3
UNCOMBUSTED FUELS AND COMBUSTION PRODUCTS: BACKGROUND INFORMATION

In addition to the partially combusted crude oil associated with the well-publicized oil-well fires, several petroleum-derived fuels were present in the Persian Gulf region during Operation Desert Shield and Operation Desert Storm, including gasoline, kerosene, diesel, and jet-propulsion fuels JP-4, JP-5, and JP-8. Those fuels were used by the military to power aircraft, ground vehicles, tent heaters, and cooking stoves. They were also used for less conventional purposes, such as suppressing sand, cleaning equipment, and burning trash. Military personnel serving in the Gulf War theater of operations could have been exposed to the uncombusted fuels, the combustion products from the burning of those fuels, or a combination of uncombusted and combusted materials.

This chapter provides background information on fuels and their combustion products separately. Information on the individual components of combustion products are discussed when it is available and relevant. The main exposure routes of concern are inhalation and dermal; ingestion of fuels by Gulf War personnel is of much less concern. As noted in Chapter 2, the committee used data from animal and in vitro studies mainly as background information and to provide support, when possible, for its conclusions. They were also used in deciding whether there is a causal relationship between exposure and disease. Most of the compounds discussed here are common pollutants on which there is a large volume of literature, including numerous reviews. In light of the committee’s use of the data, this chapter provides an overview of the compounds and their toxicology. The reader is referred to reviews for more details; primary toxicology studies are discussed only as warranted.

UNCOMBUSTED FUELS

Petroleum-derived fuels are complex mixtures that contain hundreds of aliphatic and aromatic hydrocarbon compounds; most also contain performance-enhancing additives. The composition of a particular fuel varies from batch to batch, depending on such factors as the source of the crude oil from which it is derived, the refining process used in its production, and the product specifications. The toxicity of some components of the fuels (for example, benzene, toluene, and xylenes) has been well characterized, but the toxicity of many, particularly the longer-chained carbon compounds, has not been extensively studied.

This section provides an overview of toxicologic information on gasoline, kerosene, diesel, JP-4, JP-5, and JP-8. It begins with summaries of physical and chemical properties of the



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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 3 UNCOMBUSTED FUELS AND COMBUSTION PRODUCTS: BACKGROUND INFORMATION In addition to the partially combusted crude oil associated with the well-publicized oil-well fires, several petroleum-derived fuels were present in the Persian Gulf region during Operation Desert Shield and Operation Desert Storm, including gasoline, kerosene, diesel, and jet-propulsion fuels JP-4, JP-5, and JP-8. Those fuels were used by the military to power aircraft, ground vehicles, tent heaters, and cooking stoves. They were also used for less conventional purposes, such as suppressing sand, cleaning equipment, and burning trash. Military personnel serving in the Gulf War theater of operations could have been exposed to the uncombusted fuels, the combustion products from the burning of those fuels, or a combination of uncombusted and combusted materials. This chapter provides background information on fuels and their combustion products separately. Information on the individual components of combustion products are discussed when it is available and relevant. The main exposure routes of concern are inhalation and dermal; ingestion of fuels by Gulf War personnel is of much less concern. As noted in Chapter 2, the committee used data from animal and in vitro studies mainly as background information and to provide support, when possible, for its conclusions. They were also used in deciding whether there is a causal relationship between exposure and disease. Most of the compounds discussed here are common pollutants on which there is a large volume of literature, including numerous reviews. In light of the committee’s use of the data, this chapter provides an overview of the compounds and their toxicology. The reader is referred to reviews for more details; primary toxicology studies are discussed only as warranted. UNCOMBUSTED FUELS Petroleum-derived fuels are complex mixtures that contain hundreds of aliphatic and aromatic hydrocarbon compounds; most also contain performance-enhancing additives. The composition of a particular fuel varies from batch to batch, depending on such factors as the source of the crude oil from which it is derived, the refining process used in its production, and the product specifications. The toxicity of some components of the fuels (for example, benzene, toluene, and xylenes) has been well characterized, but the toxicity of many, particularly the longer-chained carbon compounds, has not been extensively studied. This section provides an overview of toxicologic information on gasoline, kerosene, diesel, JP-4, JP-5, and JP-8. It begins with summaries of physical and chemical properties of the

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 various fuels and a compendium of exposure limits recommended by national and international government bodies and other organizations. That information is followed by a description of the toxicokinetics of the fuels and a summary of experimental studies conducted in humans and animals, focusing on studies that yielded information on chronic adverse health effects, on genetic susceptibility, or on interactions between fuels and other substances. The fuels discussed here have been the subjects of comprehensive reviews by the Agency for Toxic Substances and Disease Registry (ATSDR 1995a, 1995b, 1995c, 1998, 1999b), the International Agency for Research on Cancer (IARC 1989), the National Research Council (NRC 1996b, 2003), and Ritchie et al. (2003). The reader is referred to those sources for more detailed reviews of the toxicologic data on those fuels. Several components of hydrocarbon fuels—benzene, toluene, xylenes, and naphtha—were reviewed in Gulf War and Health, Volume 2: Insecticides and Solvents (IOM 2003) and will not be addressed individually here. The Committee on Gulf War and Health: Literature Review of Insecticides and Solvents found sufficient evidence of a causal relationship between benzene and both acute leukemia and aplastic anemia. The reader is referred to that volume for more information on adverse health effects associated with exposures to benzene, toluene, xylenes, and naphtha. Physical and Chemical Properties Some of the physical and chemical properties of gasoline, kerosene, diesel, JP-4, JP-5, and JP-8 are presented in Table 3.1. They are arranged in order of increasing carbon number, that is, according to composition of relatively longer hydrocarbon chains or heavier cut of distillates. Naphthas, middle distillates used in mixing gasoline and composed primarily of C5-C13 aliphatic hydrocarbons, would fall between gasoline and JP-4. Kerosene, JP-5, and JP-8 are very similar in composition, differing primarily in the additive packages that characterize them; hence they share several synonyms. Exposure Limits Limits of occupational exposures to several fuels have been recommended by such organizations as the American Conference of Governmental Industrial Hygienists (ACGIH), ATSDR, IARC, the National Institute for Occupational Safety and Health (NIOSH), and the Occupational Safety and Health Administration (OSHA). Those values, as summarized in Table 3.2, give a sense of what fuel exposures are currently considered safe.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 TABLE 3.1 Chemical Identity and Some Physical and Chemical Properties of Selected Fuels Properties Gasoline JP-4 JP-5 JP-8 Kerosene Diesel Synonyms Motor fuel, motor spirit, natural gasoline, petrol, mogas MIL-T-5624-L-Amd. 1 wide cut (registered trade name) NATO F-44, AVCAT, MIL-T5624M NATO F-34, AVTUR, MIL-T83133B Fuel oil no. 1, Deobase, kerosene, K-1, JP-1 Auto diesel, automotive diesel oil, diesel fuel oil, diesel oil, fuel oil no. 1-D, fuel oil no. 2, fuel oil no. 2-D, fuel oil no. 4, gas oil   aviation kerosene, kerosene, fuel oil no. 1, jet kerosene, turbo fuel A, straight run kerosene, distillate fuel oils light   CAS registry no. 8006–61–9 50815–00–4 8008–20–6 (kerosene) 70892–10–3 (fuel oil no. 1) 8008–20–6 (kerosene) 70892–10–3 (fuel oil no. 1) 8008–20–6 68334–30–5 (general diesel fuel) Average molecular weight 108 No data found No data found No data found No data found No data found Range of carbon numbers C4-C13 C4-C16 C9-C17 C9-C17 C10-C16 C10-C19 Approximate composition   -Alkanes 54.3 (wt. %) 75–78 (wt. %) 84 (vol. %) 71–78 (vol. %) 78–96 (vol. %) 64–85 (vol. %) -Alkenes 1.8 4–7 0.5 0.5–5 0–5 1–10 -Aromatics 30.5 14–15 16 12–22 4–25 5–30 Additives Octane enhancers, antioxidants, metal deactivators, ignition controllers, icing inhibitors, detergents/dispersants, corrosion inhibitors Icing inhibitors, antioxidants, corrosion inhibitors, metal deactivators, anti-static agents Icing inhibitors, antioxidants, corrosion inhibitors, anti-static agents, lubrication improvers, biocides, thermal stability improvers Icing inhibitors, static inhibitors, corrosion inhibitors, antioxidants, metal deactivators No data found Ignition improvers/centane enhancers, smoke suppressors/combustion enhancers, detergents, flow improvers, cloud-point depressors, wax anti-settlers, static inhibitors, corrosion inhibitors, antioxidants, anti-foam agents, dehazers, biocides, lubricants, odor maskers Physical state Liquid Liquid Liquid Liquid Liquid Liquid Color Colorless to pale brown Colorless to straw colored Clear Clear Colorless to brown Colorless to brown Odor Gasoline-like Like gasoline and/or Kerosene-like Kerosene-like Kerosene-like Kerosene-like

