6
Effects of Jet-Propulsion Fuel 8 on the Immune System

This chapter summarizes the studies that investigated the potential toxicity of jet-propulsion fuel 8 (JP-8), related fuels, and kerosene in humans and experimental animals. The 1996 National Research Council report Permissible Exposure Levels for Selected Military Fuel Vapors did not specifically consider the immunotoxic effects of JP-8 or related fuels. No earlier studies that addressed the influence of JP-8 exposure on the functional capacity of the immune system to respond to antigenic challenge were available. However, standard histopathologic, hematologic, and clinical chemistry determinations made as part of a standard toxicology and pathology profile data after exposure to several kerosene-based fuels, including JP-5 and JP-8, did not generate concern about immunotoxicity. Immunotoxicity is typically first detected in standard toxicology and pathology studies.

IMMUNOSUPPRESSIVE EFFECTS OF JP-8

The subcommittee reviewed several recent immunotoxicity studies of JP-8 that used immune-function assays (see Table 6-1). However, the methods for those studies largely have not been standardized through interlaboratory com-



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6 Effects of Jet-Propulsion Fuel 8 on the Immune System This chapter summarizes the studies that investigated the potential toxicity of jet-propulsion fuel 8 (JP-8), related fuels, and kerosene in humans and experimental animals. The 1996 National Research Council report Permissible Exposure Levels for Selected Military Fuel Vapors did not specifically consider the immunotoxic effects of JP-8 or related fuels. No earlier studies that addressed the influence of JP-8 exposure on the functional capacity of the immune system to respond to antigenic challenge were available. However, standard histopathologic, hematologic, and clinical chemistry determinations made as part of a standard toxicology and pathology profile data after exposure to several kerosene-based fuels, including JP-5 and JP-8, did not generate concern about immunotoxicity. Immunotoxicity is typically first detected in standard toxicology and pathology studies. IMMUNOSUPPRESSIVE EFFECTS OF JP-8 The subcommittee reviewed several recent immunotoxicity studies of JP-8 that used immune-function assays (see Table 6-1). However, the methods for those studies largely have not been standardized through interlaboratory com-

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TABLE 6-1 Immunosuppressive Effects of JP-8 Exposure in Humans and Experimental Animals Species or Cell Line Exposure Concentration Exposure Duration Effects Reference INHALATION EXPOSURE Human Measurements taken in breathing zones of subjects; median concentration of naphthalene, 1.9 μg/m3 (low-exposure group), 447 μg/m3 (high-exposure group); median concentration of benzene, 3.1 μg/m3 (low-exposure group), 242 μg/m3 (high-exposure group) High-exposure group, persistent exposure to JP-8(defined as at least 1 hr twice per wk for at least 9 mo); low-exposure group, no significant exposure to jet fuel or solvents High-exposure group had higher white-cell counts than low-exposure group; there were increased numbers of neutrophils and monocytes but no differences in total lymphocytes, T cells, NK cells, B cells; white cell, neutrophil, and monocyte counts in high-exposure group did not exceed range of normal values Rhodes et al. 2001a Human Exposed group (5,706 people) had potential occupational exposure to JP-8. Control group (5,706 people) did not work in occupations in which exposure to JP-8 would occur Not reported Health-event analysis did not find differences in immunologic measures (such as infections) between exposed and control groups Gibson et al. 2001aa Human Measurements taken in breathing zones of subjects; median concentration of naphthalene, 1.9 μg/m3 (low-exposure group), 10.4 μg/m3 (moderate-exposure group), High- and moderate-exposure groups, persistent exposure to JP-8; low exposure group, no significant Analysis of self-assessment questionnaire did not report differences among groups in immunologic-related illnesses Gibson et al. 2001ba

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  447 μg/m3 (high-exposure group); median concentration of benzene, 3.1 μg/m3 (low-exposure group), 7.45 μg/m3 (moderate-exposure group), 242 μg/m3 (high-exposure group) exposure to jet fuel or solvents   F344 rat and C57Bl/6 mouse 500 and 1,000 mg/m3 90 days continuously, followed by recovery until approximately 24 mo of age No treatment-related changes in spleen weight or hematology were observed Mattie et al. 1991 C57BL/6 mouse 100, 250, 500, 1,000, 2,500 mg/m3 (aerosol) 1 hr/day for 7 days (nose-only) Exposure at 100 mg/m3 led to decreased cellularity of thymus; exposure at 500 mg/m3 led to decreased spleen weight, cellularity; splenic T cells, B cells, macrophages were also affected by exposure at 100 and 500 mg/m3; splenic T cells, B cells, macrophages were also decreased in JP-8-exposed mice; bone marrow cellularity increased after exposure at 100, 250 mg/m3 but decreased after exposure at higher concentrations; exposure at 250 mg/m3 led to reduced spleen cell proliferation responses in vitro after stimulation with Con A or Con A + IL-2 Harris et al. 1997a

