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Toxicologic Assessment of Jet-Propulsion Fuel 8 (2003)

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

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Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Page 73
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Page 74
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Page 75
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Page 76
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 77
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 78
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 79
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 80
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 81
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 82
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 83
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 84
Suggested Citation:"6 Effects of Jet-Propulsion Fuel 8 on the Immune System." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
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Page 85

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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 experi- mental anim als. The 1996 National Research Council report Permissible Expo- sure Levels for Selected Military Fuel Vapors did not specifically consider the imm unotoxic effects of JP-8 or related fuels. No earlier studies that addressed the influence of JP-8 exposure on the functional capacity of the imm une sys- tem 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, includ ing JP-5 and JP-8, did not generate concern about im mu notoxicity. Imm unotoxicity is typically first detected in standard toxicology and pathology studies. IMMUN OSUP PRESSIVE EFFECT S OF JP-8 The subcomm ittee 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- 71

72 TABLE 6-1 Immunosuppressive Effects of JP-8 Exposure in Humans and Experimental Animals Species or Cell Line Exposure Concentration Exposure Duration Effec ts Reference INHALATION EXPOSURE Hum an Measurements taken in breathing High-exp osure High-exposure group had higher Rhodes et zones of subjects; median group, persistent white-cell counts than low-exposure al. 2001 a concentration of n aphthalene, 1.9 exposure to JP- group; there were increased num bers :g/m 3 (low-exposure group), 447 8(defined as at least 1 of neutrophils and monocytes but no :g/m 3 (high-exposure grou p); hr twice per wk for at diffe rences in total lymphocytes, T median concentration of benzene, least 9 mo); low- cells, N K cells, B cells; w hite cell, 3.1 :g/m 3 (low-exposure grou p), exposure group, no neu trophil, and mo nocyte coun ts in 242 :g/m 3 (high-exposure group) significant exposure high-exposure group did not exceed to jet fuel or solvents range of normal values Hum an Exposed group (5,706 people) had Not reported Health-event analysis did not find Gibson et potential occupational exposu re to differences in immunologic measures al. 2001a a JP-8. Control group (5,706 people) (such as infections) between exposed did not w ork in occup ations in and control groups which exposure to JP-8 would occur Hum an Measurements taken in breathing High- and moderate- Analysis of self-assessment Gibson et zones of subjects; median exposure groups, questionnaire did not report al. 2001b a concentration of n aphthalene, 1.9 persistent exposure diffe rences among grou ps in :g/m 3 (low-exposure group ), 10.4 to JP-8; low exposu re immunologic-related illnesses :g/m 3 (moderate-exposure group ), group, no significant

447 :g/m 3 (high-exposure grou p); exposure to jet fuel median concentration of benzene, or solvents 3.1 :g/m 3 (low-exposure grou p), 7.45 :g/m 3 (moderate-exposure group), 242 :g/m 3 (high-exposure group) F344 rat 500 and 1,000 mg/m 3 90 days continuously, No treatment-related changes in spleen Mattie et al. and followed by recovery weight or hematology were observed 1991 C57Bl/6 until approxim ately mou se 24 mo of age C57BL/6 100, 250, 500, 1,000, 2,500 mg/m 3 1 hr/day for 7 days Exposure at 100 mg/m 3 led to Ha rris et al. mou se (aerosol) (nose-only) decreased cellularity of thymu s; 1997a exposure at 500 mg/m 3 led to decreased spleen weight, cellularity; splenic T cells, B cells, macrophages were also affected by exposure at 100 and 500 mg/m 3; splenic T cells, B cells, macrophages were also decreased in JP-8-exposed mice; bone marrow cellularity increased after exposure at 100, 250 mg/m 3 but decreased after exposure at higher concen trations; exposure at 250 mg/m 3 led to reduced splee n cell proliferation re spon ses in vitro after stimulation with Con A or Con A + IL-2 (Continued) 73

