cancer cluster in Fallon, Ne- vada, and that exposure to JP-8, originating from a naval base located in that town, is under investigation as a possible cause of the cluster (exposures to other chemicals are being investigated as well). Since 1997, sixteen persons currently or previously living in Fallon have been diagnosed with acute lymphocytic leukemia (ALL), a type of childhood cancer. One case of ALL would be expected approxim ately every 5 yr in Churchill County, where Fallon is located, based on the size of the population (Nevada State Health Division 2002). No scientific studies were found that examined a potential relationship between ALL and JP-8 exposure; therefore, the subcommittee could not reach any conclusion concerning exposure to JP-8 and this suspected cancer cluster. CARCINOGENICITY STUDIES IN ANIMALS No data are available on long-term rodent carcinogenicity studies of expo- sure to JP-8 by any route. Easley et al. (1982) reported that JP-8, JP-5, and

Carginogenic Effects of Jet-Propulsion Fuel 8 149 DFM were administered to mice by the dermal route for 60 wk; however, the extremely limited reporting of skin-tumor findings in all treatment groups combined renders these studies uninformative with regard to carcinogenicity. Subchronic studies of 90-day inhalation exposures to JP-8, with observation for an additional 20-21 months (mo), have been conducted in rats and mice of both sexes (Mattie et al. 1991, discussed in NRC 1996); and a 90-day gavage study of JP-8 in m ale rats has been reported (Mattie et al. 1995). Given the absence of data from carcinogenicity studies on JP-8, data on other middle-distillate fraction-derived mixtures with various degrees of simi- larity to JP-8 are discussed briefly below, including studies of 12-mo inhalation exposures to JP-4 in rats and mice with observation for an additional 12 mo (Bruner et al. 1993, discussed in NRC 1996), subchronic studies of 90-day inhalation exposures to JP-5 in m ale and fem ale rats and in fem ale mice, with observation for up to an additional 21 mo (Gaworski et al. 1984, 1985, dis- cussed in NRC 1996), and several long-term mouse-skin-painting bioassays of jet fuel A (Clark et al. 1988; Freem an et al. 1993), JP-4 (Clark et al. 1988), JP-5 (NTP 1986, discussed in NRC 1996), MD API 81-07, a hydrodesulfurized kerosene (API 1988, as cited by Skisak 1991), straight-run kerosene (Nessel et al. 1998), and other mid dle distillate fractions (Freem an et al. 1993). Inhalation-Exposure Studies JP-8 has not been tested in lifetime rodent carcinogenicity bioassays by the inhalation route. It has been tested in rats and mice of both sexes in studies with 90-d ay exposu res and then observation until the age of 24 mo (Mattie et al. 1991, discussed in NR C 1996). F344 rats and C57BL/6 mice were exposed continuously to JP-8 vapor at 0, 500, or 1,000 mg/m 3 for 90 days and then allowed to recover until the age of 24 mo. No treatment-related tumors were seen in rats or mice of either sex. Male rats exhibited treatment-related accu- mulation of hyaline droplets in the proximal convoluted tubular epithelium of the kidney, which was consistent with male alpha 2u-globulin nephropathy. The short duration of exposure to JP-8 in the studies severely limits their usefulness for purposes of carcinogenicity assessment. Other jet fuels have not been tested in lifetime rodent carcinogenicity bioassays by the inhalation route, but 12-m o exposure stu dies of JP-4 and 90- day continuous-exposure studies of JP-5 discussed in the 1996 National Re- search Council report are briefly described here. Bruner et al. (1993) exposed groups of 100 F344 rats of each gender and 100 C57Bl/6 mice of each gender to JP-4 at 1,000 or 5,000 mg/m 3 for 6 hr/day, 5 days/wk for 12 mo; anim als were allow ed to live unexposed for an additional 12 m o. In rats, an increase in renal-cell tumors (three renal-cell adenomas, one carcinoma, and one sar-