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Species or Cell Line Exposure Concentration Exposure Duration Effects Reference C57BL/6 mouse 1,000, 2,500 mg/m3 (aerosol) 1 hr/day for 7 days (nose-only) In mice exposed at both doses, spleen cellularity and spleen cell proliferation persisted for more than 21 days; spleen cells in mice exposed at 1,000 mg/m3 were suppressed in ability to mediate NK activity, LAK responses, CTL responses Harris et al. 1997b C57BL/6 Mouse 250-2,500 mg/m3 JP-8 aerosol + 1 μM or 1nM substance P aerosol 1 hr/day for 7 days (nose-only) Substance P administration prevented loss of spleen and thymus cellularity after exposure to JP-8; it also partially restored proliferative response of spleen cells to Con A + IL-2 Harris et al. 1997c C57BL/6 Mouse 1,000 mg/m3 (aerosol) 1 hr/day for 7 days (nose-only) Mice showed significantly decreased NK cell function, significantly suppressed generation of LAK cell activity, suppressed generation of CTL cells from precursor T cells, inhibited helper T cell activity Harris et al. 2000 DERMAL EXPOSURE C3H/HeN Mouse 50, 250-300 μL 5 days (50 μL), single dose (250-300 μL) Induction of contact hypersensitivity was impaired in dose-dependent manner regardless of whether contact Ullrich 1999

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  allergen was applied directly to treated skin or at distant unrelated site; generation of classic delayed hypersensitivity reaction to Borellia burgdorferi (bacterial antigen) injected into subcutaneous space was suppressed by dermal application of JP-8 at distant site; ability of splenic T lymphocytes from JP-8-treated mice to proliferate in response to plate-bound monoclonal anti-CD3 was significantly suppressed; IL-10 was found in the serum of JP-8-exposed mice   C3H/HeN mouse 50-300 μL undiluted or diluted in acetone Single dose Splenic T-cells were cultured in vitro with antibody T-cell receptor; T cells from JP-8-exposed mice had reduced proliferative response; T-cell-dependent antibody responses to KLH antigen injected in Freund’s adjuvant were not altered by exposure to JP-8 Ullrich and Lyons 2000 NHEK 80-200 μg/mL diluted in absolute ethanol Single dose JP-8 induced necrosis and cell death in human keratinocytes in vitro Rosenthal et al. 2001 NHEK 0.1% Single dose for 24 hr JP-8 increased production of proinflammatory cytokines TNFα and IL-8 Allen et al. 2000

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Species or Cell Line Exposure Concentration Exposure Duration Effects Reference F344 rat 0.25 mL Single dose IL-1α, iNOS expression were induced in isolated skin samples Kabbur et al. 2001 ORAL EXPOSURE B6C3F1 mouse 1,000, 2,000 mg/kg per day Administered to pregnant mice on days 6-15 of gestation Significant suppression of PFC response in offspring when tested at age of 8 wk Keil et al. 2001 B6C3F1 and DBA/2 mouse 1,000, 2,000 mg/kg per day 1 dose/day for 7 or 14 days Significant immunologic alterations in thymic weight and antibody PFC response to SRBC Dudley et al. 2001 aBackground information about these studies can be found in Appendix B. Abbreviations: Con A, concanavalin A; CTL, cytotoxic T lymphocytes; IL, interleukin; iNOS, inducible nitric oxide synthase; KLH, keyhole-limpet hemocyanin; LAK, lymphokine-activated killer cell; NHEK, normal human epidermal keratinocyte; NK, natural killer cell; PFC, plaque-forming cell; SRBC, sheep red blood cell; TNF, tumor necrosis factor.

