9
Effects of Jet-Propulsion Fuel 8 on Reproduction and Development

This chapter reviews studies on potential reproductive and developmental toxicity of jet-propulsion fuel (JP-8). The subcommittee uses that information to assess the toxic effects of JP-8 on human reproduction and development. The National Research Council’s (NRC’s) report Permissible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) did not review reproductive and developmental effects of exposure to jet fuels. Another NRC report, Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (NRC 2001), did review the potential reproductive and developmental toxicity of JP-8. In that report, a dosage that is unlikely to cause toxicity (only for effects that are observed at birth and only for short-term exposure) was calculated to be 1 mg/kg per day (equivalent to 0.8 ppm for humans, assuming 8-hr/day exposure, 100% absorption, 69-kg body weight, and respiratory minute volume of 0.42 mL/min per kilogram of body weight).

EFFECTS OF EXPOSURE TO JP-8 IN HUMANS

No studies were found that examined the potential for developmental toxicity or adverse reproductive effects of JP-8 or other jet fuels in women. One study has examined reproductive effects in 50 men exposed to jet fuel



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9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development This chapter reviews studies on potential reproductive and developmental toxicity of jet-propulsion fuel (JP-8). The subcommittee uses that information to assess the toxic effects of JP-8 on human reproduction and development. The National Research Council’s (NRC’s) report Permissible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) did not review reproductive and developmental effects of exposure to jet fuels. Another NRC report, Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (NRC 2001), did review the potential reproductive and developmental toxicity of JP-8. In that report, a dosage that is unlikely to cause toxicity (only for effects that are observed at birth and only for short-term exposure) was calculated to be 1 mg/kg per day (equivalent to 0.8 ppm for humans, assuming 8-hr/day exposure, 100% absorption, 69-kg body weight, and respiratory minute volume of 0.42 mL/min per kilogram of body weight). EFFECTS OF EXPOSURE TO JP-8 IN HUMANS No studies were found that examined the potential for developmental toxicity or adverse reproductive effects of JP-8 or other jet fuels in women. One study has examined reproductive effects in 50 men exposed to jet fuel

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(type not specified): six sheet metal workers, six painters, 15 men who fuel jets, and 23 flight-line workers (LeMasters et al. 1999); eight unexposed men served as the control group. The men were exposed to a mixture of solvents and fuels. Breath samples from the men were collected and measured for total naphthas, benzene, 1,1,1-trichloroethane, methyl ethyl ketone, xylenes, toluene, and methylene chloride. All mean measures were less than 6 ppm. The following characteristics were analyzed: sperm production, structure, and function (sperm concentration, motility, viability, morphology, and morphometrics and stability of sperm chromatin). Measurements were made before exposure and after 15 and 30 wk of exposure. There was an increase in sperm concentration in the jet-fueler and flight-line groups and a decrease in sperm linearity in the jet-fueler group. The authors concluded that exposure to jet fuel did not have an apparent effect on semen quality for aircraft-maintenance personnel. EFFECTS OF EXPOSURE TO JP-8 IN EXPERIMENTAL ANIMALS Several studies have been conducted to assess the effects of JP-8 on the reproductive and developmental systems of experimental animals. They are described below and summarized in Table 9-1. Reproductive Toxicity Mattie et al. (2000) examined fertility in male and female rats exposed to JP-8. Male Sprague-Dawley rats were given JP-8 at 0, 750, 1,500, or 3,000 mg/kg daily by gavage for 70 days before mating and during mating with unexposed females (up to 90 days). After 90 days, the male rats were sacrificed, and sperm concentration, motile sperm concentration, percentage motility, velocity, linearity, maximal amplitude of lateral head displacement (ALH), mean ALH, and beat/cross frequency were measured. Other dimensions measured were mean radius, number of circular cells, percentage circular cells/ motile cells, and percentage circular cells/all cells. Pregnancy rate and gestation duration were recorded for all mated females. There were no adverse clinical signs, except changes in body weight. Rats exposed at 750 mg/kg showed a significant decrease in body weights (p < 0.05). There were no differences between exposed groups and the control group in any of the sperm measures. Exposure to JP-8 at the concentrations administered to the male mating partners did not have an effect on fertility of unexposed females. Female Sprague-Dawley rats were given JP-8 at 0, 325, 750, or 1,500 mg/kg daily by gavage for 21 wk (90 days before cohabitation and during