150 Toxicologic A ssessment of Jet-Propulsion F uel 8 coma versus none in controls), which did not reach statistical significance, was observed in high-dose m ales. The au thors attributed that increase in renal-cell tumors to alpha 2u-globulin accumulation and associated nephropathy. In mice, a statistically significant (p < 0.05) increase in hepatocellular adenomas was observed in high-dose females (two of 83, one of 79, and eight of 80 for control, low-dose, and high-dose groups, respectively), and a single hepatocellular carcinoma occurred in the high-dose group. Gaworski et al. (1984, 1985) exposed groups of male and female F344 rats and female C57BL/6 mice to petroleum- or shale-derived JP-5 continuously at 150 or 750 mg/m 3for 90 days. Som e animals were killed immed iately after cessation of exposu re, and others w ere allowed to live unexposed for an addi- tional 19 or 21 mo. No treatment-related tumors were observed in rats or mice. Dermal-Exposure Studies One report of carcinogenicity studies of JP-8 adm inistered dermally to mice was identified in the published literature (Easley et al. 1982), but the extremely limited reporting of skin-tumor findings render the studies uninfor- mative with regard to carcinogenicity. Briefly, groups of 15 C3H /fBd mice of each gender received dermal applications of JP-8, JP-5, or DFM 3 times/wk for 60 wk und iluted or as a 50% weight/volume dilution in cyclohexane; con- trols received cyclohexane. The entirety of the information provided in the published report on tumor occurrence consists of the statement that “skin tumors occurred in only 34 of the 360 test mice and in only 1 of 60 cyclohex- ane control mice.” Jet fuels other than JP-8 have been tested for carcinogenicity in animal studies by the dermal route. In addition to the skin-painting studies of JP-5 by the National Toxicology Program (NTP 1986) discussed in the 1996 NRC report, studies of jet fuel A (Clark et al. 1988; Freeman et al. 1993) and JP-4 (Clark et al. 1988) are described here. Jet fuel A, derived from either shale or petroleum, produced skin tum ors (squamous cell carcinoma and fibrosarcoma) in groups of 25 C3H/HeN mice of each gender treated 3 times/wk at 25 mg/dose for up to 105 wk (Clark et al. 1988). Twenty-eight percent of the shale-derived and 26% of the petroleum- derived jet fuel A-treated mice developed skin tumors; the observed skin tu- mor latency was 79 wk. Freeman et al. (1993) tested jet fuel A in the C3H mouse skin-painting model, using two treatment protocols. In the first protocol, jet fuel A was applied neat twice a week to the skin of C3H mice for 2 yr. In the second

Carginogenic Effects of Jet-Propulsion Fuel 8 151 protocol, jet fuel A was applied intermittently; treatment was suspended when marked signs of dermal irritation were noted in 20% of the animals. In the first treatment protocol, jet fuel A produced tumors in 44% of the treated mice—and marked skin irritation—compared with 0% tumors in untreated and mineral-oil controls. In the second protocol, only 2% of the treated anim als (n = 1) developed skin tumors. In the second protocol, animals re- ceived a lower total dose of jet fuel A than those in the first protocol. JP-4, derived from either shale or petroleum, produced skin tum ors (squamous cell carcinomas and fibrosarcoma) in groups of 25 C3H /HeN mice of each gender treated 3 times/wk at 25 mg/dose for up to 105 wk (Clark et al. 1988). Fifty percent of the shale-derived and 26% of the petroleum-derived JP-4-treated mice developed skin tumors; the observed skin tumor latency was 84 w k. JP-5 was applied to the skin of male and female B6C3F 1 mice at 250 or 500 mg/kg, 5 times/wk in studies conducted by the NTP (N TP 1986). Male mice were treated for 103 w k; female mice were sacrificed at 90 wk because of excessive irritation and ulceration at the site of application. No increase in skin tumors was observed in JP-5-treated mice, and the NTP concluded that “un- der the conditions of these 2-yr derm al studies, JP-5 navy fuel at doses of 250 and 500 mg/kg provided no evidence of carcinogenicity for male and female B6C3F1 m ice.” As summarized by Nessel (1999), middle distillate fractions (MDFs) have been tested in numerous lifetime mouse skin-painting studies over the last 20 yr. Early mouse skin-painting studies documenting the carcinogenicity of MDFs in mouse skin include those of Lewis et al. (1984) and Biles et al. (1988), as cited by Nessel (1999). MD API 81-07, a hydrodesulfurized kerosene, was also shown to induce skin tumors in a C3H/HeJ mouse skin-painting 2-yr bioassay in 50% of the animals w ith a tum or latency of 76 wk (API 1988, as cited by Skisak 1991). An MDF known as lightly refined paraffinic oil was tested in the C3H mouse skin-painting model, applied neat and in 25% and 50% dilutions in mineral oil or in toluene (Freeman et al. 1993). The neat