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parisons or validated for predictability (Luster et al. 1988, 1992). Several of the approaches used in recent studies would more typically be conducted as mechanistic studies, assuming that significant immunotoxicity was found in standardized toxicology and pathology studies. The potential significance of these recent findings is discussed below; however, it should be noted that the subcommittee expressed concern about the adequacy of exposure characterization and assay validation for many of the studies. Inhalation Exposure Carpenter et al. (1976) reported no statistically significant or treatment-related microscopic or histopathologic changes in the spleen of rats or dogs exposed to deodorized kerosene at up to 100 mg/m3 for 6 hr/day, 5 days/wk for 13 wk. Mattie et al. (1991) exposed Fisher 344 rats and C57Bl/6 mice of both sexes to JP-8 vapors at 0, 500, and 1,000 mg/m3 on a continuous basis for 90 days, followed by recovery until the age of about 24 months. Fifteen rats and 25 mice per dose group were sacrificed at exposure termination and necropsied, and there were interim sacrifices and necropsies. No statistically significant differences in spleen weight or hematologic measures were observed between exposed and control rats at any time. At terminal sacrifice, female rats showed increased hematopoiesis in the spleen that was dose-dependent but minimal to mild and not considered treatment-related. In mice, no significant clinical signs of JP-8 toxicity were noted. An increased incidence of deaths in treated mice appeared to be due to an increased incidence of necrotic dermatitis due to fighting. Nine months after termination of exposure, pathologic findings were limited to an increased incidence of inflammatory skin lesions and splenic hematopoiesis in male mice; these findings were not considered to be treatment-related. At 24 months after termination of exposure, histopathologic findings were minimal. Histopathologic findings at exposure termination were minimal. Nine months after exposure, pathologic findings were limited to increased incidence of inflammatory skin lesions and splenic hematopoiesis in male mice; neither effect was considered treatment-related. In contrast with the results by Mattie et al. (1991), Harris et al. (1997a,b,c, 2000) reported significant immunopathologic effects in C57Bl/6 mice exposed nose-only to aerosolized JP-8 (with a median mass aerodynamic diameter [MMAD] of 1.7-1.9 μm; M. Witten, University of Arizona, personal communication, 2002). Reported exposure at 100 mg/m3 for 1 hr/day for 7 days resulted in decreased cellularity of the thymus gland while exposure at 500 mg/m3 for 1 hr/day for 7 days resulted in decreased spleen weight and cellu-

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larity. Splenic T cells, B cells, and macrophages were affected to a similar degree. Bone marrow cellularity increased at 100 and 250 mg/m3 and then decreased at higher concentrations. Because body-weight data were not reported, it is unclear whether the changes in lymphoid tissue cellularity represent general toxicity or specific changes in lymphoid tissue. A minimal exposure at 250 mg/m3 1 hr/day for 7 days also resulted in reduced spleen cell proliferation responses in vitro after stimulation with concanavalin A (Con A) or Con A and interleukin-2 (IL-2) (Harris et al. 1997a). At 1,000 or 2,500 mg/m3, changes in spleen cellularity and spleen cell proliferation persisted for more than 21 days after the last exposure (Harris et al. 1997b). The ability of spleen cells to mediate natural killer-cell activity, lymphokine-activated killer-cell responses, or cytotoxic T-lymphocyte responses was also suppressed when cells were obtained from mice exposed to JP-8 at 1,000 mg/m3. Those results suggest that inhalation exposure to aerosolized JP-8 suppressed many of the functions of isolated spleen cells in culture that are considered to reflect the status of the immune system. No published studies have shown that in vivo immune responses or resistance to infectious disease challenges were altered in JP-8-exposed people. However, preliminary data suggest that JP-8-exposed mice do not regulate the growth of pulmonary B16 melanoma cells as well as control mice (D.T. Harris, University of Arizona, personal communication, 2001) and experience a higher mortality after nasal challenge with Hong Kong influenza virus (M. Witten, University of Arizona, personal communication, 2001). Because inhalation of aerosolized JP-8 can cause local irritation and overt injury to the lung (Robledo and Witten 1999), alterations in B16 melanoma metastases could reflect alterations in the initial deposition of intravenously injected tumor cells as a result of lung-tissue damage rather than of alterations in immune function. Physical changes in the lung after exposure to aerosolized JP-8 may also underlie the altered systemic effects on lymphoid tissue. Robledo and Witten (1999) reported that treatment of mice with substance P, a neurokinin receptor agonist, protected the lungs from the damaging effects of aerosolized JP-8, including increased permeability, epithelial necrosis, and perivascular edema. Substance P administration was also reported to prevent the loss of spleen and thymus cellularity after JP-8 exposure (250-2,500 mg/m3) and to partially restore the proliferative response of spleen cells to Con A + IL-2 (Harris et al. 1997c). The results of the studies by Harris and colleagues (1997 a,b,c; 2000) raise concerns about the immunotoxic potential of JP-8 exposure. However, there are also questions as to why those studies showed such profound changes in lymphoid tissues when prior studies that examined the effects of vaporized JP-8 failed to show such effects. Specifically, the subcommittee suspects that the