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Properties Gasoline JP-4 JP-5 JP-8 Kerosene Diesel   kerosene   Melting point −90.5–−95.4°C −46°C −46°C −52°C −45.6°C −48–18°C Boiling point 39–204°C 45–300°C 150–290°C 175–300°C 175–325°C 101–588°C Density 0.7–0.8 g/ml (temperature not specified) 0.75–0.80 g/ml (at 15°C) 0.79–0.85 g/ml (at 15°C) 0.79–0.85 g/ml (at 15°C) 0.80 g/ml (at 20°C) 0.87–1.0 g/ml (at 20°C) Solubility   -Water Insoluble (at 20°C) 57 mg/L (at 20°C) ≈5 mg/L (at 20°C) ≈5 mg/L (at 20°C) ≈5 mg/L (at 20°C) ≈5 mg/L (at 20°C) -Organic solvents Absolute alcohol, ether, chloroform, benzene Generally miscible with organic solvents Miscible with other petroleum solvents Miscible with other petroleum solvents Miscible with other petroleum solvents No data found Flashpoint −46°C −23–1°C 60°C 38°C 38°C 38–58°C NOTES: CAS=Chemical Abstracts Services; JP-4=jet-propulsion fuel 4; JP-5=jet-propulsion fuel 5; JP-8=jet-propulsion fuel 8. When several data points were found for a property of a given fuel, they are presented as a range. SOURCES: ATSDR (1995a, 1995b, 1995c, 1998, 1999b), Budavari et al. (1989), HSDB (2003a, 2003b), NRC (1996b, 2003), WHO (1996).

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 TABLE 3.2 Recommended Exposure Limits for Fuels Organization Fuel Type Type of Exposure Limit Recommended Exposure Value Reference Occupational Exposure Limits ACGIH Gasoline TLV STEL 300 ppm=890 mg/m3, A3 (adopted 1996) 500 ppm=1,480 mg/m3 ACGIH 2003   Diesel (as a total hydrocarbons) TLV 100 mg/m3, A3, Skin (adopted 2001) ACGIH 2003   Kerosene (8088–20–6) (as a total hydrocarbon vapor) TLV 200 mg/m3, A3, Skin (proposed 2002) ACGIH 2003   Jet fuels (94114–58–6) (as a total hydrocarbon vapor) TLV 200 mg/m3, A3, Skin (proposed 2002) ACGIH 2003 AFOSH Petroleum distillates (naphtha) PEL STEL 400 ppm 500 ppm Air Force 1989   JP-5 PEL STEL 350 mg/m3 (interim) 1,000 mg/m3 (interim) Ritchie et al. 2003 NIOSH Gasoline — Carcinogen: lowest possible concentration NIOSH 1998   Kerosene REL 100 mg/m3 NIOSH 1997   Petroleum distillates (naphtha) REL 85 ppm=350 mg/m3 NIOSH 1997     Ceiling (15-min) 438 ppm=1,800 mg/m3       IDLH 10,000 ppm NIOSH 1997 OSHA Gasoline (in workroom air) PEL STEL 300 ppm=900 mg/m3 550 ppm=1,500 mg/m3 OSHA 1989 (29 CFR 1910.1000)   Petroleum distillates (naphtha) PEL 500 ppm=2,000 mg/m3 OSHA 1997 (29 CFR 1910.1000) Exposure Limits for the General Population ATSDR Gasoline (automotive) MRL None developed because of data gaps ATSDR 1995a   Diesel (fuel oil no. 2) MRL 0.02 mg/m3 (acute inhalation exposure) ATSDR 1995b

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Organization Fuel Type Type of Exposure Limit Recommended Exposure Value Reference   Kerosene (fuel oil no. 1) MRL 0.01 mg/m3 (intermediate-duration inhalation exposure) ATSDR 1995b   JP-4 MRL 9 mg/m3 (intermediate-duration inhalation exposure) ATSDR 1995c   JP-5/JP-8 MRL 3 mg/m3 (intermediate-duration inhalation exposure) ATSDR 1998 IARC Gasoline Evaluation of carcinogenicity Possibly carcinogenic to humans (group 2B) IARC 1989   Distillate (light) diesel   Not classifiable as to its carcinogenicity to humans (group 3)     Jet fuel   Not classifiable as to its carcinogenicity to humans (group 3)   NOTES: ACGIH=American Conference of Governmental Industrial Hygienists; TWA=Time-Weighted Average; TLV=Threshold Limit Value (TWA for 8-hr workday during 40-hr workweek); A3=Confirmed Animal Carcinogen with Unknown Relevance to Humans; Skin=potentially large contribution to exposure by dermal route; STEL=Short-Term Exposure Limit (15-min TWA); Ceiling=value never to be exceeded; AFOSH=Air Force Office of Safety and Health; ATSDR=Agency for Toxic Substances and Disease Registry; MRL=minimal risk level; JP-4, 5, or 8=jet-propulsion fuel 4, 5, or 8; IARC=International Agency for Research on Cancer; NIOSH=National Institute for Occupational Safety and Health; REL=Recommended Exposure Limit (TWA for 10-hr workday during 40-hr workweek); IDHL=Immediately Dangerous to Life or Health; OSHA=Occupational Safety and Health Administration; PEL=Permissible Exposure Limit (TWA for 8-hr workday during 40-hour workweek).

