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 National Research Council report Permissible 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 summarized in Table 12-1. Because the available data on JP-8 are sparse, the subcommittee also reviewed carcinogenicity and genotoxicity data on some individual components of JP-8 that are identified as major components (by weight percent) or as carcinogens. The subcommittee used the body of available information to assess the carcinogenic potential of JP-8 in humans.

SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT

The National Research Council (NRC) Subcommittee 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



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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 National Research Council report Permissible 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 summarized in Table 12-1. Because the available data on JP-8 are sparse, the subcommittee also reviewed carcinogenicity and genotoxicity data on some individual components of JP-8 that are identified as major components (by weight percent) or as carcinogens. The subcommittee used the body of available information to assess the carcinogenic potential of JP-8 in humans. SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT The National Research Council (NRC) Subcommittee 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

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TABLE 12-1 Carcinogenic Effects of Fuels in Humans and Experimental Animals Fuel Type Species or Cell Line Exposure Concentration Exposure Duration Effects Reference Jet fuel Human (historical prospective cohort study of 2,176 men in Swedish armed forces) Not reported Not reported No evidence of association between exposure to jet fuel and lymphatic malignancies Selden and Ahlborg 1991 as cited in ATSDR 1998 Jet fuel Human (population-based case-referent study of cohort of 3,726 cancer patients) Not reported Not reported Screening-level analyses suggested association between kerosene exposure and stomach cancer, but result was not confirmed by in-depth analyses; screening analyses indicated that subjects with prior exposure to jet fuel (n = 43) had OR of 2.1 for colon cancer (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 Siemaitycki et al. 1987 Jet fuel Human (population-based case-control study; Not reported Not reported Indication of excess risk of renal-cell carcinoma among aircraft mechanics and others with workplace exposures to jet fuel Parent et al. 2000

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  142 male patients with renal cancer, 1,900 controls with other types of cancers, 533 population-based controls)   JP-8 F344 rat, C57B/6 mouse 500, 1,000 mg/m3 (inhalation) 90 days continuously, then non-exposure period until 24 mo of age No treatment-related tumors were observed in rats or mice of either sex; male rats had treatment-related accumulation of hyaline droplets in proximal convoluted tubular epithelium of kidney consistent with male alpha-2u-globulin nephropathy, a condition is specific to male rats Mattie et al. 1991 JP-8 F344 rat 750, 1,500, 3,000 mg/kg per day (oral gavage) 90 days No treatment-related tumors observed in rats; alpha-2u-globulin nephropathy, a condition specific to male rats, was observed Mattie et al. 1995 JP-5 F344 rat, C57Bl/6 mouse, Beagle dog 150, 750 mg/m3 (inhalation) 90 days continuously No increase in tumors was observed in JP-5-treated mice Gaworski et al. 1984, 1985 JP-5 B6C3F1 mouse 250 or 500 mg/kg (dermal) 5 times/wk, 103 wk (males), 90 wk (females) No increase in skin tumors was observed in JP-5-treated mice NTP 1986

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Fuel Type Species or Cell Line Exposure Concentration Exposure Duration Effects Reference JP-4 F344 rat 1,000, 5,000 mg/m3 (inhalation) 6 hr/day, 5 days/wk for 12 mo, followed by a non-exposure period of 12 mo Males in the high-dose group had statistically nonsignificant increase in renal cell tumors; authors concluded that increase in tumors was due to alpha-2u-globulin accumulation and associated nephropathy Bruner et al. 1993 Jet fuel A, lightly refined paraffinic oil C3H mouse Jet fuel A, undiluted; middle distillates, undiluted or 25% or 50% dilution in mineral oil or toluene; chemicals applied dermally Neat 2 times/wk for 2 yr or on a intermittent schedule Skin tumors found in 44% of mice treated with jet fuel A 2 times/wk and no tumors in control animals; skin tumors found in 2% of mice treated with jet fuel A intermittently; skin tumors found in 8% of mice treated with neat paraffinic oil and no tumors in mice treated with diluted material Freeman et al. 1993 Jet fuel A, JP-4 C3H/HeN mouse 25 mg/dose (dermal) 3 times/wk for up to 105 wk Skin tumors found in 28% of mice treated with shale-derived jet fuel A, 26% of mice treated with petroleum-derived jet fuel A, and skin-tumor latency was 79 wk; skin tumors found in Clark et al. 1988

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  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 middle distillates, including kerosene C3H, CD-1 mouse Undiluted or 50% or 28.6% dilutions in mineral oil 2 times/wk (undiluted), 7 times/wk (28.6%), and 4 times/wk (50%) for 52 wk or 2 yr following initiation with DMBA Mice exposed to undiluted materials had significant increases in skin tumors, with incidence of 23-57%; exposure to diluted materials did not lead to increases in numbers of skin tumors Nessel et al. 1998; Nessel et al. 1999 Lightly refined paraffinic oil CD-1 mouse Undiluted material 6 times over a 2-wk period followed by promotion with TPA (initiation assay) or DMBA treatment followed by 28-wk exposure (promotion study) Oil was not a tumor initiator; had weak tumor-promoting activity (17% skin-tumor response, compared with 0% in controls) Mckee et al. 1989

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Fuel Type Species or Cell Line Exposure Concentration Exposure Duration Effects Reference MD API 81-07 (middle distillates) CD-1 mouse Undiluted material 2 times/wk for 25 wk after initiation MD API 81-70 had tumor-promoting effects; induced tumors were squamous cell carcinoma and papilloma of skin; treatment with dexamethasone inhibited tumor promotion Skisak 1991 Abbreviations: DMBA, dimethylbenzanthracene; TPA, 12-O-tetradecanoyl-phorbol-13-acetate.