74 TABLE 6-1 Continued Species or Cell Line Exposure Concentration Exposure Duration Effec ts Reference 3 C57BL/6 1,000, 2,500 mg/m (aero sol) 1 hr/day for 7 days In mice exposed at both doses, spleen Ha rris et al. mou se (nose-only) cellularity and spleen cell proliferation 1997b persisted for m ore than 21 d ays; spleen cells in mice exposed at 1,000 mg/m 3 were suppressed in ability to med iate NK activity, LAK responses, CTL responses C57BL/6 250-2,500 mg/m 3 JP-8 aerosol + 1 1 hr/day for 7 days Substance P administration prevented Ha rris et al. Mouse :M or 1nM substance P aerosol (nose-only) loss of splee n and thym us cellularity 1997c after exposure to JP-8 ; it also partially restored proliferative response of spleen cells to Con A + IL-2 C57BL/6 1,000 mg/m 3 (aero sol) 1 hr/day for 7 days Mice showed significantly decreased Ha rris et al. Mouse (nose-only) NK cell fun ction, significantly 2000 suppressed generation of LA K cell activity, suppressed generation of CTL cells from precursor T cells, inhibited helper T cell activity DERMAL EXPOSURE C3H/H eN 50, 250-300 :L 5 days (50 :L), single Induction of contact hypersensitivity Ullrich 1999 Mouse dose (250-300 :L) was impaired in dose-dependent manner regardless of whether contact

allergen was applied directly to treated skin o r at distant u nrelated 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-tre ated m ice to proliferate in response to plate-bound monoclonal anti-CD 3 was sign ificantly suppressed; IL-10 was found in the serum of JP-8-exposed mice C3H/H eN 50-300 :L undiluted or diluted in Single dose Splenic T-cells were cultured in vitro Ullrich and mou se acetone with antibody T-cell receptor; T cells Lyons 2000 from JP-8-exposed mice had reduced proliferative respo nse; T -cell- dependent antibody responses to KLH antigen injected in Freund’s adjuvant were no t altered by exposu re to JP-8 NHEK 80-200 :g/m L diluted in absolute Single dose JP-8 ind uce d ne crosis and cell death in Rosenthal et ethanol hum an keratinocytes in vitro al. 2001 NHEK 0.1% Single dose for 24 hr JP-8 increased production of Allen et al. proinflammatory cytokines TNF" and 2000 IL-8 (Continued) 75

76 TABLE 6-1 Continued Species or Cell Line Exposure Concentration Exposure Duration Effec ts Reference F344 rat 0.25 mL Single dose IL-1", iNO S expression were induced Kabbur et in isolated skin samples al. 2001 ORAL EXPOSURE B6C3F1 1,000, 2,000 mg/kg per day Administered to Significant suppression of PFC Keil et al. mou se pregnant mice on response in offspring when tested at 2001 days 6-15 of gestation age of 8 wk B6C3F1 1,000, 2,000 mg/kg per day 1 dose/day for 7 or Significant imm uno logic alterations in Dudley et and 14 days thymic weight and antibody PFC al. 2001 DBA/2 response to SRBC mou se a Background information about these studies can be found in Appendix B. Abbreviations: Con A, concanavalin A; CTL, cytotoxic T lymphocytes; IL, interleukin; iNO S, inducible nitric oxide synthase; KLH, keyhole-limpet hemocyanin; LAK, lymphokine-activated killer cell; NHEK, normal human epidermal keratinocyte; NK, natu ral killer cell; P FC , plaque-form ing cell; SR BC , sheep red blo od cell; TNF, tumor necrosis factor.