lightly refined paraf- finic oil induced tumors in 8% of the treated mice; no tumors were observed in animals that received the diluted material. Skin irritation was observed in anim als that received either the neat material or material diluted in toluene but not in anim als that received material diluted in mineral oil. The role of skin irritation in the development of skin tumors was investi- gated by Nessel et al. (1998). In lifetime C3H mouse skin-painting studies, MD Fs, including a straight-run kerosene, were applied neat and in 50% and 28.6% dilutions. Treatment with the neat straight-run kerosene induced skin tumors and skin irritation; treatment with the diluted material produced neither

152 Toxicologic A ssessment of Jet-Propulsion F uel 8 skin tumors nor irritation. In followup studies described by N essel (1999), equal weekly doses of irritating (neat), minimally irritating (50% dilution), and nonirritating (28.6% d ilution) MD Fs, including a straight-run kerosene, were applied to the skin of C3H mice for 2 yr. Skin tumors were induced in mice that received the neat straight-run kerosene but not in mice that received equal doses of the straight-run kerosene in a diluted, nonirritating form. Oral-Exposure Studies JP-8 has not been tested in lifetime rodent carcinogenicity bioassays by the oral route. A 90-day gavage study in male Sprague-Dawley rats, although inadequate for purposes of carcinogenicity assessm ent, reported that JP-8 treatment w as associated with the development of alpha 2u-globulin nephro- pathy (M attie et al. 1995). OTHER RELEVANT DATA Other relevant data not included in the 1996 National Research Council report but considered in the present assessment includ e those from tumor- initiation and -promotion studies of jet fuels and other middle distillates and those on the carcinogenicity and genotoxicity of several individual com ponents of JP-8. Tum or Initiation and Promotion JP-8 has not been tested for tumor-initiating or -promoting activity. Jet fuel A has been tested for tumor promoting activity in the CD-1 mouse model of skin tumors initiated by dimethylbenzanthracene (DM BA) (Nessel et al. 1999). Other MDFs have been tested for tumor-promoting activity in the same model system. In addition, hydrodesulfurized kerosene, hydrodesulfur- ized middle distillates, and lightly refined paraffinic oil have been tested for initiating activity with the model. Those studies are briefly described below. Nessel et al. (1999) conducted a 1-yr tumor-promotion study of jet fuel A in CD-1 m ice, comparing equal weekly doses of irritating and minimally irritat- ing or nonirritating test material, to assess whether tumor promotion occurred as a secondary response to irritation. Jet fuel A was applied to DM BA-initiated CD -1 mouse skin at 100% 2 tim es/wk, or 50% dilution in mineral oil 4 times/wk, or 28.6% dilution in mineral oil 7 times/wk. Jet fuel A (100% ) was very irritating to the skin and was an effective tumor prom oter: about 40% of

Carginogenic Effects of Jet-Propulsion Fuel 8 153 treated mice developed squamous cell carcinomas or papillomas. Diluted jet fuel A was not irritating to the skin, nor did it have any tumor-promoting effects. As summ arized by Nessel (1999), MD Fs have been tested in several initiation-promotion mouse skin-painting studies designed to investigate the multistage process of tumorigenesis. Hydrodesulfurized kerosene (MD API 81-07) and hydrodesulfurized middle distillates (MD API 81-10) were tested for tumor-initiating and tum or-prom oting activity in CD-1 mouse skin-paint- ing studies (A PI 1989, as summ arized by Nessel 1999). Both test materials were negative in the initiation assay compared with acetone-treated controls. Both hydrodesulfurized kerosene (MD API 81-07) and hydrodesulfurized middle distillates (MD A PI 81-10) w ere strong promoters compared with toluene-treated controls after initiation w ith DMBA . McK ee et al. (1989) tested the initiating and prom oting activity of a lightly refined paraffinic oil in the CD-1 male mouse skin-painting model. In the initiator test, the lightly refined paraffinic oil was applied to mouse skin 6 times over a 2-wk period, and then the promoter 12-0-tetradecanoylphorbol 13- acetate (TPA) w as adm inistered for a period of 1 yr. Lightly refined paraffinic oil was not a tumor initiator in this assay: only three of 30 animals that were treated