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petroleum-based mixtures, such as gasoline; however, no studies of JP-5, JP-8, or DFM were located. Among 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 among 3,726 subjects in Montreal. Screening analyses suggested an association between kerosene exposure and stomach cancer, but it was not confirmed by more in-depth analyses. Screening analyses indicated that people with exposure to jet fuel (e.g., aircraft mechanics and repairmen) (n = 43) had odds 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 OR 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 support the conclusion that exposure to military jet fuels carries an excess risk of cancer at any site. The Subcommittee on Permissible Exposure Levels for Military 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 DFM 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 relevant to the present assessment. Those studies are discussed below with additional studies included in the current assessment.

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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 information collected in association with the population-based case-control study reported by Siemiatycki et al. (1987), examining the association between occupational 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 potential confounders. Multivariate logistic-regression models based on population, cancer controls, or a pool of both groups were used to estimate ORs. 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 subcommittee is aware of a suspected cancer cluster in Fallon, Nevada, 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 approximately 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 exposure to JP-8 by any route. Easley et al. (1982) reported that JP-8, JP-5, and

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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 male 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 similarity 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 male and female rats and in female mice, with observation for up to an additional 21 mo (Gaworski et al. 1984, 1985, discussed in NRC 1996), and several long-term mouse-skin-painting bioassays of jet fuel A (Clark et al. 1988; Freeman 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 middle distillate fractions (Freeman 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-day exposures and then observation until the age of 24 mo (Mattie et al. 1991, discussed in NRC 1996). F344 rats and C57BL/6 mice were exposed continuously to JP-8 vapor at 0, 500, or 1,000 mg/m3 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 accumulation 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-mo exposure studies of JP-4 and 90-day continuous-exposure studies of JP-5 discussed in the 1996 National Research 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/m3 for 6 hr/day, 5 days/wk for 12 mo; animals were allowed to live unexposed for an additional 12 mo. In rats, an increase in renal-cell tumors (three renal-cell adenomas, one carcinoma, and one sar-

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coma versus none in controls), which did not reach statistical significance, was observed in high-dose males. The authors 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/m3for 90 days. Some animals were killed immediately after cessation of exposure, and others were allowed to live unexposed for an additional 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 administered 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 uninformative 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 undiluted or as a 50% weight/volume dilution in cyclohexane; controls 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 cyclohexane 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 tumors (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 tumor 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

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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 animals (n = 1) developed skin tumors. In the second protocol, animals received a lower total dose of jet fuel A than those in the first protocol. JP-4, derived from either shale or petroleum, produced skin tumors (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 wk. JP-5 was applied to the skin of male and female B6C3F1 mice at 250 or 500 mg/kg, 5 times/wk in studies conducted by the NTP (NTP 1986). Male mice were treated for 103 wk; 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 “under the conditions of these 2-yr dermal studies, JP-5 navy fuel at doses of 250 and 500 mg/kg provided no evidence of carcinogenicity for male and female B6C3F1 mice.” 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 with a tumor 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 paraffinic 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 animals that received either the neat material or material diluted in toluene but not in animals that received material diluted in mineral oil. The role of skin irritation in the development of skin tumors was investigated by Nessel et al. (1998). In lifetime C3H mouse skin-painting studies, MDFs, 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

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skin tumors nor irritation. In followup studies described by Nessel (1999), equal weekly doses of irritating (neat), minimally irritating (50% dilution), and nonirritating (28.6% dilution) MDFs, 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 assessment, reported that JP-8 treatment was associated with the development of alpha 2u-globulin nephropathy (Mattie et al. 1995). OTHER RELEVANT DATA Other relevant data not included in the 1996 National Research Council report but considered in the present assessment include those from tumor-initiation and -promotion studies of jet fuels and other middle distillates and those on the carcinogenicity and genotoxicity of several individual components of JP-8. Tumor 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 (DMBA) (Nessel et al. 1999). Other MDFs have been tested for tumor-promoting activity in the same model system. In addition, hydrodesulfurized kerosene, hydrodesulfurized 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 mice, comparing equal weekly doses of irritating and minimally irritating or nonirritating test material, to assess whether tumor promotion occurred as a secondary response to irritation. Jet fuel A was applied to DMBA-initiated CD-1 mouse skin at 100% 2 times/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 promoter: about 40% of