Effects of Jet-Propulsion Fuel 8 on the Im mune System 77 parisons or validated for predictability (Luster et al. 1988, 1992). Several of the approaches used in recent studies would more typically be conducted as mech- anistic studies, assuming that significant immunotoxicity was found in stan- dardized toxicology and pathology studies. The potential significance of these recent findings is discussed below; however, it should be noted that the sub- comm ittee 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/m 3 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/m 3 on a continuou s basis for 90 days, followed by recovery until the age of about 24 m onths. 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 ob- served between exposed and control rats at any time. At terminal sacrifice, female rats showed increased hematopoiesis in the spleen that was dose-de- pendent 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 derm atitis due to fighting. Nine months after termination of expo- sure, pathologic findings were limited to an increased incidence of inflamma- tory 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 m inimal. Nine m onths after exposure, pathologic findings were limited to increased incidence of inflammatory skin lesions and splenic hematopoiesis in male mice; neither effect was considered treatm ent- 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 :m; M. W itten, University of Arizona, personal comm uni- cation, 2002). Reported exposure at 100 mg/m 3 for 1 hr/day for 7 days re- sulted in decreased cellularity of the thymus gland while exposure at 500 mg/m 3 for 1 hr/day for 7 days resulted in decreased spleen weight and cellu-

78 Toxicologic A ssessment of Jet-Propulsion F uel 8 larity. Splenic T cells, B cells, and macrophages were affected to a similar de- gree. Bone marrow cellularity increased at 100 and 250 mg/m 3 and then de- creased at higher concentrations. Because body-weight data were not reported, it is unclear whether the changes in lymphoid tissue cellularity represent gen- eral toxicity or specific changes in lymphoid tissue. A minimal exposure at 250 mg/m 3 1 hr/d ay 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/m 3, 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/m 3. 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 imm une system. No published studies have shown that in vivo immu ne responses or resis- tance 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 melanom a cells as well as control mice (D.T. Harris, University of Arizona, personal commu nication, 2001) and experience a higher mortality after nasal challenge with Hong Kong influenza virus (M. Witten, University of Arizona, personal com mu nication, 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 m etastases could reflect alter- ations in the initial deposition of intravenously injected tum or cells as a result of lung-tissu e damage rather than of alterations in immu ne function. Physical changes in the lung after exposure to aerosolized JP-8 may also und erlie 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/m 3) and to partially restore the proliferative response of spleen cells to Con A + IL-2 (H arris 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 show ed such profound changes in lymphoid tissues when prior studies that examined the effects of vaporized JP- 8 failed to show such effects. Specifically, the subcomm ittee suspects that the

Effects of Jet-Propulsion Fuel 8 on the Im mune System 79 actual exposures in Harris et al. (1997 a,b,c; 2000) w ere underreported. JP-8 concentrations were not assessed in the aerosol, blood, or tissue, and this could lead to erroneous assumptions regarding exposu re concentrations. However, even if the actual concentrations were 10 times as high (e.g., exposure was at a concentration of 1,000 mg/m 3), 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/m 3 (assuming the application of commonly used uncertainty factors). It is also likely that exposu re to aerosolized JP-8 is more toxic than exposure to vaporized JP-8. In addition, the nose-only expo- sure 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, com- pared with whole-body exposu re. A comparison of changes in white-blood-cell cou nts after JP-8 exposure may be revealing in that white-blood-cell counts in military personnel exposed to JP-8 have been measured (Rhod es 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/m 3) and increased at higher concentrations (Harris et al. 1997a). Differential analysis revealed concentration-dependent neutrophilia. In addi- tion, 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/m 3) white-blood-cell counts were reduced to num- bers insufficient for analysis. In m ilitary 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 lympho- cytes, 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 m ilitary per- sonnel exposed to JP-8 did not exceed the norm al ranges. A previous pilot study by O lsen et al. (1998) found no difference in total white-blood-cell and differential counts among A ir Force personnel before and 18 months after the Air Force converted to JP-8. The functional status of the imm une 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 infec- tious 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