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Toxicokinetics Given that gasoline, kerosene, diesel, JP-4, JP-5, and JP-8 are composed of hundreds of hydrocarbon compounds, it is impractical to describe here the toxicokinetics of each component. Because fuels contain many different components, they will exhibit a wide range of variability regarding absorption, metabolism, and excretion. General aspects of the toxicokinetics of JP-8 were presented in the recent National Research Council report Toxicologic Assessment of Jet-Propulsion Fuel 8 (NRC 2003). The principles are applicable to gasoline, kerosene, diesel, JP-4, and JP-5, and they are repeated here. The major determinants of hydrocarbon toxicokinetics after systemic uptake are disposition-related physiologic properties of the organism—such as alveolar ventilation, cardiac output and blood flow to the organs, and organ volume—and partition coefficients of the fuel components. Hydrocarbons with high blood:air partition coefficients are absorbed to a greater extent than compounds with poor blood solubility. Given that most hydrocarbons have fairly high fat:air and fat:blood partition coefficients, it is not surprising that fat or adipose tissue is a major storage depot for many of the fuel components. For hydrocarbons with high fat:blood partition coefficients, metabolic clearance after cessation of exposure is especially important. Hydrocarbons and their metabolites accumulate in lipid-rich tissues, so the absence of hydrocarbons and their metabolites in exhaled air, blood, or urine does not necessarily mean the absence of systemic exposure. Cytochrome P450 enzymes metabolize most hydrocarbons by such reactions as aliphatic hydroxylation, aromatic hydroxylation, and epoxidation. Alcohol and aldehyde dehydrogenases play an important role in metabolizing alcohols into their corresponding keto acids. Phase II reactions—including conjugation with glutathione, glucuronic acid, sulfate, and glycine—are important in formation of water-soluble metabolites. Data on absorption, distribution, metabolism, and elimination of gasoline, kerosene, diesel, JP-4, JP-5, and JP-8 are sparse. The components of each of these fuels are processed primarily according to their own physicochemical properties. When Tsujino et al. (2002) applied 1ml of kerosene dermally to the abdomen of rats for 1, 3, or 6 hr, it was absorbed and distributed via blood circulation, but the aromatic compound trimethylbenzene was absorbed by the skin to a greater degree than the aliphatic hydrocarbons. Kimura et al. (1988) had similar results with inhaled gasoline and kerosene. Local and systemic effects observed after exposure to those fuels indicated that they are absorbed by the respiratory tract, the gastrointestinal tract, and the skin. Toxicokinetic information on several fuel components is available (in particular, benzene, toluene, and xylenes); but their interactions with each other and with other hydrocarbon components may affect their toxicokinetic properties (ATSDR 1989, 1990, 1991, 1995e; NRC 1996a). Experimental Studies Controlled studies of the toxicity of gasoline, kerosene, diesel, JP-4, JP-5, and JP-8 in humans and laboratory animals are summarized here, with emphasis on studies that addressed whether effects persist after cessation of exposure. Epidemiologic studies of the adverse health effects of the fuels will be discussed in later chapters.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Cancer MacFarland et al. (1984) exposed Fischer 344 rats and B6C3F1 mice to unleaded gasoline vapors by inhalation at up to about 2,000 ppm for 2 years. There was an increased incidence of hepatocellular adenomas and carcinomas in the exposed female mice but not in the exposed males. There was an increased incidence of renal adenomas and carcinomas in the exposed male rats, but not in the exposed females; these kidney tumors were probably related to a male-rat-specific nephropathy (see discussion of renal effects later in this section) that is not considered relevant to humans (ATSDR 1995a). Gasoline contains 2–3% benzene, a known human carcinogen that has been shown to cause an increased incidence of leukemia in occupationally exposed workers (ATSDR 1991; IARC 1989). No studies that assessed cancer in laboratory animals from dermal or oral exposure to gasoline were found. Middle-distillate fuels (MDFs)—which include kerosene, diesel, JP-5, and JP-8—have been shown to cause skin tumors in mice (reviewed in IARC 1989; and also reviewed in Nessel 1999). MDFs have low or no mutagenic activity and no tumor-initiating activity. They are, however, active skin-tumor promoters, requiring chronic dermal irritation and skin injury. That profile indicates that dermal carcinogenesis associated with MDFs is the result of a nongenotoxic process (Nessel 1999). No carcinogenicity studies that assessed cancer in laboratory animals from inhalation or oral exposure to MDFs were found. Genotoxicity Several in vivo and in vitro assays have shown gasoline, kerosene, diesel, JP-5, and JP-8 not to be highly genotoxic (reviewed in ATSDR 1995a, 1995b, 1995c, 1998; NRC 2003). They are not mutagenic in multiple strains of Salmonella typhinurium with and without activation (Brusick and Matheson 1978a, 1978b; Conaway et al. 1984; Deininger et al. 1991; McKee et al. 1994, 1989; Nessel 1999). Mixed results have been reported concerning mutagenicity from the in vitro mouse lymphoma assay and from in vitro and in vivo assays of induction of sister-chromatid exchanges (API 1988a, 1988b). Neurologic Effects Several studies assessed nervous system effects after cessation of exposure of laboratory animals to hydrocarbon fuels. The relevance to humans of neurobehavioral effects observed in animals, however, is not well understood. Kainz and White (1983) exposed CD-1 mice to diesel-fuel vapors at up to 204 mg/m3 for 8 hr/day for 5 days and followed the exposure with a 24-hr no-exposure period. They found that motor coordination, as measured by a rotarod test, was progressively decreased in the mice given the highest dose, but showed signs of recovery after 24 hr. Inconclusive results were reported for the hot-plate test, and no effects were observed when the mice were given the inclined-plane test or the corneal-reflex test. A series of light naphtha distillates, which are used in mixing gasoline, were tested in Sprague-Dawley rats according to a common protocol: exposure at up to 7,500 ppm for 6 hr/day 5 days/week for 13 weeks followed by motor-activity evaluation, a functional observational battery, and a neuropathology examination after a 4-week no-exposure period. Significantly higher motor activity was observed in the males given high doses of light catalytic reformed naphtha, but no other nervous system effects were observed among rats exposed to that agent

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 (Schreiner et al. 2000), to light alkylate naphtha (Schreiner et al. 1998), or to light catalytic cracked naphtha (Lapin et al. 2001). Nordholm et al. (1999) exposed Sprague-Dawley rats by inhalation to JP-4 vapors at 2,000 mg/m3 for 6 hr/day for 14 days and followed the exposure with no-exposure periods of 14 or 60 days. Similarly, Sprague-Dawley rats were exposed by inhalation to JP-8 or JP-5 vapors at up to 1,000 or 1,200 mg/m3, respectively, for 6 hr/day 5 days/week for 6 weeks, and the exposure was followed by a 65-day no-exposure period (Ritchie et al. 2001; Rossi et al. 2001). Subtle but apparently persistent changes in neurophysiologic and psychologic capacity detectable only with appropriate test batteries were observed, but no dose-response relationships were demonstrated. Koschier (1999) reported that rats dermally exposed to hydrodesulfurized kerosene at up to 495 mg/kg for 5 days/week for 13 weeks followed by a 4-week no-exposure period did not show any adverse neurobehavioral or histologic effects compared with the control group. Although this study was not an experimental investigation, former “gasoline-sniffers” (after at least a 6-month hiatus) showed higher rates of abnormal tandem gait, bilateral palmomental reflexes, and cognitive deficits in visual recognition memory and pattern-location paired associate learning than a control group (Goodheart and Dunne 1994). The magnitude of neurologic and cognitive effects correlated with duration of gasoline-sniffing and with blood lead concentrations, so the outcomes might not have been attributable entirely to the petrochemical components of the gasoline. Respiratory Effects Various respiratory effects (such as increased pulmonary resistance, interstitial edema, and damage to bronchiolar epithelium) have been observed in some subchronic and chronic animal studies immediately following exposure to hydrocarbon fuels but other studies did not find such effects (as reviewed in ATSDR 1995a, 1995b, 1995c, 1998; NRC 2003). It is not known whether the observed respiratory effects would have persisted or reversed themselves after a no-exposure period. A single large study of persistence of respiratory effects after a no-exposure period in laboratory animals exposed to a hydrocarbon fuel was found. Bruner et al. (1993) exposed mice and rats of both sexes to JP-4 vapors at 1,000 or 5,000 mg/m3 for 12 months. Immediately after the 12-month exposure period, the low-dose female mice showed mild pulmonary inflammation and the low-dose males of both species showed hyperplasia of the nasolacrimal duct epithelium. No effects were present in either species 12 months after exposure. Hepatic Effects A number of studies have assessed the potential of subchronic or chronic exposure to hydrocarbon fuels to cause hepatic effects in laboratory animals immediately after exposure (as reviewed in ATSDR 1995a, 1995b, 1995c, 1998; NRC 2003). Several studies of subchronic or chronic exposure of mice to unleaded gasoline vapors at about 2,000 ppm showed hepatic effects, such as hypertrophy, increased cytochrome P450 content, and tumor-related necrosis and hemorrhage. Other studies of subchronic or chronic exposure at similar concentrations did not find any adverse hepatic effects in rats and monkeys (ATSDR 1995a). Increased liver weight has been associated with subchronic exposure of mice, rats, dogs, and monkeys to JP-4 vapors at up to 5,000 mg/m3 (MacNaughton and Uddin 1984). Reversible