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TABLE 9-1 Effects of Jet Fuel Exposure on Reproduction and Development in Experimental Animals Fuel Type Species Exposure Concentration Exposure Duration Effects Reference REPRODUCTIVE EFFECTS JP-8 Male, female Sprague-Dawley rats Males, 750, 1,500, 3,000 mg/kg per day; females, 325, 750, 1,500 mg/kg per day (gavage) Males, 70 days before mating and during mating (up to 90 days); females, 90 days before mating and during mating, gestation, delivery, lactation Males: no differences between exposed and control groups in sperm concentration, motile sperm concentration, percentage motility, velocity, linearity, maximal ALH, mean ALH, beat/cross frequency, mean radius, number of circular cells, percentage circular cells/motile cells, and percentage circular cells/all cells; no effect on fertility of unexposed female mating partners Females: no significant differences between exposed and control groups in pregnancy rates, gestation lengths, number of pups/litter, litter size, viability and survival of pups; pups from dams exposed at 1,500 mg/kg per day had significantly reduced body weight compared with controls Mattie et al. 1995, 2000 JP-8 Male rats 1,000 mg/m3 6 wk No significant differences between exposed and control groups on sperm maturation, total counts, viability, and morphology Briggs et al. 1999 (meeting abstract)

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Fuel Type Species Exposure Concentration Exposure Duration Effects Reference JP-8 Male rats 250, 500, 1,000 mg/m3 6 hr/day, 7 days/wk for 90 days No significant differences between exposed and control groups on sperm count and concentration; no pathologic findings in testes of treated animals; significant difference between the treated and control animals in sperm motility Price et al. 2001 (meeting abstract) JP-5 B6C3F1 mice 2,000-8,000 mg/kg (dermal) 5 applications/wk for 13 wk No histologic changes in reproductive systems NTP 1986, as cited in ATSDR 1998 HDS Kerosene Male, female Sprague-Dawley rats 165, 330, 494 mg/kg (dermal) Males, 8 wk starting 14 days before mating; females, 7 wk starting 14 days before mating, sacrificed on days 4-6 of lactation No treatment-related effect on fertility; no treatment-related microscopic changes in testes or epididymides of adult male rats or in ovaries of adult female rats Schreiner et al. 1997 DEVELOPMENTAL EFFECTS JP-8 Female Sprague-Dawley rats 500, 1,000, 1,500, 2,000 mg/kg per day (oral) Days 6-15 of pregnancy Maternal and fetal body weights were markedly reduced in 1,000-, 1,500-, and 2,000-mg/kg per day groups; number and type of fetal malformations and variations did not differ Cooper and Mattie 1996

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  significantly between groups; progressive increase in overall incidence of fetal alterations with increasing dose between 500- and 1,500-mg/kg per day groups, but not for 2,000-mg/kg per day groups   Jet Fuel A Rats 100, 400 ppm (vapor) 6 hr/day on days 6-15 of pregnancy No embryonic, fetotoxic, or teratogenic effects observed Beliles and Mecler 1982, as cited in Koschier 1999 HDS Kerosene Male, female Sprague-Dawley rats 165, 330, 494 mg/kg (dermal) Males, 8 wk starting 14 days before mating; females, 7 wk starting 14 days before mating, sacrificed on days 4-6 of lactation No treatment-related developmental toxicity Schreiner et al. 1997 Kerosene Rats 0.76, 2.6 mg/L (106, 365 ppm) 6 hr/day on days 6-15 of pregnancy No adverse developmental effects in dams or progeny API 1979, as cited in Koschier 1999 Abbreviations: ALH, amplitude of lateral head displacement; HDS, hydrodesulfurized

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cohabitation, gestation, delivery, and lactation) (Mattie et al. 2000). Male mating partners were not exposed to JP-8. Pregnancy rate, gestation duration, size of litter, number of pups born dead, and pup weight were recorded. A number of hematologic and clinical chemistry characteristics were measured. Urine was collected and analyzed for pH, specific gravity, total protein, and creatine. A pathologic (clinical pathologic and histopathologic) examination was conducted on the females. There were no adverse clinical signs, except changes in body weight, and no mortality. Body weights decreased in female rats exposed at 1,500 mg/kg. There were no significant differences in pregnancy rates, gestation lengths, number of pups per litter, litter size, and viability and survival of pups between exposed groups and the control group. The pups from the dams exposed at 1,500 mg/kg had significantly lower body weight (10% lower) than the control group. In another study, male and female Sprague-Dawley rats were given hydrodesulfurized (HDS) kerosene at 0, 165, 330, or 494 mg/kg daily by the dermal route (Schreiner et al. 1997). Males were treated for about 8 wk starting 14 days before mating. Females were treated for about 7 wk, also starting 14 days before mating; they were sacrificed on days 4-6 of lactation. Pathologic examinations of the reproductive organs from males and females were conducted. Pregnancy rate, gestation duration, size of litter, number of pups born dead, and pup weight were recorded. No clinical signs of systemic toxicity were observed. Skin irritation increased in a dose-dependent manner. All groups had a fertility index of at least 80%. No treatment-related microscopic changes were observed in the testes or epididymides of adult male rats or in the ovaries of adult female rats. Briggs et al. (1999) exposed male rats to JP-8 by inhalation at 1,000 mg/m3 for 6 wk. Computer-assisted sperm analysis (CASA) was used to analyze sperm quality end points. The authors concluded that exposure to JP-8 had no significant influences on sperm maturation, total counts, viability, motility, and morphology. Price et al. (2001) exposed male rats to JP-8 by inhalation at 0, 250, 500, or 1,000 mg/m3 for 6 hr/day, 7 days/wk for 90 days. Following cessation of exposure, rat semen was analyzed with CASA. There were no significant differences between the treated and control groups in sperm count and concentration. There were no pathologic findings in the testes. There was a significant difference between animals treated at the highest concentration and control animals in sperm motility. Some information about reproductive effects of JP-8 can be obtained from toxicity studies that were not specifically designed to assess reproductive toxicity. Mattie et al. (1995) observed JP-8 had no effect on testis weight or histopathologic findings in a 90-day gavage study in male rats exposed at 0, 750, 1,500, or 3,000 mg/kg daily by gavage for 90 days. A study by the Na-