80 Toxicologic A ssessment of Jet-Propulsion F uel 8 not differ betw een m oderate and high-exposure groups and a low-exposure group (Gibson et al. 2001b); a limitation of this study was that the question- naire used addressed only ear infections, and the incidence of colds or flu might have been more relevant. Dermal Ex posure Ullrich (1999) reported that dermal exposure of C3H /HeN mice to JP-8 in multiple small doses (50 :L/day for 4-5 days) or in larger single doses (300 :L) resulted in local and systemic effects on immu ne 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-hypersensi- tivity response to a bacterial antigen injected subcutaneously was suppressed by derm al JP-8 exposure. W hen splenic T cells were stimu lated 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 w as not altered by JP-8 exposure (Ullrich and Lyons 2000). Serum concentration of IL-10, a cytokine that sup- presses 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 abro- gated 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 selec- tively 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 TNF" and IL-8 (Allen et al. 2000). Dermal exposure of rats also induced IL-1" and inducible nitric oxide synthetase expression in isolated skin samples (Kabbur et al. 2001). The immunosuppressive effects of derm al JP-8 were dose-dependent: 50 :L for 1-3 days was not significantly suppressive, nor were single doses smaller than 300 :L. The effects of JP-8 were also time-dependent: T-cell prolifera- tion 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-:L dose in the mouse was calculated by the authors to be 100 m L. Those results raise concern about potential health effects of prolonged or repeated dermal expo- sure of military personnel to JP-8.

Effects of Jet-Propulsion Fuel 8 on the Im mune System 81 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 m g/kg in rats. Parker et al. (1981) reported a decrease in w hite 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 lympho- cytes decreased. There were no histologic changes in the spleen or lymph nodes, but relative spleen weight was increased at the highest exposure concen- tration. 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 thym ic 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 signif- icant differences in resistance to Listeria infection or growth of B16 melanoma cells suggests selective effects of JP-8 on hum oral im mu nity. The selectivity of oral exposure for suppressing hum oral 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 subcom mittee’s charge. AL LERGIC P OT EN TIA L O F JP-8 If components of JP-8 are seen as foreign by the im mune 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 subseq uent JP-8 exposure. Except for anaphylaxis, similar symptoms can result from a nonspe- cific inflamm atory response to irritants that does not involve sensitization of the im mu ne system . The murine local lymph node assay is one predictor of the skin-sensitiza- tion potential of chemicals (Basketter et al. 1996). When JP-8 was tested in the assay with CBA/Ca m ice, a strain that shows increased responsiveness to

82 Toxicologic A ssessment of Jet-Propulsion F uel 8 contact allergens (Kimber and W eisenberger 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 applica- tion of JP-8 also show ed w eak 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 evalu- ated sensitization after inhalation of JP-8 were found. Allergic sensitization of hum ans to JP-8 or other jet fuels has not been reported . AU TO IMMUN E EFFEC TS OF JP-8 No studies that addressed the effects of JP-8 exposure on development or exacerbation of autoim mu ne disease were found. CONCLUSIONS AND RECOMMENDATIONS No histopathologic effects related to the im mu ne system were found in F344 rats and C57BL/6 mice exposed continuously to JP-8 vapors at concen- trations up to 1,000 mg/m 3 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 m ice to JP-8 aerosols at a concentration of 100 mg/m 3 for 1 hr/day for 7 days led to de- creased cellularity of the thymus, exposure at 500 mg/m 3 for 1 hr/day for 7 days led to decreased spleen weight and cellularity, and exposure at 1,000 mg/m 3 for 1 hr/day for 7 days led to decreased ability of spleen cells to medi- ate several immu ne 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/m 3) (i.e., if exposure was at a concentration of 1,000 mg/m 3), the observation of posi- tive effects from a short exposure duration (1 hr/day for 7 days) at that con- centration leads the subcom mittee to conclude that the interim perm issible exposure level of 350 mg/m 3 might be too high to be protective of human health (assuming the application of commonly used uncertainty factors).