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 hepatocellular fatty changes in mice, but not in rats and dogs, have been associated with subchronic exposure to JP-4 vapors at up to 1,000 mg/m3 (MacEwen and Vernot 1984). Inconsistent results have been reported in inhalation-, oral-, and dermal-exposure studies of hepatic effects caused by kerosene, JP-5, and JP-8 (which are similar in composition). Several subchronic inhalation studies found hepatic effects: increased glycolysis in rats (Starek and Vojtisek 1986); increased hepatic basophilic foci in male rats but not in female rats or in mice (Mattie et al. 1991); and reversible diffuse mild swelling of hepatocytes, decreased serum glutamic pyruvic transaminase, mild hepatic hyperplasia, increased hepatocyte vacuolization, fatty changes in hepatocytes, and increased liver adenomas in rats, mice, and dogs and increased liver weight only in dogs (Keller et al. 1984). Other studies with similar exposure conditions did not report any hepatic effects (Bogo et al. 1983; Carpenter et al. 1976; Parton 1994). Two studies assessed the persistence of hepatic effects after a no-exposure period in laboratory animals exposed to a hydrocarbon fuel. Dennis (1982) found no hepatic lesions 14 days after applying JP-4 at 2,000 mg/kg to the skin of rabbits. (Bruner et al. 1993) observed no liver toxicity in rats exposed to JP-4 vapors at 1,000 or 5,000 mg/m3 for 6 hr/day 5 days/week for 12 months. However, after a 12-month no-exposure period, non-dose-related decreases were found in the liver weights of the male, but not female, rats. Of mice exposed at the same concentrations and for the same duration, only high-dose females had an increase in lymphocytic inflammatory infiltrates in the liver at the end of the exposure period, but that effect was no longer found at the end of the 12-month no-exposure period (Bruner et al. 1993). Cardiovascular Effects Because hydrocarbons historically have been used as anesthetics and abused as narcotics, inhalation of hydrocarbons is well known to have acute effects on the cardiovascular system (NRC 1996b). They can induce potentially fatal cardiac arrhythmias, but for arrhythmias to occur epinephrine must be released simultaneously with inhalation (Garb and Chenoweth 1948). Chronic effects of hydrocarbon fuels on the cardiovascular system have not been well studied. Gastrointestinal Effects Gastrointestinal effects have been observed in laboratory animals after oral exposure to gasoline (gastric erythema, erosion of the gastric mucosa, and ulceration of the epithelium) and kerosene (gastritis and hyperplasia) and after inhalation exposure to JP-4 (emesis) (reviewed in ATSDR 1995a, 1995b, 1995c, 1995e, 1998). Immimologic Effects MDFs have been shown to be weak to moderate skin sensitizers in laboratory animals (Cowan and Jenkins 1981; Kanikkannan et al. 2000; Kimber and Weisenberger 1989; Kinkead et al. 1992a, 1992b; Schultz et al. 1981). Dermal exposure of mice to several MDFs (kerosene, JP-5, and JP-8) has been found to cause a variety of local and systemic immune effects, such as decreases in relative weights of lymph nodes and thymus, in thymocyte counts, in bone marrow nucleated cell counts, in thymic cortical lymphocytes, and in cellularity of thymic lobules, and in suppression of contact and delayed hypersensitivity responses (Ullrich 1999; Upreti et al. 1989). Immune-system effects have also been observed in rats exposed to diesel fuel aerosol and JP-8 aerosol by inhalation (Dalbey et al. 1987; Harris et al. 1997b, 1997a, 2000), but no immune-system effects were found in rats exposed to JP-8 vapor by inhalation or in rats or monkeys

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 exposed to gasoline by inhalation (Kuna and Ulrich 1984; Mattie et al. 1991). JP-8 aerosols are believed to be more immunotoxic than JP-8 vapors (NRC 2003). Oral exposure of rats and mice to kerosene or JP-8 caused immune-system effects, such as decreases in white-cell count, in relative spleen weight, in thymic weight, and in antibody plaque-forming cell response to sheep red cells (Dudley et al. 2001; Mattie et al. 1995; Parker et al. 1981). Keil et al. (2003) found that in utero exposure of mice to JP-8 at 1,000 or 2,000 mg/kg by gavage on gestation days 6–15 impaired the immune function of the offspring later in life. Renal Effects Some hydrocarbon fuels have been shown to induce hydraline droplet nephropathy syndrome in male rats (but not in female rats or in males and females of any other species) exposed subchronically or chronically by inhalation or ingestion (reviewed in ATSDR 1995a, 1995b, 1995c, 1998; Bruner et al. 1993; Cowan and Jenkins 1981; Keller et al. 1984; Mattie et al. 1991, 1995; NRC 2003; Parker et al. 1981; Parton 1994). The components of hydrocarbon fuels determined to be largely responsible for the syndrome in the male rat are the branched alkane compounds with six or more carbons (ATSDR 1995a). Hydraline droplet nephropathy syndrome is sex- and species-specific and is not considered to be relevant to humans (Alden 1986; Flamm and Lehman-McKeeman 1991). Reproductive and Developmental Effects No developmental effects were observed in the fetuses of rats exposed to unleaded gasoline vapors at 1,600 ppm during gestation (Litton Bionetics 1978). Unleaded-gasoline vapors did not cause developmental defects (malformations, total variations, resorptions, low fetal body weight, or low offspring viability) in the offspring of rats exposed at up to 23,900 mg/m3 (9,000 ppm) for 6 hr/day on gestation days 6–19 (Roberts et al. 2001). Exposure to unleaded-gasoline vapors at about 2,000 ppm for 2 years did not lead to histologic changes in the reproductive systems of rats or mice (MacFarland et al. 1984). No reproductive effects were found in a two-generation reproduction-toxicity test in which male and female rats were exposed to vapors of gasoline (presumably unleaded) at up to 20,000 mg/m3 (McKee et al. 2000). Inhalation exposure of pregnant rats to petroleum naphtha at 100 or 400 ppm on days 6–15 of gestation did not produce teratogenic effects (Beliles and Mecler 1982). A similar protocol to test for reproductive and developmental effects was used with three types of light naphtha distillates: alkylated (Bui et al. 1998), catalytic cracked (Schreiner et al. 1999), and catalytic reformed (Schreiner et al. 2000). The results were uniformly negative for all three test agents when male and female rats were exposed at up to 25,000 mg/m3, at 7,500 ppm, and at 7,500 ppm, respectively, daily from 2 weeks before mating through delivery. No studies of the reproductive- or developmental-toxicity potential of JP-4 were found, but kerosene-related fuels have been tested for reproductive and developmental effects of dermal, oral, and inhalation exposure. No reproductive or developmental effects were observed when male and female rats were dermally exposed to hydrodesulfurized kerosene at up to 494 mg/kg per day for 7–8 weeks from before mating through gestation (Schreiner et al. 1997). No histologic changes were observed in the reproductive systems of mice dermally exposed to JP-5 at up to 8,000 mg/kg 5 times per week for 13 weeks (NTP/NIH 1998). No reproductive effects were observed in male and female rats exposed to JP-8 by gavage at up to 1,500 (females) or 3,000 (males) mg/kg per day before and during mating and, in the