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tional Toxicology Program (NTP 1986 as cited in ATSDR 1998) found no histologic changes in the reproductive systems of mice treated dermally with JP-5 at 2,000-8,000 mg/kg, five times per week for 13 wk or at 250 or 500 mg/kg, five times per week for 103 wk. Developmental Toxicity Sprague-Dawley rats were given JP-8 orally at 0, 500, 1,000, 1,500, 2,000 mg/kg per day on days 6-15 of pregnancy (Cooper and Mattie 1996; NRC 2001). Dams exposed at 1,000 mg/kg per day or above gained significantly less body weight during pregnancy than did control rats. Several maternal deaths among exposed animals were attributed to the presence of JP-8 in the lungs. Fetal body weight at the two highest doses was significantly lower than in controls, but those doses were associated with even greater reduction in maternal weight gain during pregnancy. Fetal weight was reduced by 12% and 25%, and maternal gestational weight gain was reduced by 70% and 85% at 1,500 and 2,000 mg/kg per day, respectively. It is unclear whether the fetal weight reduction was causally associated with obvious signs of maternal toxicity. The numbers and types of congenital malformations and variations observed did not differ significantly between dose groups. A progressive increase in the overall incidence of fetal alterations (variations and malformations) with increasing dose was reported from 500 mg/kg per day to 1,500 mg/kg per day, but not at 2,000 mg/kg per day. It should be noted that the number of fetuses and litters exposed at 2,000 mg/kg per day and available for examination was much lower than in other dose groups because about one-third of the dams died; one surviving dam had a totally resorbed litter. Variations included dilated renal pelvis, ureter, and lateral ventricle; unossified sternebra; rudimentary 14th rib; fewer than four metatarsals; and external and subdural hematomas. Observed malformations included malformed sternum, missing centrum, hydronephrosis, ectopic heart, short tail, no tail, and encephalomyelcele. Male and female Sprague-Dawley rats were exposed to HDS kerosene daily by the dermal route at 0, 165, 330, or 494 mg/kg diluted in mineral oil (Schreiner et al. 1997). Males were treated for about 8 wk, starting 14 days before mating. Females were treated for about 7 wk, also starting 14 days before mating, and were sacrificed on days 4-6 of lactation. There was no apparent developmental toxicity due to repeated topical application of HDS kerosene. There were no statistically significant differences between treated and control groups with regard to mean number of corpora lutea or number