Effects of Jet-Propulsion Fuel 8 on the Im mune System 83 Dermal exposure of mice to JP-8 in multiple small doses (50 :L/d ay for 4-5 days) or in larger single doses (300 :L) resulted in local and systemic effects on the immune system (e.g., suppressed contact- and delayed-hypersensitivity responses). The subcomm ittee recomm ends that experimental animal studies examin- ing the imm unotoxicity 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 genera- tion, aerosol physics, and quantification of vapors and aerosols to ensure accu- rate characterization of the exposure atmospheres. Because the composition of JP-8 varies from batch to batch, scientists w ith expertise in petroleum toxi- cology 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 com- ponent 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 experim ental anim als are observed in humans. Furthermore, the subcomm ittee recomm ends that military personnel avoid direct, prolonged skin contact with JP-8. REFERENCES Allen, D.C ., J.E. Riviere, an d N .A. Monteiro-Riviere. 2000 . Identification of early biomark ers 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. G erberick, I. Kimbe r, 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. Na chreiner, L.J. Sullivan, and J.M. King. 1976. P etr ole um 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 Investiga- tion of Oil Shale D evelopm ent, M.R. G uerin,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 imm uno- toxicity in Ah-respon sive and Ah-non responsiv e m ice. Toxicol. Sci. 59(2):251- 259.

84 Toxicologic A ssessment of Jet-Propulsion F uel 8 Gibson, R.L., S. Shanklin, and R.L. Warner. 2001a. Health effects comparisons. Pp. 125-129 in JP-8 Final Risk Assessment Report. The Institute of Environmental and Human H ealth (TIEHH), Lubbock, TX. August 2001. Gibson, R.L., S. Shanklin, and R.L. Warner. 2001b. Self-reported health status. Pp. 132-139 in JP-8 F inal Risk A ssessm ent Report. The Institute of Environmental and Human H ealth (TIEHH), Lubbock, TX. August 2001. Harris, D.T., D. Sakiestewa, R.F. Robledo, and M. Witten. 1997a. Immunotoxico- logical effects of JP -8 jet fuel exposure . Toxicol. Ind. H ealth 13(1):43-5 5. Harris, D.T., D. Sakiestewa, R.F. Robledo, and M. Witten. 1997b. Short-term expo- sure to JP-8 jet fuel results in long-term imm uno toxic ity. Toxico l. Ind. Health 13(5 ): 559-570. Harris, D.T., D. Sakiestewa, R.F. Robledo, and M. Witten. 1997c. Protection from JP-8 jet fuel induced immunotoxicity by administration of aerosolized substance P. Toxicol. Ind . Health 13(5):571-588. Harris, D.T., D. Sakiestew a, R.F. R obled o, and M. W itten. 2000. Effects of short- term JP-8 jet fuel exposure on cell-mediated imm unity. Toxicol. Ind. Health 16(2):78-84. Kabb ur, M.B., J.V. Rogers, P.G. Gunasekar, C.M . Garrett, K.T. Geiss, W.W. Brinkley, and J.N. McD ougal. 2001. Effect of JP-8 jet fuel on molecular and biological param eters related to acute skin irritation . Toxicol. Appl. Pharmacol. 175(1):83- 88. Kanikkannan, N., T. Jackson, M. Sud han Shaik, and M . Singh. 2000. Evaluation of skin sensitization potential of jet fuels by mu rine local lymph node assay. Toxicol. Lett. 116(1-2):165-170. Keil, D.E., D.A. Warren, M .M. Peden-Ad ams, and J. EuDaly. 2001. The effects of JP-8 on immune function and thyroid hormone levels in B6C3F1 mice exposed in utero. Toxicologist 60(1):218. Kim ber, I., and C. Weisenberger. 1989. A murine local lymph node assay for the identification of contact allergens. Assay development and results of an initial validation study. Arch. Toxicol. 63(4):274-282. Kinkead, E.R., S.A. Salins, and R.E. Wolfe. 1992a. Acute irritation and sensitization potential of JP-8 jet fuel. J. A m. Coll. Toxicol. 11(6):700. Kinkead, E.R., R.E. Wolfe, and S.A. Salins. 1992b. Acute irritation and sensitization potential of shale-derived JP-5 jet fuel. J. Am. Coll. Toxicol. 11(6):705. Luster, M.I., A.E. Mun son, P.T. Thom as, M.P. Holsapple, J.D. Fen ters, K .L. W hite Jr., L.D. Lauer, D.R. Germolec, G.J. Rosenthal, and J.H. Dean. 1988. Development of a testing battery to assess chem ical-induced imm uno toxicity: National To xicol- ogy Program?s guidelines for immunotoxicity evaluation in mice. Fundam . Appl. Toxicol. 10(1):2-19. Luster, M.I., C. Portier, D.G. Pait, K.L. W hite Jr., C. Gennings, A.E. Munson, and G .J. Rosenthal. 1992. Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests. Fundam. Appl. Toxicol. 18(2):200-210.