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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 summarized by Nessel (1999), MDFs 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 tumor-promoting activity in CD-1 mouse skin-painting studies (API 1989, as summarized 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 API 81-10) were strong promoters compared with toluene-treated controls after initiation with DMBA. McKee et al. (1989) tested the initiating and promoting 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) was administered 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 DMBA-treated mouse skin in a 28-wk study. The lightly refined paraffinic oil had weak promoting activity, producing a 17% skin tumor response (five of 30 mice) compared with a 0% skin tumor response (none of 30 mice) in DMBA-treated mice that did not receive promoter treatment (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 secondary 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/wk. Both lightly refined paraffinic oil and C10-C14 normal paraffins were tumor promoters, and both were irritating to the skin when applied undiluted. Dilution greatly reduced skin irritation and tumor-promoting activity. Skisak (1991) tested the tumor-promoting activity of MD API 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 API 81-07 had tumor-promoting effects, inducing squamous cell carcinoma and papilloma of the skin. Acanthosis, a uniform thickening of the epidermis due

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to hyperplasia of the stratum spinosum, was the most common finding in MD API 81-07 treated animals. Inflammation of the skin was observed in some animals, as were excessive numbers of inflammatory 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 requirement for development of skin tumors in this initiation-promotion model. Treatment with dexamethasone, a potent antimitotic and anti-inflammatory agent that inhibits mouse epidermal DNA synthesis, 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 small amount 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 benzene as a known human carcinogen (Group 1) on the basis of sufficient evidence that benzene causes leukemia in humans and sufficient evidence of carcinogenicity in animals (IARC 1987). Butylbenzene Butylbenzene is one of the top 10 constituents of JP-8 (by weight percentage). No data on the carcinogenicity of butylbenzene were identified in the published literature. Tert-butylbenzene was not mutagenic when tested in five Salmonella strains and two strains of Escherichia coli. It did not induce mitotic

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gene conversion in Saccharomyces cerevisiase, and it did not induce chromosomal aberrations in rat liver (RL1) cells in vitro (HSDB 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 tumor-promoting activity (Van Duuren 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 human carcinogen (Group 2B) on the basis of sufficient evidence of carcinogenicity in experimental animals 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 percentage). 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 Duuren and Goldschmidt 1976).

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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 evidence of carcinogenicity in experimental animals and inadequate evidence in humans (IARC 2002). Two-year inhalation carcinogenicity studies in B6C3F1 mice and F344/N rats of both sexes were conducted 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 basis of increased 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 concentration 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 (ACGIH 1999). One male each in the 30- and 60-ppm groups had metastases of olfactory epithelial neuroblastoma to the lungs. Olfactory epithelial neuroblastoma and respiratory epithelial adenoma 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 B6C3F1 mouse studies, animals were exposed to naphthalene vapors at 0, 10, or 30 ppm 6 hr/day, 5 days/wk for 2 yr, and an increased incidence of alveolar/bronchiolar adenoma was observed in the 30-ppm group of female mice (NTP, 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 lymphoblastoid MCL-5 cells, and somatic mutations and recombination in Drosophila. Naphthalene was not mutagenic in Salmonella, nor did it induce DNA damage in E. coli (as reviewed by NTP 2000). Tetradecane Tetradecane is one of the top 10 constituents of JP-8 (by weight percentage). It exhibited cocarcinogenicity by enhancing the mouse skin carcinogenic-

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ity of benzo[a]pyrene (when applied to the skin 3 times/wk with a low dose of benzo[a]pyrene) (Van Duuren and Goldschmidt 1976) and of ultraviolet radiation (Bingham and Nord 1977). Tetradecane was also tested as a tumor promoter in a two-stage carcinogenesis assay and found to have tumor-promoting activity (Van Duuren 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 published literature. It was not mutagenic in Salmonella, 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 Wyszynska 1999). Undecane Undecane 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 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 epidemiologic 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 continuous 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 cultured 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 (volume/volume) of the fuel, are known to be carcinogenic. The

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carcinogenicity data available on mixtures similar to JP-8 (such as other jet fuels and MDFs) indicate that most of these materials induce skin tumors in mice when topically applied in excessive amounts. The mixtures 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 subcommittee concludes that the available data are insufficient to draw a conclusion regarding the carcinogenicity of inhaled JP-8. However, 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 Defense (DOD) conduct lifetime carcinogenicity bioassays by the inhalation route in two animal species to determine whether JP-8 is carcinogenic via inhalation. The subcommittee also recommends that DOD follow a cohort of military personnel (including obtaining their exposure history) to determine whether exposure to JP-8 is associated with an increased incidence of various types of cancers. The subcommittee is aware that Air Force personnel engaged in particular jobs (such as fuel-cell workers) are sometimes dermally exposed to substantial amounts of JP-8 (see Chapter 2). The subcommittee recommends that appropriate protective clothing be worn to avoid dermal exposures to JP-8. REFERENCES Abdo, K.M., S. Grumbein, B.J. Chou, and R. Herbert. 2001. Toxicity and carcinogenicity 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 mice. Inhal. Toxicol. 4(4):393-409. ACGIH (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 Dermal 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 Promotion Phases. Final Report. API 36-32643. Washington, DC: American Petroleum 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, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA.

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