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of implantation sites per dam. All groups had a live-birth index of at least 97%. Pups from control and treated groups had comparable birth weights and weight gains. There were no statistically significant differences between pups from treated and control groups in viability index or mean number of live pups per litter. No signs of embryonic, fetotoxic, or teratogenic effects were observed in rats after exposure to jet fuel A vapor at 100 and 400 ppm on days 6-15 of gestation for 6 hr/day (Beliles and Mecler 1982 as cited in Koschier 1999). Kerosene produced no adverse effects in dams or their progeny after inhalation exposure at 0.76 or 2.6 mg/L (106 or 365 ppm) for 6 hr/day on days 6-15 of gestation (API 1979 as cited in Koschier 1999). CONCLUSIONS AND RECOMMENDATIONS No studies were found in the literature that examined potential female reproductive effects or developmental effects of JP-8 or other jet fuels in humans. One study assessed male reproductive effects of inhalation of jet fuel (type not specified) and hydrocarbon solvents after 15 and 30 wk of exposure. In that study, exposure to jet fuel increased sperm concentration in workers who fueled jets and decreased sperm linearity in flight-line workers; exposure to jet fuels did not appear to affect semen quality in aircraft-maintenance workers. Male and female Sprague-Dawley rats exposed to JP-8 by oral gavage at concentrations up to 1,500 (females) or 3,000 (males) mg/kg per day prior to and during mating and, in the case of the females, during gestation and lactation, showed a decrease in body weight, but no adverse effects on fertility were observed in either sex. Dermal exposure of rats to HDS kerosene at doses up to 494 mg/kg per day did not affect fertility in males or females exposed prior to and during mating and, in the case of the females, during gestation and lactation. Maternal-gestational weight gain and fetal body weights were reduced in Sprague-Dawley rats exposed to JP-8 by oral gavage at 1,500 or 2,000 mg/kg per day on days 6-15 of pregnancy; the types of fetal abnormalities did not differ significantly between JP-8 dose groups and the unexposed animals, and there was a progressive increase in the overall incidence of abnormalities with increasing dose from 500 to 1,500 mg/kg per day, but not at 2,000 mg/kg per day. No developmental toxicity was reported in the offspring of Sprague-Dawley rats dermally exposed to HDS kerosene at doses up to 494 mg/kg per day. There are no developmental-toxicity studies that evaluate postnatal and long-term effects (such as neurologic effects) of in utero exposures.

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Because of the paucity of data and because military personnel are occupationally exposed to JP-8, the subcommittee recommends that experimental-animal studies be conducted to determine the reproductive and developmental toxicity potential of JP-8. REFERENCES API (American Petroleum Institute). 1979. Teratology Study in Rats, Kerosine. Report No. 27-32175. Washington DC: American Petroleum Institute. ATSDR (Agency for Toxic Substances and Disease Registry). 1998. Toxicological Profile for Jet Fuels (JP-5 and JP-8). U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. Beliles, R.P., and F.J. Mecler. 1982. Inhalation teratology of jet fuel A, fuel oil, and petroleum naphtha in rats. Pp. 233-238 in Proceedings of a Symposium-The Toxicology of Petroleum Hydrocarbons, H.N. MacFarland, C.E. Holdsworth, J.A. MacGregor, R.W. Call, and M.L. Lane, eds. Washington, DC: American Petroleum Institute. Briggs, G.B., W.A. Price, A.F. Walsh, K.R. Still, and W.K. Alexander. 1999. Evaluation of JP-8 jet fuel potential to produce male reproductive toxicity using the computer-assisted sperm analysis system. Teratology 59(6):415. Cooper, J.R., and D.R. Mattie. 1996. Developmental toxicity of JP-8 jet fuel in the rat. J. Appl. Toxicol. 16(3):197-200. Koschier, F.J. 1999. Toxicity of middle distillates from dermal exposure. Drug Chem. Toxicol. 22(1):155-164. Lemasters, G.K., D.M. Olsen, J.H. Yiin, J.E. Lockey, R. Shukla, S.G. Selevan, S.M. Schrader, G.P. Toth, D.P. Evenson, and G.B. Huszar. 1999. Male reproductive effects of solvent and fuel exposure during aircraft maintenance. Reprod. Toxicol. 13(3):155-166. Mattie, D.R., G.B. Marit, C.D. Flemming, 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. Health 11(4):423-435. Mattie, D.R., G.B. Marit, J.R. Cooper, T.R. Sterner, and C.D. Flemming. 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. Human Effectiveness Directorate, Air Force Research Laboratory, Wright Patterson AFB, OH. March. NRC (National Research Council). 1996. Permissible Exposure Levels for Selected Military Fuel Vapors. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: National Academy Press. NTP (National Toxicology Program). 1986. Toxicology and Carcinogenesis Studies

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of Marine Diesel Fuel and JP-5 Navy Fuel (CAS No. 8008-20-6) in B6C3F1 Mice (Dermal Studies). NTP 310. NIH 86-2566. Research Triangle Park, NC: National Toxicology Program/National Institutes of Health. Price, W.A., G.B. Briggs, K.A. Grasman, and K.R. Still. 2001. Evaluation of reproductive toxicity from exposure of male rats to jet propulsion fuel JP-8 vapor. Toxicologist 60(1):251(1194). Schreiner, C., Q. Bui, R. Breglia, D. Burnett, F. Koschier, P. Podhasky, L. Lapadula, R. White, M. Feuston, A. Kruegger, and S. Rodriquez. 1997. Toxicity evaluation of petroleum blending streams: Reproductive and developmental effects of hydrodesulfurized kerosene. J. Toxicol. Environ. Health 52(3):211-229.