with the test material and TPA developed skin tumors compared with nine of 30 control animals that were treated with acetone and TPA. In the promoter test, the lightly refined paraffinic oil was applied to DMB A-treated mouse skin in a 28-wk study. The lightly refined paraffinic oil had weak pro- moting activity, producing a 17% skin tumor response (five of 30 mice) com- pared with a 0% skin tumor response (none of 30 mice) in DMBA -treated mice that did not receive prom oter treatm ent (p = 0.026, one-tailed test) (McKee et al. 1989). Lightly refined paraffinic oil and C10-C14 normal paraffins were tested in 1-yr tumor-promotion studies in DMBA -treated CD-1 mice (Nessel et al. 1999). Equal weekly doses of irritating and minimally irritating or nonirritating test materials were compared to assess whether tumor promotion was a sec- ondary response to these effects. Test materials were applied to CD-1 mouse skin at 100% 2 times/wk at 50% dilution in mineral oil 4 times/wk, or at 28.6% dilution in mineral oil 7 times/w k. Both lightly refined paraffinic oil and C10-C14 normal paraffins were tumor promoters, and both w ere irritating to the skin when applied undiluted. Dilution greatly reduced skin irritation and tum or-promoting activity. Skisak (1991) tested the tum or-promoting activity of M D A PI 81-07, a hydrosulfurized kerosene, in CD -1 mouse skin treated with DMBA. MD API 81-07 was applied 2 times/wk for 25 wk to the skin of treated mice. MD A PI 81-07 had tumor-promoting effects, inducing squamous cell carcinoma and papilloma of the skin. Acanthosis, a uniform thickening of the epidermis due

154 Toxicologic A ssessment of Jet-Propulsion F uel 8 to hyperplasia of the stratum spinosum, was the most comm on finding in MD API 81-07 treated animals. Inflammation of the skin was observed in some animals, as were excessive num bers of inflam matory cells in the dermis (mixed population of neutrophils, lymphoid cells, histocytes, and mast cells). The author noted that subacute inflammation at early to midstudy points did not correlate well with tumor incidence and concluded that subacute inflammation was not a significant factor in tumor promotion by MDFs such as MD API 81- 07. The author suggested that induction of a lasting, mild hyperplasia is an essential but not sufficient requirem ent for development of skin tum ors in this initiation-promotion model. Treatment with dexamethasone, a potent antim i- totic and anti-inflammatory agent that inhibits mouse epidermal DN A synthe- sis, reduced acanthosis and completely inhibited tumor promotion by MD API 81-07. Carcinogenicity and Genotoxicity of Individual Components of JP-8 The available data on the carcinogenicity of JP-8 are sparse. In light of that sparseness, and the sm all am ount of data available on related mixtures, such as other jet fuels and MDFs, the carcinogenicity and genotoxicity of some individual components of JP-8 that are identified as being among the top 10 constituents of the liquid fuel (by weight percentage) or as carcinogens are briefly discussed below. Benzene Benzene is present at low concentrations in JP-8, generally at 0.1-0.8 wt %. The International Agency for Research on Cancer (IARC) has classified ben- zene as a known human carcinogen (Group 1) on the basis of sufficient evi- dence that benzene causes leukemia in humans and sufficient evidence of carcinogenicity in animals (IA RC 1987). Butylbenzene Butylbenzene is one of the top 10 constituents of JP-8 (by weight percent- age). No data on the carcinogenicity of butylbenzene were identified in the published literature. Tert-butylbenzene was not mutagenic when tested in five Salm onella strains and tw o strains of Escherichia coli. It did not induce m itotic

Carginogenic Effects of Jet-Propulsion Fuel 8 155 gene conversion in Saccharomyces cerevisiase, and it did not induce chromosomal aberrations in rat liver (RL1) cells in vitro (H SDB 2001). Decane Decane is one of the top 10 constituents of JP-8 (by weight percentage). It exhibited cocarcinogenicity by enhancing the mouse skin carcinogenicity of benzo[a]pyrene (Van Duuren and Goldschmidt 1976) and of ultraviolet light (Bingham and Nord 1977). Decane was also tested as a tumor promoter in a two-stage carcinogenesis assay, and found to have tum or-promoting activity (Van D uuren and Goldschmidt 1976). Dodecane Dodecane is one of the top 10 constituents of JP-8 (by weight percentage). It exhibited cocarcinogenicity by enhancing the mouse skin carcinogenicity of benzo[a]pyrene (when used as the diluent) (Bingham and Falk 1969) and of ultraviolet light (Bingham and Nord 1977). Ethylbenzene Ethylbenzene is present at low concentrations in JP-8. IARC has classified it as a possible hum an carcinogen (Group 2B ) on the basis of sufficient evi- dence of carcinogenicity in experimental anim als and inadequate evidence in humans (IARC 2000). In 2-yr inhalation bioassays conducted by the NTP, increased incidences of renal tumors and testicular adenomas were observed in male rats exposed to ethylbenzene at 750 ppm, and the incidences of several tumor types in the lung, liver, thyroid, and pituitary of mice were significantly increased (NTP 1999). Studies on the genotoxicity of ethylbenzene have generally shown a lack of genetic effects (IARC 2000). Hexadecane Hexadecane is one of the top 10 constituents of JP-8 (by weight percent- age). It partially inhibited the mouse skin carcinogenicity of benzo[a]pyrene when it was applied to the skin 3 times/wk with a low dose of benzo[a]pyrene (Van D uuren and Goldschmidt 1976).

156 Toxicologic A ssessment of Jet-Propulsion F uel 8 Naphthalene Naphthalene is present in JP-8 at about 1.14 wt %. It has been used as a biomarker of JP-8 exposure in that it is detectable in breath, blood, and urine of people exposed to JP-8. The International Agency for Research on Cancer (IARC) has classified napthalene as a possible human carcinogen (Group 2B) on the basis of sufficient evid ence of carcinogenicity in experimental anim als and inadequate evidence in hum ans (IARC 2002). Two-year inhalation carci- nogenicity studies in B6C3F1 mice and F344/N rats of both sexes were con- ducted by the NTP. The NTP found clear evidence of the carcinogenicity of naphthalene in male and female F344/N rats exposed to naphthalene vapors at 0, 10, 30, or 60 ppm for 6 h/day, 5 days/wk for 2 yr on the b asis of in- creased incidences of respiratory epithelial adenoma (males, control, low-dose, middle-dose, and high-dose groups, 0%, 12%, 17% , and 31%, respectively; females, 0%, 0%, 8%, and 4%, respectively) and olfactory epithelial neuroblastoma of the nose (males, 0%, 0%, 8%, and 6%; females, 0%, 4%, 6%, and 24%) (Abdo et al. 2001; NTP 2000). The lowest exposure concentra- tion used in the rat studies equals the threshold limit value for the 8-hr, time- weighted average established by the American Conference of Governmental Industrial Hygienists (A CG IH 1999). O ne m ale each in the 30- and 60-ppm groups had metastases of olfactory epithelial neuroblastoma to the lungs. Olfactory epithelial neuroblastom a and respiratory epithelial adenom a are unusual in the F344/N rat and had not been observed previously in NTP studies. Neuroblastomas of the nasal olfactory epithelium are rare neoplasms in rodents and humans (Pino et al. 1999; McElroy et al. 1998, as cited by Abdo et al. 2001). In the B6C3F 1 mouse studies, animals were exposed to naphthalene va- pors at 0, 10, or 30 ppm 6 hr/day, 5 days/wk for 2 yr, and an increased inci- dence of alveolar/bronchiolar adenoma was observed in the 30-ppm group of female m ice (N TP, 1992, Abdo et al, 1992). As reviewed by the NTP (2000), naphthalene has been shown to cause sister chromatid exchanges (SCEs) and chromosomal aberrations in Chinese hamster ovary cells, micronuclei (MNs) in human lym phoblastoid MC L-5 cells, and somatic mutations and recombination in Drosophila. Naphthalene was not mu tagenic in Salm onella, nor did it induce DNA damage in E. coli (as reviewed by N TP 2000). Tetradecane Tetradecane is one of the top 10 constituents of JP-8 (by weight percent- age). It exhibited cocarcinogenicity by enhancing the mouse skin carcinogenic-