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actual exposures in Harris et al. (1997 a,b,c; 2000) were underreported. JP-8 concentrations were not assessed in the aerosol, blood, or tissue, and this could lead to erroneous assumptions regarding exposure concentrations. However, even if the actual concentrations were 10 times as high (e.g., exposure was at a concentration of 1,000 mg/m3), the observation of positive effects from a short duration (1 hr/day for 7 days) at that concentration might yield a safe exposure level of less than 350 mg/m3 (assuming the application of commonly used uncertainty factors). It is also likely that exposure to aerosolized JP-8 is more toxic than exposure to vaporized JP-8. In addition, the nose-only exposure protocol may have concentrated the JP-8 aerosol and led to an increase in cell membrane damage, or it may have induced stress in the animals, compared with whole-body exposure. A comparison of changes in white-blood-cell counts after JP-8 exposure may be revealing in that white-blood-cell counts in military personnel exposed to JP-8 have been measured (Rhodes et al. 2001). In mice, white-blood-cell counts were decreased after exposure to JP-8 at lower concentrations (i.e., 100 and 250 mg/m3) and increased at higher concentrations (Harris et al. 1997a). Differential analysis revealed concentration-dependent neutrophilia. In addition, JP-8 exposure was associated with a concentration-dependent reduction in T cells and macrophages but no effect on B cells. At the highest exposure concentration (2,500 mg/m3) white-blood-cell counts were reduced to numbers insufficient for analysis. In military personnel exposed to JP-8, tank-entry workers, considered to be among the most highly exposed population, were found to have higher white-blood-cell counts than a low-exposure group (Rhodes et al. 2001). Differential analyses revealed increased numbers of neutrophils and monocytes but no differences in total numbers of lymphocytes, T cells, NK cells, or B cells. Those findings suggest that JP-8 exposure might induce an inflammatory response in humans but do not corroborate the decrease in immune-cell numbers seen in mice. It is important to note that the increase in white-blood-cells, neutrophils, and monocytes in the military personnel exposed to JP-8 did not exceed the normal ranges. A previous pilot study by Olsen et al. (1998) found no difference in total white-blood-cell and differential counts among Air Force personnel before and 18 months after the Air Force converted to JP-8. The functional status of the immune system has not been evaluated in military personnel exposed to JP-8. If impairment of immune function was induced, one would expect to see an increased incidence and severity of infectious disease in highly exposed workers. However, a health-event analysis of outpatient medical records conducted by the Air Force (Gibson et al. 2001a) found no differences in health-seeking events between fuel-cell workers and other base personnel. In a related study, self-reported prevalence of illness did