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Other systemic effects have also been seen. Those effects, such as hemodynamic effects, increased the risk of heart attack and stroke and effects on hematopoiesis are thought to be secondary to the lung injury seen (EPA 2003a). One component of PM that might provide some biologic plausibility for its toxic effects is PAHs. As discussed earlier, reactive epoxide intermediates can form in the metabolism of PAHs; the intermediates are genotoxic and could lead to carcinogenicity. Schulte et al. (1994) saw an increase in all lung tumors and a dose-dependent increase in malignant tumors in mice exposed to PAH-enriched exhaust containing benzo[a]pyrene at 0.05 or 0.09 mg/m3. Tumors of the nasal cavity, pharynx, larynx, and trachea were seen in a dose-dependent manner in hamsters exposed to benzo[a]pyrene at 9.5 or 46.5 mg/m3 for 109 weeks, but no lung tumors were seen in those animals (Thyssen et al. 1981). No effects were seen in the lungs, nose, and kidneys of Fischer rats exposed by nose to an aerosol of benzo[a]pyrene at 7.7 mg/m3 for 2 hr/day 5 days/week for 4 weeks (Wolff et al. 1989). Skin disorders have been seen in animals after dermal exposure to PAHs. In an early study, suppression of sebaceous glands was seen in Swiss mice treated with benzo[a]pyrene, benz[a]anthracene, and dibenz[a,h]anthracene, but no controls were used (Bock and Mund 1958). Increased cell proliferation and inflammation were seen after exposure to a single treatment of 16, 32, or 64 µg once a week for 29 weeks (Albert et al. 1991). There is also evidence that PAHs are photosensitizers in mice, but that effect appears to be reversible (Forbes et al. 1976) and there is evidence of skin carcinogenicity in animals treated dermally with PAHs; a number of studies showed that intermediate exposure to PAHs produces skin tumors (ATSDR 1995d). INDIVIDUAL SUSCEPTIBILITY Because of variations in genetic makeup, a genetically susceptible person will exhibit responses to a hydrocarbon fuel or to combustion products different from those of most persons exposed to an identical dose. Little has been documented about specific differences in genetic susceptibility to hydrocarbon fuels and their components, but exploration of the human genome promises advances in the near future. Some information suggests that people with an erythrocyte glucose-6-phosphate dehydrogenase deficiency may have increased susceptibility to the hemolytic effects of naphthalene (ATSDR 1999b). People with aryl hydrocarbon hydroxylase that is particularly susceptible to induction and people with genetic diseases associated with DNA-repair deficiencies (such as Down syndrome and familial retinoblastoma) may be particularly susceptible to the carcinogenic effects of PAHs (ATSDR 1999b). Little is known also about specific differences in genetic susceptibility with respect to combustion products. Some components of combustion products are metabolized to active metabolites, which are later detoxified. Differences in the activity of the enzymes involved in those toxification and detoxification pathways can alter a person’s susceptibility to combustion-product components. For example, increased formation of the epoxide intermediates by increased activity of p450 enzymes that activate PAHs would increase a person’s susceptibility to PAHs, whereas increased activity of epoxide hydrolase, which detoxifies epoxide metabolites, would protect against the toxicity of PAHs (Klaassen 2001). In addition to altered susceptibility resulting from enzyme activity, whether genetic or by induction of enzymes by coexposure to other compounds, people could have altered susceptibility to combustion products because of