Carginogenic Effects of Jet-Propulsion Fuel 8 157 ity of benzo[a]pyrene (w hen applied to the skin 3 times/wk with a low dose of benzo[a]pyrene) (Van Duuren and Goldschmidt 1976) and of ultraviolet radia- tion (Bingham and Nord 1977). Tetradecane was also tested as a tumor pro- moter in a two-stage carcinogenesis assay and found to have tumor-promoting activity (V an D uuren and Goldschmidt 1976). 1,2,4,5-Tetramethylbenzene 1,2,4,5-Tetramethylbenzene is one of the top 10 constituents of JP-8 (by weight percentage). No data on its carcinogenicity were identified in the pub- lished literature. It was not mutagenic in Salm onella, and it did not induce MNs in the in vivo mouse bone marrow cell assay (Janik-Spiechowicz and Wyszynska 1999). It did induce SCEs in the bone marrow of mice in a dose- dependent manner (Janik-Spiechowicz and W yszynska 1999). Undecane Undecane is one of the top 10 constituents of JP-8 (by weight percentage). It exhibited cocarcinogenicity by enhancing the mou se skin carcinogenicity of benzo[a]pyrene (when applied to the skin 3 times/wk together with a low dose of benzo[a]pyrene) (Van Duuren and Goldschmidt 1976). Undecane was not mutagenic in Salmonella in the presence or absence of metabolic activation (Connor et al. 1985). CONCLUSIONS AND RECOMMENDATIONS The carcinogenicity of JP-8 has not been investigated in epidem iologic studies. Chronic lifetime inhalation-exposure studies have not been conducted in experimental animals to determine the carcinogenicity of JP-8 or related jet fuels. No increase in the incidence of tumors was observed in 90-day continu- ous inhalation-exposure studies of JP-5 conducted in F344 rats and C57BL/6 mice (with a 19- or 21-mo observation period after cessation of exposure). Positive results of in vitro genotoxicity tests in cu ltured human and rat cell lines suggest that JP-8 has the potential to induce DNA damage; however, the genotoxicity of JP-8 has not been evaluated adequately in vivo. As described in Chapter 3, JP-8 is a complex chemical mixture that comprises about 1,000 components. Among those on which carcinogenicity data are available, three chemicals (benzene, ethylbenzene, and naphthalene), which together make up 1% or less (volum e/volum e) of the fuel, are know n to be carcinogenic. The

158 Toxicologic A ssessment of Jet-Propulsion F uel 8 carcinogenicity data available on mixtures sim ilar to JP-8 (such as other jet fuels and MDFs) indicate that most of these m aterials induce skin tum ors in mice when topically applied in excessive amounts. The m ixtures have also been shown to have tumor-promoting but not tumor-initiating activity in the two-stage mouse skin tumor model. However, those carcinogenic effects are observed only under conditions of excessive skin irritation. The subcom mittee concludes that the available data are insufficient to draw a conclusion regarding the carcinogenicity of inhaled JP-8. H owever, because some studies show that chronic dermal exposure to high doses of jet fuels or other petroleum products produces skin tumors, the subcommittee recommends that the Department of D efense (DOD) conduct lifetime carci- nogenicity bioassays by the inhalation route in two animal species to determine whether JP-8 is carcinogenic via inhalation. T he subcomm ittee also recom- mends that DOD follow a cohort of military personnel (including obtaining their exposure history) to determ ine w hether exposu re to JP-8 is associated with an increased incidence of various types of cancers. The subcomm ittee is aware that Air Force personnel engaged in particular jobs (such as fuel-cell workers) are sometimes dermally exposed to substantial amou nts of JP-8 (see Chapter 2). The subcomm ittee recommends that appro- priate protective clothing be worn to avoid dermal exposures to JP-8. REFERENCES Abdo, K.M ., S. Grum bein, B.J. Chou , and R . Herb ert. 2001. Toxicity and carcinoge- nicity study in F344 rats following 2 years of whole-body exposure to naphthalene vapors. Inhal. Toxicol. 13(10):931-950. Abdo, K.M., S.L. Eustis, M. McDonald, M.P. Jokinen, B. Adkins Jr, and J.K. Haseman. 1992. Naphthalene: A respiratory tract toxicant and carcinogen for m ice. Inhal. Toxicol. 4(4):393-409. AC GIH (American Conference of Governmental Industrial Hygenists). 1999. 1999 TLVs and BEIs: Threshold Limit Values for Chemical Substances and Physical Agents. Biological Exposure Indices. Cincinnati, OH: ACGIH. API (American Petroleum Institute). 1988. Lifetime Derm al Carcinogenesis Bioassay of Refinery Streams in C3H/HeJ Mice (API 135r). API Med. Res. Publ. 36- 31364. Washington, DC: American Petroleum Institute. API (American Petroleum Institute). 1989. Short-Term Dermal Tumorigenesis Study of Selected Petroleum Hydrocarbons in Male CD-1 Mice: Initiation and Promo- tion Phases. Final Report. AP I 36-32643. Washington, DC: American Petro- leum Institute. 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, Pub lic Health Service, Agency for Toxic Su bstances and Disease R egis- try, Atlanta, GA.