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not differ between moderate and high-exposure groups and a low-exposure group (Gibson et al. 2001b); a limitation of this study was that the questionnaire used addressed only ear infections, and the incidence of colds or flu might have been more relevant. Dermal Exposure Ullrich (1999) reported that dermal exposure of C3H/HeN mice to JP-8 in multiple small doses (50 μL/day for 4-5 days) or in larger single doses (300 μL) resulted in local and systemic effects on immune responses. Contact- and delayed-hypersensitivity responses were suppressed by JP-8 exposure. That induction of a contact-hypersensitivity response was reduced when a contact allergen was applied directly to JP-8-treated skin or at a distant site indicates both local and systemic immune suppression. Similarly, the delayed-hypersensitivity response to a bacterial antigen injected subcutaneously was suppressed by dermal JP-8 exposure. When splenic T cells were stimulated to divide in vitro by cross-linking the T-cell receptors, T cells from JP-8-exposed mice showed reduced proliferative response. In contrast, the antibody response to keyhole limpet hemocyanin in adjuvant was not altered by JP-8 exposure (Ullrich and Lyons 2000). Serum concentration of IL-10, a cytokine that suppresses some T-cell functions, was increased within 48 hr after JP-8 exposure (Ullrich 1999). Furthermore, neutralization of IL-10, administration of IL-12 (to bypass IL-10 effects), or blocking of prostaglandin E2 production abrogated the immunotoxic effects of JP-8. The authors hypothesize that IL-10 and prostaglandin E2 are produced as a result of damage to keratinocytes and are released systemically and induce immunosuppression by JP-8 that acts selectively on cell-mediated immune responses. JP-8 has been shown to induce necrosis and cell death in human keratinocytes in vitro (Rosenthal et al. 2001) and to increase the production of proinflammatory cytokines TNFα and IL-8 (Allen et al. 2000). Dermal exposure of rats also induced IL-1α and inducible nitric oxide synthetase expression in isolated skin samples (Kabbur et al. 2001). The immunosuppressive effects of dermal JP-8 were dose-dependent: 50 μL for 1-3 days was not significantly suppressive, nor were single doses smaller than 300 μL. The effects of JP-8 were also time-dependent: T-cell proliferation was suppressed within 3-4 days after a single exposure and lasted for about 3 wk. The human dermal dose equivalent to the threshold 300-μL dose in the mouse was calculated by the authors to be 100 mL. Those results raise concern about potential health effects of prolonged or repeated dermal exposure of military personnel to JP-8.

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Oral Exposure No changes in spleen weight or splenic histologic findings were observed after a single oral dose of kerosene at 12,000 mg/kg or of deodorized kerosene at 12,150 mg/kg in rats. Parker et al. (1981) reported a decrease in white cells in rats after a single oral dose of JP-5 at 18,912 mg/kg and an increase in red cells, postulated to be due to hemoconcentration related to dehydration. Mattie et al. (1995) exposed rats to JP-8 in the diet for 90 days at 0, 750, 1,500, or 3,000 mg/kg. Circulating neutrophil counts increased and lymphocytes decreased. There were no histologic changes in the spleen or lymph nodes, but relative spleen weight was increased at the highest exposure concentration. Mice exposed to JP-8 at 1,000 or 2,000 mg/kg per day for 7 or 14 days via oral gavage had significant immunologic alterations, including decreases in thymic weight and antibody plaque-forming cell response to sheep red-blood cells (Dudley et al. 2001). The suppression of the plaque-forming cell response occurred in the absence of changes in spleen cellularity. The absence of significant differences in resistance to Listeria infection or growth of B16 melanoma cells suggests selective effects of JP-8 on humoral immunity. The selectivity of oral exposure for suppressing humoral rather than cell-mediated immune function is the opposite of what was observed after dermal exposure to JP-8. Because JP-8 is irritating to the gastrointestinal tract and because the oral route is not considered to be relevant to routine occupational exposures, those data were not considered relevant to the subcommittee’s charge. ALLERGIC POTENTIAL OF JP-8 If components of JP-8 are seen as foreign by the immune system, JP-8 exposure could produce an immune response that leads to allergic response. Symptoms depend on the route of exposure: contact dermatitis after dermal exposure, rhinitis and asthma after inhalation, and vomiting or diarrhea after ingestion. If JP-8 components are systemic sensitizers, anaphylaxis, a life-threatening systemic allergic reaction, could occur following subsequent JP-8 exposure. Except for anaphylaxis, similar symptoms can result from a nonspecific inflammatory response to irritants that does not involve sensitization of the immune system. The murine local lymph node assay is one predictor of the skin-sensitization potential of chemicals (Basketter et al. 1996). When JP-8 was tested in the assay with CBA/Ca mice, a strain that shows increased responsiveness to