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 illness. An example is asthma-related increased susceptibility to many of the effects of combustion products. INTERACTIONS Because hydrocarbon fuels and their combustion products contain hundreds of components, it is probably not possible to identify all the possible interactions between a fuel and other substances, between components of a fuel, between combustion products and other substances, or between components of combustion products. Additive, synergistic, or antagonistic effects might occur; however, data on such effects are sparse. For example, primarily as a consequence of modifications in enzyme induction, the toxicity of benzene, a component of hydrocarbon fuels, can be altered by alcohol, drugs, industrial chemicals, radiation, metals, halogenated hydrocarbons, and pesticides (ATSDR 1995a). Several recent studies have evaluated interactions between a hydrocarbon fuel and other substances. Peden-Adam et al. (2001) assessed immunotoxic effects of concurrent exposure of mice to pyridostigmine bromide (an anti-nerve-gas agent), N,N-diethyl-m-toluamide (DEET, an insect repellent), and JP-8. The findings of their study indicate that combined exposure to those three materials does not significantly alter many immunologic end points (body, spleen, and thymus mass; spleen and thymus cellularity; peripheral white-cell populations; lymphocyte proliferation; macrophage nitrite production; and natural killer-cell and cytotoxic T-lymphocyte activity) but does selectively target functional end points, such as delayed-type hypersensitivity responses. Baynes et al. (2001) studied the influence of three JP-8 performance additives on dermal disposition of two fuel components: naphthalene and dodecane. Jet-A, which has the same hydrocarbon composition as JP-8 but without the performance additives, was mixed with up to three performance additives, and disposition was assayed by using isolated perfused porcine skin flaps. The data show that various combinations of the three performance additives can potentially alter the dermal disposition of the fuel components and that products of two-factor interactions were not predictable from single-factor exposures. Riviere et al. (2002) also used the isolated perfused porcine skin-flap model to evaluate potential interactions among various combinations of low sulfur mustard, JP-8, DEET, and permethrin exposures. Data from the study suggest that JP-8 exposure may modulate transdermal flux of permethrin. There has also been research on the components of combustion products that indicated that the presence of one component affects the toxicity of other components. For example, there is evidence of antagonistic effects between O3 and SO2 that depend on the end point (Schlesinger and Graham 1992), and, as discussed previously, components adsorbed on PM behave differently from those not adsorbed on PM. REFERENCES ACGIH (American Conference of Industrial Hygienists). 2003. 2003 TLVs and BEIs: Threshold Limit Values for Chemical Substances and Physical Agents. Biological Exposure Indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. Air Force. 1989. The Installation Restoration Program Toxicology Guide. Volume 4. Oak Ridge, TN: Biomedical and Environmental Information Analysis; as cited in ATSDR 1998.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Alarie Y, Ulrich CE, Busey WM, Krumm AA, MacFarland HN. 1972. Long-term continuous exposure to sulfur dioxide in cynomolgus monkeys. Archives of Environmental Health 24(2):115–128. Alarie YC, Krumm AA, Busey WM, Urich CE, Kantz RJ. 1975. Long-term exposure to sulfur dioxide, sulfuric acid mist, fly ash, and their mixtures. Results of studies in monkeys and guinea pigs. Archives of Environmental Health 30(5):254–262. Albert RE, Miller ML, Cody T, Andringa A, Shukla R, Baxter CS. 1991. Benzo[a]pyrene-induced skin damage and tumor promotion in the mouse. Carcinogenesis 12(7):1273–1280. Alden CL. 1986. A review of unique male rat hydrocarbon nephropathy. Toxicologic Pathology 14(1):109–111. API (American Petroleum Institute). 1988a. In Vivo Sister Chromatid Exchange (SCE) Assay with API 81–07: Hydrodesulferized Kerosene. API Med. Res. Publ. 36–30043. Washington, DC: American Petroleum Institute, Health and Environmental Science Department; as cited in Skisak et al. 1995. API. 1988b. Sister Chromatid Exchange (SCE) Assay in Chinese Hamster Ovary (CHO) Cell with API 81–07: Hydrodesulferized Kerosene. API Med. Res. Publ. 35–32482. Washington, DC: American Petroleum Institute, Health and Environmental Science Department; as cited in Skisak et al. 1995. ATSDR (Agency for Toxic Substances and Disease Registry). 1989. Toxicological Profile for Toluene. Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1990. Toxicological Profiles for 1,3-Butsdiene, 1,2-Dibromoethane, Ethylbenzene and Xylene. Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1991. Toxicological Profiles for Benzene and Lead. Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1995a. Toxicological Profile for Automotive Gasoline. Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1995b. Toxicological Profile for Fuel Oils. Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1995c. Toxicological Profile for Jet Fuels (JP4 and JP7). Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1995d. Toxicological Profile for Polycyclic Aromatic Hydrocarbons (PAHs) (Update). Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1995e. Toxicological Profile for Xylenes (Update). Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1998. Toxicological Profile for Jet Fuels (JP-5 and JP-8). Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1999a. Toxicological Profile for Hydrogen Sulfide. Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. ATSDR. 1999b. Toxicological Profile for Total Petroleum Hydrocarbons (TPH). Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. Basbaum C, Gallup M, Gum J, Kim Y, Jany B. 1990. Modification of mucin gene expression in the airways of rats exposed to sulfur dioxide. Biorheology 27(3–4):485–489. Baynes RE, Brooks JD, Budsaba K, Smith CE, Riviere JE. 2001. Mixture effects of JP-8 additives on the dermal disposition of jet fuel components. Toxicology and Applied Pharmacology 175(3):269–281. Beliles RP, Mecler FJ. 1982. Inhalation teratology of jet fuel A, fuel oil and petroleum naphtha in rats. In: MacFarland H, Holdsworth C, MacGregor JA, Call R, Kane M, eds. Proceedings of the Symposium: The Toxicology of Petroleum Hydrocarbons. Washington, DC: American Petroleum Institute. Pp. 233–238. Bock FG, Mund R. 1958. A survey of compounds for activity in the suppression of mouse sebaceous glands. Cancer Research 18(8 Part 1):887–892. Bogo B, Young RW, Hill TA, Feser CL, Nold J, Parker GA, Cartledge. R.M. 1983. The Toxicity of Petroleum and Shale JP5. AFRRI SR83–26. Bethesda, MD: Armed Forces Radiobiology Research Institute. Pp. 46–66.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Brain JD, Long NC, Wolfthal SF, Dumyahn T, Dockery DW. 1998. Pulmonary toxicity in hamsters of smoke particles from Kuwaiti oil fires. Environmental Health Perspectives 106(3):141–146. Bruner RH, Kinkead ER, O’Neill TP, Flemming CD, Mattie DR, Russell CA, Wall HG. 1993. The toxicologic and oncogenic potential of JP-4 jet fuel vapors in rats and mice: 12-month intermittent inhalation exposures. Fundamental and Applied Toxicology 20(1):97–110. Brusick DJ, Matheson DW. 1978a. Mutagen and Oncogen Study on JP-4. AMRL-TR-78–24. Wright Patterson Air Force Base, OH: Aerospace Medical Research Laboratory. Brusick DJ, Matheson DW. 1978b. Mutagen and Oncogen Study on JP-8 AMRL-TR-78–20. Wright Patterson Air Force Base, OH: Aerospace Medical Research Laboratory. Budavari S, O’Neil MJ, Smith A. 1989. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. Rahway, NJ: Merck and Co. Bui QQ, Burnett DM, Breglia RJ, Koschier FJ, Lapadula ES, Podhasky PI, Schreiner CA, White RD, Dalbey WE, Feuston MH. 1998. Toxicity evaluation of petroleum blending streams: Reproductive and developmental effects of a distillate from light alky late naphtha. Journal of Toxicology and Environmental Health. Part A. 53(2):121–133. Carpenter CP, Geary DL Jr, Myers RC, Nachreiner DJ, Sullivan LJ, King JM. 1976. Petroleum hydrocarbon toxicity studies. XI. Animal and human response to vapors of deodorized kerosene. Toxicology and Applied Pharmacology 36(3):443–456. Chang LY, Huang Y, Stockstill BL, Graham JA, Grose EC, Menache MG, Miller FJ, Costa DL, Crapo JD. 1992. Epithelial injury and interstitial fibrosis in the proximal alveolar regions of rats chronically exposed to a simulated pattern of urban ambient ozone. Toxicology and Applied Pharmacology 115(2):241–252. CIIT (Chemical Industry Institute of Toxicology). 