Carginogenic Effects of Jet-Propulsion Fuel 8 159 Biles, R.W ., R.H. McKee, S.C . Le wis, R.A. Scala, and L.R. DePass. 1988. Dermal carcinogenic activity of petroleum -derived m iddle distillate fu els. Toxicology 53(2-3):301-314. Bingham, E., and H.L. Falk. 1969. Environm ental carc inogens. The modifying effect of cocarcinogens on the threshold response. Arch. Environ. Health 19(6):779- 783. Bingham, E., and P.J. Nord. 1977. Cocarcinogenic effects of n-alkanes and ultravio- let light on mice. J. Natl. Cancer Inst. 58(4):1099-1101. Brune r, R.H ., E.R. Kinkead, T.P. O ’Neill, C.D . Flem ming, D .R. M attie, 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. Clark, C.R., M.K. Walter, P.W. Ferguson, and M. Katchen. 1988. Comparative dermal carcinogenesis of shale and petroleum-derived distillates. Toxicol. Ind . Health 4(1):11-22. Conn or, T.H., J.C. Theiss, H.A. Hanna, D.K. Monteith, and T.S. Matney. 1985. Genotoxicity of organic chemicals frequently found in the air of mobile hom es. Toxicol. Lett. 25(1):33-40. Easley, J.R., J.M . Holland, L.C. Gipson, and M.J. Whitaker. 1982. Renal toxicity of middle distillate s of shale oil and petroleu m in mice. Toxicol. Ap pl. Pharm acol. 65(1):84-91. Freeman, J.J., T.M . Fed erici, and R.H. McKee. 1993. Evaluation of the contribution of chronic skin irritation and selected com positional parameters to the tumorige- nicity of petroleum middle distillates in mouse skin. Toxicology 81(2):103-112. Gaworski, C.L., J.D. MacEwen, E.H. Vernot, R.H. Brun er, 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. Applied Toxicology of Petroleum Hydrocarbons, H.N. MacFarland, C.E. Holdworth, J.A. MacGregor, R.W. Call, and M.L. Lane, eds. Princeton, NJ: Princeton Scientific Publishers. Gaworski, C.L ., J.D. Mac Ewan, E.H. Vernot, C.C. Hau n, H.F. Leah y, R.H. Brun er, G.B. Baskin and M.J. Cowan Jr. 1985. Evaluation of the 90-day Inhalation Tox- icity of Petroleum and O il Shale JP-5 Jet Fuels. AFAM RL-TR-85-035. NM RI 85- 18. Air Force Aerospace Medical Research Laboratory, Wright Patterson Air Force Base, OH . April 1985. HSDB (Hazardous Substance Data Bank). 2001. Tertiary-butylbenzene. Hazardous Substance Data Bank, National Library of Medicine. [Online]. Available: http://toxnet.nlm.nih.gov/ [May 31, 2002]. IARC (International A gency fo r Re search on Cancer). 1987. Pp. 120-222 in O verall Evaluation of Carcinogenicity: An Updating of IARC Mono graphs Vo lumes 1 to 42. IARC M onographs on the Evaluation of the Carcinogen ic Risk to Hu- mans, Suppl. 7. Lyon: IARC. IARC (International Agency for Research on Cancer). 2000. Ethylbenzene. Pp. 227-266 in Some Industrial Chemicals, IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans, Vol. 77. Lyon: IARC. IARC (International Agency for Research on Cancer). 2002. Some Traditional Herbal

