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Toxicologic Assessment of Jet-Propulsion Fuel 8 (2003)

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

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Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." 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:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." 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 114
Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." 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 115
Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 116
Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 117
Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 118
Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 119
Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 120
Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." National Research Council. 2003. Toxicologic Assessment of Jet-Propulsion Fuel 8. Washington, DC: The National Academies Press. doi: 10.17226/10578.
×
Page 121
Suggested Citation:"9 Effects of Jet-Propulsion Fuel 8 on Reproduction and Development." 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 122

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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 developm ent. The National Research Council’s (NRC’s) report Perm issible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) did not review reproductive and devel- opmental effects of exposure to jet fuels. Another NR C report, Evaluating Chemical and Other Agent Ex posures for Reproductive and Developm ental 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) w as calculated to be 1 mg/kg per day (equivalent to 0.8 ppm for hum ans, assum ing 8-hr/day exposure, 100% absorption, 69-kg body weight, and respiratory minute volume of 0.42 mL/m in 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 113

114 Toxicologic A ssessment of Jet-Propulsion F uel 8 (type not specified): six sheet metal workers, six painters, 15 men who fuel jets, and 23 flight-line workers (LeM asters 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 w ere collected and measured for total naphthas, benzene, 1,1,1-trichloroethane, m ethyl ethyl ketone, xylenes, toluene, and methylene chloride. All mean m easures were less than 6 ppm. The fol- lowing characteristics w ere analyzed: sperm production, structure, and function (sperm concentration, motility, viability, morphology, and morphometrics and stability of sperm chrom atin). Measurem ents 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. EFFECT S OF EXP OSUR E TO JP -8 IN EXPERIMENTAL ANIMALS Several studies have been conducted to assess the effects of JP-8 on the reproductive and developmental system s of experimental animals. They are described below and sum marized in Table 9-1. Rep roductive Toxicity Mattie et al. (2000) exam ined fertility in male and fem ale 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 sacri- ficed, and sperm concentration, motile sperm concentration, percentage motil- ity, 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 gesta- tion duration were recorded for all mated females. There w ere 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. Fem ale 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

TABLE 9-1 Effects of Jet Fuel Exposure on Reproduction and Development in Experimental Animals Exposu re Fuel Type Species Concentration Exposure Duration Effec ts Reference REPRODUCTIVE EFFECTS JP-8 Male, Males, 750, Males, 70 days Males: no differences between exposed and Mattie et al. fem ale 1,500, 3,000 before mating and control group s in spe rm concentration, motile 1995, 2000 Sprague- mg/kg per during mating (up sperm concentration, percentage motility, Dawley rats day; fem ales, to 90 days); velocity, linearity, maximal ALH, mean ALH, 325, 750, females, 90 days beat/cross frequency, mean radius, number of 1,500 mg/kg before mating and circular cells, percentage circular ce lls/m otile per day during mating, cells, and percentage circular cells/all cells; no (gavage) gestation, delivery, effect on fertility of unexposed female mating lactation partners Females: no significant differences between exposed and con trol groups in pregnanc y 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 JP-8 Male rats 1,000 mg/m 3 6 wk No significant differences between exposed Briggs et al. and control groups on sperm maturation, total 1999 counts, viability, and morphology (meeting abstract) (Continued) 115

TABLE 9-1 Continued 116 Exposu re Fuel Type Species Concentration Exposure Duration Effec ts Reference JP-8 Male rats 250, 500, 6 hr/day, 7 No significant differences between exposed Price et al. 1,000 mg/m 3 days/wk for 90 and control groups on sperm count and 2001 days concentration; no pathologic findings in testes (meeting of treated animals; significant difference abstract) betw een the tre ated and control an ima ls in sperm motility JP-5 B6C3F1 2,000-8,000 5 applications/wk No histologic changes in reproductive systems NTP 1986, mice mg/kg for 13 wk as cited in (dermal) ATSDR 1998 HDS Male, 165, 330, 494 Males, 8 wk starting No treatment-related effect on fertility; no Schreiner et Kerosene fem ale mg/kg 14 days before treatment-related microscopic changes in testes al. 1997 Sprague- (dermal) mating; fem ales, 7 or epididymides of adult male rats or in ovaries Dawley rats wk starting 14 days of adult fem ale rats before mating, sacrificed on days 4-6 of lactation DEVELOPMENTAL EFFECTS JP-8 Female 500, 1,000, Days 6-15 of Maternal and fetal body weights were m arkedly Cooper and Sprague- 1,500, 2,000 pregnancy reduced in 1,000-, 1,500-, and 2,000-mg/kg per Mattie 1996 Dawley rats mg/kg per day day groups; number and type of fetal (oral) malformations and variations did not differ