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contact allergens (Kimber and Weisenberger 1989), increased lymphocyte proliferation was observed, with a stimulation index of 3.17. An index greater than 3 is considered evidence of skin sensitization; apparently JP-8 was a weak skin sensitizer. Exposure to Jet A and JP-8 + 100 also increased lymphocyte proliferation, but the indexes were less than 3. Those results suggest that the additives in JP-8 + 100 may reduce the sensitization potential of JP-8 (Kanikkannan et al. 2000). Kinkead et al. (1992a) reported that topical application of JP-8 also showed weak skin sensitization in guinea pigs. Studies with other jet fuels have indicated only weak skin sensitization if any (Cowan and Jenkins 1981; Schultz et al. 1981; Kinkead et al. 1992b). No studies that evaluated sensitization after inhalation of JP-8 were found. Allergic sensitization of humans to JP-8 or other jet fuels has not been reported. AUTOIMMUNE EFFECTS OF JP-8 No studies that addressed the effects of JP-8 exposure on development or exacerbation of autoimmune disease were found. CONCLUSIONS AND RECOMMENDATIONS No histopathologic effects related to the immune system were found in F344 rats and C57BL/6 mice exposed continuously to JP-8 vapors at concentrations up to 1,000 mg/m3 for 90 days. No additional studies that tested the toxicity of JP-8 vapors in experimental animals were located. Harris et al. reported that inhalation exposure of C57BL/6 mice to JP-8 aerosols at a concentration of 100 mg/m3 for 1 hr/day for 7 days led to decreased cellularity of the thymus, exposure at 500 mg/m3 for 1 hr/day for 7 days led to decreased spleen weight and cellularity, and exposure at 1,000 mg/m3 for 1 hr/day for 7 days led to decreased ability of spleen cells to mediate several immune responses. Those studies raise concern about the potential of JP-8 to cause immunotoxicity. The subcommittee reviewed the methods used to generate the exposure atmospheres in the studies by Harris et al. and suspects that the total JP-8 concentration in the atmosphere may have been underreported. However, even if the actual concentration was 10 times as high as the lowest concentration at which effects were observed (100 mg/m3) (i.e., if exposure was at a concentration of 1,000 mg/m3), the observation of positive effects from a short exposure duration (1 hr/day for 7 days) at that concentration leads the subcommittee to conclude that the interim permissible exposure level of 350 mg/m3 might be too high to be protective of human health (assuming the application of commonly used uncertainty factors).

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Dermal exposure of mice to JP-8 in multiple small doses (50 μL/day for 4-5 days) or in larger single doses (300 μL) resulted in local and systemic effects on the immune system (e.g., suppressed contact- and delayed-hypersensitivity responses). The subcommittee recommends that experimental animal studies examining the immunotoxicity of JP-8 via the inhalation route be conducted with careful control of vapor and aerosol concentrations in the atmosphere and with consideration of appropriate controls. The studies need to be designed in collaboration with scientists who are knowledgeable about aerosol generation, aerosol physics, and quantification of vapors and aerosols to ensure accurate characterization of the exposure atmospheres. Because the composition of JP-8 varies from batch to batch, scientists with expertise in petroleum toxicology should be consulted to design the best approach for testing the immunotoxicity of JP-8 (e.g., testing JP-8 samples at the extremes of their composition ranges or testing JP-8 samples so that the concentrations of component classes can be correlated with toxic end points). The subcommittee recommends that human blood samples from JP-8-exposed persons be assayed for indicators of immunotoxicity to determine whether effects in experimental animals are observed in humans. Furthermore, the subcommittee recommends that military personnel avoid direct, prolonged skin contact with JP-8. REFERENCES Allen, D.C., J.E. Riviere, and N.A. Monteiro-Riviere. 2000. Identification of early biomarkers of inflammation produced by keratinocytes exposed to jet fuels Jet A, JP-8, and JP-8(100). J. Biochem. Mol. Toxicol. 14(5):231-237. Basketter, D.A., G.F. Gerberick, I. Kimber, and S.E. Loveless. 1996. The local lymph node assay: A viable alternative to currently accepted skin sensitization tests. Food Chem. Toxicol. 34(10):985-997. Carpenter, C.P., D.L. Geary Jr., R.C. Myers, D.J. Nachreiner, L.J. Sullivan, and J.M. King. 1976. Petroleum hydrocarbon toxicity studies. XI. Animal and human response to vapors of deodorized kerosene. Toxicol. Appl. Pharmacol. 36(3):443-456. Cowan, M.J., and L.J. Jenkins. 1981. U.S. Navy toxicity study of shale and petroleum JP-5 aviation fuel and diesel fuel marine. Pp. 129-140 in Health Effects Investigation of Oil Shale Development, M.R. Guerin, W.H. Griest, and D.L. Coffin, eds. Ann Arbor, MI: Ann Arbor Science. Dudley, A.C., M.M. Peden-Adams, J. EuDaly, R.S. Pollenz, and D.E. Keil. 2001. An aryl hydrocarbon receptor independent mechanism of JP-8 jet fuel immunotoxicity in Ah-responsive and Ah-nonresponsive mice. Toxicol. Sci. 59(2):251-259.

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