1983a. Ninety-day vapor inhalation toxicity study of hydrogen sulfide in B6C3F1 mice. CIIT Docket No. 42063. Research Triangle Park, NC: Chemical Industry Institute of Toxicology. CIIT. 1983b. Ninety-day vapor inhalation toxicity study of hydrogen sulfide in Fischer-344 rats. CIIT Docket No. 22063. Research Triangle Park, NC: Chemical Industry Institute of Toxicology. CIIT. 1983c. Ninety-day vapor inhalation toxicity study of hydrogen sulfide in Sprague-Dawley rats. CIIT Docket No. 32063. Research Triangle Park, NC: Chemical Industry Institute of Toxicology. Cofer WR, Stevens RK, Winstead EL. 1992. Kuwaiti oil fires: Compositions of source smoke. Journal of Geophysical Research 97:14521–14525. Coffin DL, Blommer EJ. 1967. Acute toxicity of irradiated auto exhaust. Its indication by enhancement of mortality from streptococcal pneumonia. Archives of Environmental Health 15(1):36–38. Cohen MD, Sisco M, Li Y, Zelikoff JT, Schlesinger RB. 2001. Ozone-induced modulation of cell-mediated immune responses in the lungs. Toxicology and Applied Pharmacology 171(2):71–84. Cohen MD, Zelikoff JT, Qu Q, Schlesinger RB. 1996. Effects of ozone upon macrophage-interferon interactions. Toxicology 114(3):243–252. Conaway DD, Schreiner CA, Cragg ST. 1984. Mutagencity evaluation of petroleum hydrocarbons. In: MacFarland HN, Holdsworth CE, MacGregor JA, Call RW, Lane ML, eds. Advances in Modern Environmental Toxicology. Vol. 6, Applied Toxicology of Petroleum Haydrocarbons. Princeton, NJ: Princeton Scientific. Pp. 89–197; as cited in IARC 1989. Cooper JR, Mattie DR. 1996. Developmental toxicity of JP-8 jet fuel in the rat. Journal of Applied Toxicology 16(3):197–200. Costa DL. 2001. Air Pollution. In: Klaassen C, ed. Casarett andDoull’s Toxicology: The Basic Science of Poisons. 6th ed. New York: McGraw-Hill. Pp. 979–1012. Costa DL, Tepper JS, Stevens MA, Watkinson WP, Doerfler DL, Gelzleichter TR, Last JA. 1995. Restrictive lung disease in rats exposed chronically to an urban profile of ozone. American Journal of Respiratory and Critical Care Medicine 151(5):1512–1518. Cowan MJ, Jenkins LJ. 1981. U.S. Navy toxicity study of shale and petroleum JP-5 aviation fuel and diesel fuel marine. In: Guerin MR, Griest WH, Coffin DI, eds. Health Effects Investigation of Oil Shale Development. Ann Arbor, MI: Ann Arbor Science. Pp. 129–140.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Curtis SE, Anderson CR, Simon J, Jensen AH, Day DL, Kelley KW. 1975. Effects of aerial ammonia, hydrogen sulfide and swine-house dust on rate of gain and respiratory-tract structure in swine. Journal of Animal Science 41(3):735–739. Dalbey W, Henry M, Holmberg R, Moneyhun J, Schmoyer R, Lock S. 1987. Role of exposure parameters in toxicity of aerosolized diesel fuel in the rat. Journal of Applied Toxicology 7(4):265–275. Deininger G, Jungen H, Wenzel-Hartung RP. 1991. Middle Distillates: Analytical Investigations of Mutagenicity Studies. Research Reports No. 412–1. Hamburg, Germany: DGMK; as cited in NRC 2003. Dennis MW. 1982. Acute Dermal LD50 Toxicity Study E-2B, E-6-B, E-8B, E-10, E-12. Document #88–8100360. Washington, DC: U.S. Environmental Protection Agency, Office of Toxic Substances; as cited in ATSDR 1995c. Draxler RR, McQueen JT, Stunder BJB. 1994. An evaluation of air pollutant exposures due to the 1991 Kuwait oil fires using a Lagrangian model. Atmospheric Environment 28(13):2197–2210. Dubuis E, Gautier M, Melin A, Rebocho M, Girardin C, Bonnet P, Vandier C. 2002. Chronic carbon monoxide enhanced IbTx-sensitive currents in rat resistance pulmonary artery smooth muscle cells. American Journal of Physiology. Lung Cellular and Molecular Physiology 283(1):L120–L129. Dudley AC, Peden-Adams MM, EuDaly J, Pollenz RS, Keil DE. 2001. An aryl hydrocarbon receptor independent mechanism of JP-8 jet fuel immunotoxicity in Ah-responsive and Ah-nonresponsive mice. Toxicological Sciences 59(2):251–259. Ehrlich R, Findlay JC, Gardner DE. 1979. Effects of repeated exposures to peak concentrations of nitrogen dioxide and ozone on resistance to streptococcal pneumonia. Journal of Toxicology and Environmental Health 5(4):631–642. Ehrlich R, Henry MC. 1968. Chronic toxicity of nitrogen dioxide. I. Effect on resistance to bacterial pneumonia. Archives of Environmental Health 17(6):860–865. EPA (Environmental Protection Agency). 1993. Air Quality Criteria for Oxides of Nitrogen. EPA-600/8–91/049aF. Research Triangle Park, NC: Environmental Criteria and Assessment Office. EPA. 1996. Air Quality Criteria for Ozone and Related Photochemical Oxidants. EPA-600/P-93–004aF-cF. Research Triangle Park, NC: National Center for Environmental Assessment-RTP Office. EPA. 2002. Health Assessment Document for Diesel Engine Exhaust. EPA/600/8–90/057F. Research Triangle Park, NC: National Center for Environmental Assessment. EPA. 2003a. Air Quality Criteria for Particulate Matter, Volume 2. EPA/600/P-99/002bD. Research Triangle Park, NC: National Center for Environmental Assessment-RTP. EPA. 2003b. SO2: What Is It? Where Does It Come From? [Online]. Available: http://www.epa.gov/air/urbanair/so2/what1.html [accessed February 2004]. Flamm WG, Lehman-McKeeman LD. 1991. The human relevance of the renal tumor-inducing potential of d-limonene in male rats: Implications for risk assessment. Regulatory Toxicology and Pharmacology 13(1):70–86. Forbes PD, Davies RE, Urbach F. 1976. Phototoxicity and photocarcinogenesis: comparative effects of anthracene and 8-methoxypsoralen in the skin of mice. Food and Cosmetics Toxicology 14(4):303–306. Garb J, Chenoweth MB. 1948. Studies on hydrocarbon-epinephrine induced ventricular fibrillation. Journal of Pharmacology and Experimental Therapeutics 94:12–18; as cited in NRC 1996b. Gearhart JM, Schlesinger RB. 1989. Sulfuric acid-induced changes in the physiology and structure of the tracheobronchial airways. Environmental Health Perspectives 79:127–136. Ghio AJ, Silbajoris R, Carson JL, Samet JM. 2002. Biologic effects of oil fly ash. Environmental Health Perspectives 110(Suppl 1):89–94. Gilmour MI, Park P, Selgrade MK. 1993. Ozone-enhanced pulmonary infection with Streptococcus zooepidemicus in mice. The role of alveolar macrophage function and capsular virulence factors. American Review of Respiratory Disease 147(3):753–760. Goldring IP, Greenburg L, Park SS, Ratner IM. 1970. Pulmonary effects of sulfur dioxide exposure in the Syrian hamster. II. Combined with emphysema. Archives of Environmental Health 21(1):32–37.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Gong H Jr. 1992. Health effects of air pollution. A review of clinical studies. Clinics in Chest Medicine 13(2):201–214. Goodheart RS, Dunne JW. 1994. Petrol sniffer’s encephalopathy. A study of 25 patients. Medical Journal of Australia 160(4):178–181; as cited in ATSDR 1995a. Goto Y, Ishii H, Hogg JC, Shih CH, Yatera K, Vincent R, van Eeden SF. 2004. Particulate matter air pollution stimulates monocyte release from the bone marrow. American Journal of Respiratory and Critical Care Medicine 170(8):891–897. Haider SS. 1985. Effects of exhaust pollutant sulfur dioxide on lipid metabolism of guinea pig organs. Industrial Health 23(2):81–87. Hannah RS, Hay den LJ, Roth SH. 1989. Hydrogen sulfide exposure alters the amino acid content in developing rat CNS. Neuroscience Letters 99(3):323–327. Hannah RS, Roth SH. 1991. Chronic exposure to low concentrations of hydrogen sulfide produces abnormal growth in developing cerebellar Purkinje cells. Neuroscience Letters 122(2):225–228. Harris DT, Sakiestewa D, Robledo RF, Witten M. 1997a. Immunotoxicological effects of JP-8 jet fuel exposure. Toxicology and Industrial Health 13(1):43–55. Harris DT, Sakiestewa D, Robledo RF, Witten M. 1997b. Protection from JP-8 jet fuel induced immunotoxicity by administration of aerosolized substance P. Toxicology and Industrial Health 13(5):571–588. Harris DT, Sakiestewa D, Robledo RF, Young RS, Witten M. 2000. Effects of short-term JP-8 jet fuel exposure on cell-mediated immunity. Toxicology and Industrial Health 16(2):78–84. Hayashi Y, Kohno T, Ohwada H. 1987. Morphological effects of nitrogen dioxide on the rat lung. Environmental Health Perspectives 73:135–145. Hayden LJ, Goeden H, Roth SH. 1990. Growth and development in the rat during sub-chronic exposure to low levels of hydrogen sulfide. Toxicology and Industrial Health 6(3–4):389–401. Ho CY, Kou YR. 2002. Mechanisms of wood smoke-induced increases in nasal airway resistance and reactivity in rats. European Journal of Pharmacology 436(1–2):127–134. Hobbs PV, Raadke LF. 1992. Airborne studies of the smoke from Kuwait oil fires. Science 256:987–991. HSDB (Hazardous Substances Data Bank). 2003a. Gasoline. [Online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed August 2004]. HSDB. 2003b. Kerosene. [Online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed August 2004]. IARC (International Agency for Research on Cancer). 1989. Occupational Exposures in Petroleum Refining: Crude Oil and Major Petroleum Fuels. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. 45. Lyon, France: IARC. IOM (Institute of Medicine). 2003. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. Kainz R, White L. 1983. Consequences associated with the inhalation of uncombusted diesel vapor. In: MacFarland H, Holdsworth C, MacGregor J, Call R, Kane M, eds. Proceedings of the Symposium: The Toxicology of Petroleum Hydrocarbons May, 1982 Washington, DC. Washington DC: American Petroleum Institute. Pp. 233–243. Kanikkannan N, Jackson T, Sudhan Shaik M, Singh M. 2000. Evaluation of skin sensitization potential of jet fuels by murine local lymph node assay. Toxicology Letters 116(1–2):165–170. Keil DE, Warren DA, Jenny MJ, EuDaly JG, Smythe J, Peden-Adams MM. 2003. Immunological Function in Mice Exposed to JP-8 Jet Fuel In Utero. Toxicological Sciences 76(2):347–356. Keller WC, Olson CT, Back KC, Gaworski CL. 1984. Teratogenic assessment of three methylated hydrazine derivatives in the rat. Journal of Toxicology and Environmental Health 13(1):125–131. Kimber I, Weisenberger C. 1989. A murine local lymph node assay for the identification of contact allergens. Assay development and results of an initial validation study. Archives of Toxicology 63(4):274–282. Kimura K, Nagata T, Hara K, Kageura M. 1988. Gasoline and kerosene components in blood—a forensic analysis. Human Toxicology 7(4):299–305.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Kinkead ER, Salins SA, Wolfe RE. 1992a. Acute irritation and sensitization potential of JP-9 fuel. Journal of the American College of Toxicology 11(6):700. Kinkead ER, Wolfe RE, Salins SA. 1992b. Acute irritation and sensitization potential of shale-derived JP-5 jet fuel. Journal of the American College of Toxicology 11(6):705. Klaassen C, ed. 2001. Casarett andDoull’s Toxicology: The Basic Science of Poison. 6th ed. New York: McGraw-Hill. Koschier FJ. 1999. Toxicity of middle distillates from dermal exposure. Drug and Chemical Toxicology 22(1):155–164. Krasnowska M, Kwasniewski A, Rabczynski J, Fal A, Kuryszko J. 1998. Effect of heparin on the course of sulphur dioxide induced bronchitis in rats. Archivum Immunologiae Et Therapiae Experimentalis 46(1):17–24. Kuna RA, Ulrich CE. 1984. Subchronic inhalation toxicity of two motor fuels. Journal of the American College of Toxicology 3:217–229; as cited in ATSDR 1995a. Lamb D, Reid L. 1968. Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchial epithelium during exposure to sulphur dioxide. Journal of Pathology and Bacteriology 96(1):97–111. Lapin C, Bui Q, Breglia R, Koschier F, Podhasky P, Lapadula E, Roth R, Schreiner C, White R, Clark C, Mandella R, Hoffman G. 2001. Toxicity evaluation of petroleum blending streams: Inhalation subchronic toxicity/neurotoxicity study of a light catalytic cracked naphtha distillate in rats. International Journal of Toxicology 20(5):307–319. Last JA, Reiser KM, Tyler WS, Rucker RB. 1984. Long-term consequences of exposure to ozone. I. Lung collagen content. Toxicology and Applied Pharmacology 72(1):111–118. Liang CK, Quan NY, Cao SR, He XZ, Ma F. 1988. Natural inhalation exposure to coal smoke and wood smoke induces lung cancer in mice and rats. Biomedical and Environmental Sciences 1(1):42–50. Liang CK, Quan NY, Ma F, Zhang Y, Wang EM, Yin XR. 1984. Carcinogenicity of extract of soot from Xuan Wei County administering subcutaneously to mice. Environmental Science Research 31:826–827; as cited in Liang et al. 1988. Lippman M. 1992. Ozone. In: Rom WN, ed. Environmental and Occupational Medicine. 2nd ed. Boston: Little, Brown and Company. Pp. 489–502. Litton Bionetics I. 1978. Teratology study in rats: Unleaded gasoline. Kensington, MD: Litton Bionetics, Inc.; as cited in ATSDR 1995a. Lock S, Dalbey W, Schmoyer R. 1984. Chemical Characterization and Toxicologic evaluation of airborne mixtures: Inhalation toxicology of diesel fuel obscurant aerosol in Sprague-Dawley rats. ORNL/TM-9403. Oak Ridge TN: Oak Ridge National Laboratory; as cited in ATSDR 1995b. Lohani M, Dopp E, Weiss DG, Schiffmann D, Rahman Q. 2000. Kerosene soot genotoxicity: enhanced effect upon co-exposure with chrysotile asbestos in Syrian hamster embryo fibroblasts. Toxicology Letters 114(1–3):111–116. Lopez I, Acuna D, Webber DS, Korsak RA, Edmond J. 2003. Mild carbon monoxide exposure diminishes selectively the integrity of the cochlea of the developing rat. Journal of Neuroscience Research 74(5):666–675. MacEwen JD, Vernot EH. 1984. Toxic Hazards Research Unit Annual Technical Report. AMRL-TR-84–001. Wright-Paterson Air Force Base, OH: Aerospace Medical Research Laboratory. MacFarland HN, Ulrich CE, Holdsworth CE. 1984. A chronic inhalation study with unleaded gasoline vapor. Journal of the American College of Toxicology 3:231–248; as cited in ATSDR 1995a and IARC 1989. MacNaughton MG, Uddin DE. 1984. Toxicology of mixed distillate and high-energy synthetic fuels. In: Mehlman MA, Hemstreet GP III, Thorpe JJ, Weaver NK, eds. Renal Effects of Petroleum Hydrocarbons. Princeton, NJ: Princeton Scientific Publishers. Mattie DR, Alden CL, Newell TK, Gaworski CL, Flemming CD. 1991. A 90-day continuous vapor inhalation toxicity study of JP-8 jet fuel followed by 20 or 21 months of recovery in fischer 344 rats and C57BL/6 mice. Toxicologic Pathology 19(2):77–87.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Mattie DR, Marit GB, Cooper JR, Sterner TR, Flemming CD. 2000. Reproductive Effects of JP-8 Jet Fuel on Male and Female Sprague-Dawley Rats After Exposure by Oral Gavage. AFRL-HE-WP-TR-2000–0067. Wright Patterson Air Force Base, OH: Aerospace Medical Research Laboratory. Mattie DR, Marit GB, Flemming CD, Cooper JR. 1995. The effects of JP-8 jet fuel on male Sprague-Dawley rats after a 90-day exposure by oral gavage. Toxicology and Industrial Health 11(4):423–435. McKee RH, Amoruso MA, Freeman JJ, Przygoda RT. 1994. Evaluation of the genetic toxicity of middle distillate fuels. Environmental and Molecular Mutagenesis 23(3):234–238. McKee RH, Plutnick RT, Przygoda RT. 1989. The carcinogenic initiating and promoting properties of a lightly refined paraffinic oil. Fundamental and Applied Toxicology 12(4):748–756. McKee RH, Trimmer GW, Whitman FT, Nessel CS, Mackerer CR, Hagemann R, Priston RA, Riley AJ, Cruzan G, Simpson BJ, Urbanus JH. 2000. Assessment in rats of the reproductive toxicity of gasoline from a gasoline vapor recovery unit. Reproductive Toxicology 14(4):337–353. Melin A, Obert P, Rebocho M, Bonnet P. 2002. Cardiac morphology and function following long-term exposure to carbon monoxide at high altitude in rats. Journal of Toxicology and Environmental Health. Part A 65(23):1981–1998. Miyata T, Ishii T, Sugiyama N, Okano Y, Nishi N, Takahama K, Ogasawara S, Oda Y, Yokoyama K, Murata Y, Kai H. 1990. Effect of N-acetylneuraminic acid on respiratory tract secretion and inflammation in the bronchitic rabbit. Archives Internationales De Pharmacodynamie Et De Therapie 304:277–289. Moeller RB Jr, Kalasinsky VF, Razzaque M, Centeno JA, Dick EJ, Abdal M, Petrov II, DeWitt TW, al-Attar M, Pletcher JM. 1994. Assessment of the histopathological lesions and chemical analysis of feral cats to the smoke from the Kuwait oil fires. Journal of Environmental Pathology, Toxicology and Oncology 13(2):137–149. Mumford JL, Helmes CT, Lee XM, Seidenberg J, Nesnow S. 1990. Mouse skin tumorigenicity studies of indoor coal and wood combustion emissions from homes of residents in Xuan Wei, China with high lung cancer mortality. Carcinogenesis 11(3):397–403. Murray FJ, Schwetz BA, Crawford AA, Henck JW, Quast JF, Staples RE. 1979. Embryotoxicity of inhaled sulfur dioxide and carbon monoxide in mice and rabbits. Journal of Environmental Science and Health. Part C: Environmental Health Sciences 13(3):233–250. Musthapa MS, Lohani M, Tiwari S, Mathur N, Prasad R, Rahman Q. 2004. Cytogenetic biomonitoring of Indian women cooking with biofuels: Micronucleus and chromosomal aberration tests in peripheral blood lymphocytes. Environmental and Molecular Mutagenesis 43(4):243–249. Nessel CS. 1999. A comprehensive evaluation of the carcinogenic potential of middle distillate fuels. Drug and Chemical Toxicology 22(1):165–180. Nikula KJ. 2000. Rat lung tumors induced by exposure to selected poorly soluble nonfibrous particles. Inhalation Toxicology 12(1–2):97–119. NIOSH (National Institute for Occupational Safety and Health). 1997. NIOSH Pocket Guide to Chemical Hazards. Cincinnati, OH: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, NIOSH. NIOSH. 1998. International Chemical Safety Cards. [Online]. Available: http:www.cdc.gov/niosh/ipcsneng/neng0183.html [accessed February 10, 2004]. Nordholm AF, Rossi J 3rd, Ritchie GD, McInturf S, Hulme ME, McCool C, Narayanan L, MacMahon KL, Eggers J, Leahy HF, Wolfe RE. 1999. Repeated exposure of rats to JP-4 vapor induces changes in neurobehavioral capacity and 5-HT/5-HIAA levels. Journal of Toxicology and Environmental Health. Part A. 56(7):471–499. NRC (National Research Council). 1985. Emergency Exposure Guidance Level. Vol 4. Washington, DC: National Academy Press. NRC. 1996a. Hydrazine. In: NRC. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants. Vol. II. Washington, DC: National Academy Press. Pp. 213–234. NRC. 1996b. Permissible Exposure Levels for Selected Military Fuel Vapors. Washington, DC: National Academy Press.

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