Effects of Jet-Propulsion Fuel 8 on the Im mune System 85 Mattie, D.R., C.L. Alden, T.K . Newell, C.L. Gaworski, an d C .D. F lem ming. 19 91. 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 m ice. Toxicol. Pathol. 19(2 ):77-8 7. Mattie, D.R., G.B. M arit, C.D. Flemm ing, and J.R. Cooper. 1995. The effects of JP-8 jet fuel on male Sprague-Dawley rats after a 90-day exposure by oral gavage. Toxicol. Ind. H ealth 11(4):423-435. NRC (Na tional Research C oun cil). 1996. Permissible Exposure Levels for Selected Military Fuel V apors. Washington , DC: N ational Acade my P ress. Olsen, D.M., D.R. Mattie, W.D. Gould, F. Witzmann, M. Ledbetter, G.K . Lemasters, and J.H. Yin. 1998. Pilot Study of O ccupational A ssessment of A ir Force Pe r- sonnel Exposure to Jet Fuel Before and After Conversion to JP-8. AFRL-HE- WP-TR-1998-0107. Air Force Research Laboratory, Operational Toxicology Branch, Wright-Patterson AFB, OH. 43pp. Parker, G.A., V. Bogo, and R.W . You ng. 19 81. Acute toxicity of conventional versus shale-derived JP5 jet fuel: Light microscopic, hematologic, and serum chem istry studies. Toxicol. Appl. Pharmacol. 57(3):302-317. Rhod es, A.G., G.K . LeM asters, J.E. Lockey, J.W. Smith, J.H. Yiin, R. Gibson, and S. Rappaport. 2001. The effects of JP8 jet fuel on immune cell counts of tank entry workers. Pp. 100-120 in JP-8 Final Risk Assessment Report. The Institute of Environmental and Human H ealth (TIEHH), Lubbock, TX. August 2001. Robledo, R.F., and M.L. W itten. 1999. NK 1-receptor activation prevents hydroca r- bon induced lung injury in mice. Am. J. Physiol. 276(2 Pt 1):L229-L238. Rosenthal, D.S., C.M. Sim bulan-Rosen thal, W.F. Liu, B.A. Stoica, and M.E. Smulson. 2001. Mechanisms of JP-8 jet fuel cell toxicity. II. Inductio n of n ecrosis in skin fibroblasts and keratinocytes and mo dulation of levels of Bcl-2 fam ily mem bers. Toxicol. Appl. Pharmcol. 171(2):107-116. Schultz, T.W ., H. Witschi, L.H. Smith, W.M. Haschek, J.M. Holland, J.L. Epler, R.M. Fry, T.K. Rao, F.W. Larimer, and J.N. Dum ont. 1981. Health Effects Research in Oil Shale Development. ORNL /TM-8034. Oak Ridge, TN: Oak Ridge National La boratory. 61pp. Ullrich, S.E. 1999. Dermal application of JP-8 jet fuel induces immune suppression. Toxicol. Sci. 52(1):61-67. Ullrich, S.E., and H.J. Lyons. 2000. Mechanisms involve d in the immu notoxicity induced by dermal application of JP-8 jet fuel. Toxicol. Sci. 58(2):290-298.

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

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