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 6 hr/day on days 6- No embryonic, fetotoxic, or teratogenic effects Beliles and (vapor) 15 of pregnancy observed Mecler 1982, as cited in Koschier 1999 HDS Male, 165, 330, 494 Males, 8 wk starting No treatm ent-related developmental toxicity Schreiner et Kerosene fem ale mg/kg 14 days before al. 1997 Sprague- (dermal) mating; fem ales, 7 Dawley rats wk starting 14 days before mating, sacrificed on days 4-6 of lactation Kerosene Rats 0.76, 2.6 mg/L 6 hr/day on days 6- No adverse developmental effects in dams or API 1979, (106, 365 15 of pregnancy progeny as cited in ppm) Koschier 1999 Abbreviations: ALH, amplitude of lateral head displacement; HDS, hydrodesulfurized 117

118 Toxicologic A ssessment of Jet-Propulsion F uel 8 cohabitation, gestation, delivery, and lactation) (Mattie et al. 2000). Male mat- ing 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 num ber 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 con- ducted on the fem ales. There were no adverse clinical signs, except changes in body weight, and no mortality. Body weights decreased in female rats ex- posed at 1,500 m g/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 w eight w ere 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 micro- scopic 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/m 3 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/m 3 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 histopatho logic 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-

Effects of Jet-Propulsion Fuel 8 on Reproduction and Development 119 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. Develop mental Toxicity Sprague-D awley 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). Dam s 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 toxic- ity. The numbers and types of congenital malformations and variations ob- served 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 m g/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; rudimen- tary 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 encephalomy- elcele. 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 m ineral 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

120 Toxicologic A ssessment of Jet-Propulsion F uel 8 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 fu el 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 fem ale 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 work- ers. Male and female Sprague-Dawley rats exposed to JP-8 by oral gavage at concentrations up to 1,500 (females) or 3,000 (m ales) mg/kg per day prior to and during m ating and, in the case of the females, during gestation and lacta- tion, 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-D awley 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 d id 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 developm ental-toxicity studies that evaluate postnatal and long-term effects (such as neurologic effects) of in utero exposures.

Effects of Jet-Propulsion Fuel 8 on Reproduction and Development 121 Because of the paucity of data and because military personnel are occupa- tionally exposed to JP-8, the subcommittee recomm ends 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. W ashin gton DC : Am erican P etroleum Institute. ATSDR (Agency for Toxic Su bstances 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 R egis- try, 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 . MacFarlan d, C.E. Holdsworth, J.A. MacGregor, R.W. Call, and M.L. Lane, eds. Washington, DC: American Petro- leum Institute. Briggs, G.B., W.A. Price, A.F. Walsh, K.R. Still, and W.K. Alexander. 1999. Evalua- tion of JP-8 jet fuel potential to produce male reproductive toxicity using the computer-assisted sperm analysis system. Teratology 59(6):415. Coop er, J.R., and D.R. Mattie. 1996. D evelopmental toxicity of JP-8 jet fuel in the rat. J. Appl. To xicol. 16(3):197-200. Koschier, F.J. 19 99. T oxicity of m iddle distillates from dermal exposure. Drug Chem. Toxicol. 22(1):155-164. Lem asters, G.K., D .M. O lsen, J.H. Yiin, J.E. Lockey, R. Shukla, S.G. Selevan, S.M. Schrad er, 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. M arit, C.D . Flem ming, an d J.R . Cooper. 1995. The effec ts 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. M arit, J.R. Cooper, T.R . Sterner, and C.D . Flem ming. 2000. Re- productive Effec ts of JP-8 Jet Fuel on M ale and Fem ale Sprague -Dawley Rats After Exposure by Oral Gavage. AFRL-HE-WP -TR-2000-0067. Human Effec- tiveness Directorate, Air Force Research Laboratory, Wright Patterson AFB, OH. March. NRC (Na tional Research C oun cil). 1996. Permissible Exposure Levels for Selected Military Fuel V apors. Washington, DC: National Acad emy Press. NRC (National Research Council). 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: National A cadem y Press. NTP (National Toxicology Program). 1986. Toxicology and Carcinogenesis Studies

122 Toxicologic A ssessment of Jet-Propulsion F uel 8 of Marine Diesel Fuel and JP-5 Navy Fuel (CAS N o. 8008-20-6) in B6C3F1 Mice (Derm al Stu dies). NT P 310. NIH 8 6-2566. Research Triangle Park, NC: Na- tional Toxicology Program /N ational Institu tes of Health. Price, W.A., G.B. Briggs, K.A. Grasman, and K.R. Still. 2001. Evaluation of repro- duc tive toxicity from exposure of male rats to jet propulsion fuel JP-8 vapor. Toxicologist 60(1):251(1 194). 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 developmenta l effects of hydrodesulfurized kerosene. J. Toxicol. Environ. Health 52(3):211-229.

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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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