160 Toxicologic A ssessment of Jet-Propulsion F uel 8 Medicines, Some Mycotoxins, Naphthalene and Styrene, IARC M onographs on the Evaluation of the Carcinogenic Risk to Humans, Vol. 82 (in preparation, as cited at http://monograp hs.iarc.fr/ htdocs/ announ cem ents/vol82.ht). Janik-Spiechow icz, E., and K. Wyszynska. 1999. Genotoxicity evaluation of tetramethylbenzenes. Mutat. Res. 439(1):69-75. Lew is, S.C., R.W . King, S.T. Cragg, and D .W. Hillm an. 1984. Skin carc inogenic potential of petroleum hydrocarbons: Crude oil, distillate fractions and chemical class subfractions. Pp 139-150 in Advances in M odern Environm ental Toxicol- ogy, Vol. 6. Applied Toxicology of Petroleum Hyd rocarbons, H.N. MacFarland, C.E. Holdworth, J.A. M acG rego r, R.W . Call, and M.L. La ne, eds. Princeton, N J: Princeton Scientific Publishers. Mattie, D.R ., C.L. Alden, T .K. N ewell, C.L. Gaworski, an d C .D. F lem ming. 19 91. A 90-day continu ous 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. Tox icol. Pathol. 19(2 ):77-8 7. Mattie, D.R., G.B. Marit, C.D. F lem ming, an d 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. McElroy, E.A., Jr., J.C. Buckner, and J.E. Lewis. 1998. Chemotherapy for advanced esthesioneuroblastoma: The Mayo Clinic experience. Neurosurgery 42(5):1023- 1028. McKee, R.H., R.T. Plutnick, and R.T. Przy god a. 1989. The carcinogenic initiating and promoting properties of a lightly re fined para ffinic oil. Fundam . Appl. To xicol. 12(4): 748-756. Nessel, C.S. 1999. A co mpre hensive evaluation of the carcinogenic potential of middle distillate fuels. Drug Chem. Toxicol. 22(1):165-180. Nessel, C.S., J.J. Freem an, R .C. Forga sh, and R.H. M cKee. 1999. The role of dermal irritation in the skin tu mor prom oting activity of petroleum mid dle distillates. Toxicol. Sci. 49(1):48-55. Nessel, C.S., R.A. Priston, R.H. McKee, G. Cruzan, A.J. Riley, R. Hagemann, R.T. Plutnick, and B.J. Simpson. 1998. A comprehensive evaluation of the mecha- nism of skin tumorigenesis by straight-run and cracked petroleum mid dle d istil- lates. Toxicol. Sci. 44(1):22-31. Nevada State Health D ivision. 2002. Churchill County (Fallon) Childhood Leuke mia Update, August 20, 2002 Comm unity Meeting. [Online] Available : http://health2 k.state.nv.us/healthofficer/Leukemia/Fallon.htm [October 28, 2002]. NRC (National Research Council). 1996. Permissible Exposure Levels for Selected Military Fuel V apors. Washington , DC: N ational Acade my P ress. NTP (National Toxicology Program). 1986. Toxicology and Carcinogenesis Studies of Marine Diesel Fuel and JP-5 Navy Fuel (CAS No. 8008-20-6) in B6C3F1 M ice (Dermal Studies). NTP 310. NIH 86-2566. Research T riangle Park, NC: Na- tional Toxicology Program/National Institutes of Health. NTP (National Toxicology Program). 1992. NTP Technical Report on the T oxicol- ogy and C arcinogenesis Studies of N aphthalene (C AS No. 91-20-3) in B6C2F 1 Mice (Inhalation Studies). NT P TR 410. N IH 92-3 141. Research T riangle Park,

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This report provides a critical review of toxicologic, epidemiologic, and other relevant data on jet-propulsion fuel 8, a type of fuel in wide use by the U.S. Department of Defense (DOD), and an evaluation of the scientific basis of DOD's interim permissible exposure level of 350 mg/m3

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