Effects of ammonium dinitramide on preimplantation embryos in Sprague-Dawley rats.

Ammonium dinitramide (ADN) is a class 1.1 oxidizer that may be used in rocket propellants and explosives. Previous studies have shown that ADN is a female reproductive toxicant, causing implantation failure in Sprague-Dawley rats when it is administered during the preimplantation period of gestation. The purpose of this follow-up study was to identify the mechanism(s) associated with implantation failure following exposure to ADN. Mated female rats were treated with 2.0 grams per liter (g l-1) ADN in their drinking water for 24, 48, 72, or 96 h before preimplantation embryos were harvested from the oviducts or uterine horns. On gestation day 1 (GD-1), comparable numbers of morphologically normal two-cell embryos were harvested from the oviducts of the treatment and control groups. On GD-2, the development of the embryos harvested from the treated animals was either slowed or halted when compared to the control embryos. By GD-4, 98% of the embryos harvested from the control group had developed to the morula or blastocyst stage; these were collected from the uterine horns. On GD-4 in the treated group, 41% of the harvested embryos remained at the two- to six-cell stage and 59% were degenerate; 82% of these embryos were collected from the oviducts. These data suggest that the implantation failure seen in animals treated with ADN is due to embryolethality.

In vivo/in vitro comparison of the pharmacokinetics and pharmacodynamics of 3,3',4,4'-tetrachlorobiphenyl (PCB77).

The rat hepatoma cell line, H4IIE, serves as a useful tool to assess potential biological effects such as induction of cytochrome P4501A1 expression. The objectives of this study were twofold: to investigate the kinetic time course and dosimetry of PCB77 in rat hepatoma cells dosed with PCB77 and in liver of rats given i.p. doses of PCB77, and to compare in vitro and in vivo P4501A1 enzyme induction responses. For the 4-day time-course study, H4IIE cells were exposed with two doses of [14C]PCB77 (0.9 and 3 microg/plate) and harvested at 15 and 30 min, 1, 2, 4, 8, and 12 hr, and 1, 2, 3, and 4 days. PCB77-derived radioactivity was detected in the cells as early as 15 min postdosing. For the dose-response study, the cells were dosed with various concentrations of PCB77 (0.00316-5.37 microg/plate) and harvested on Day 3 since ethoxyresorufin O-deethylase (EROD) activity in vitro reached its maximum on the third day postdosing. Time-course and dose-response studies revealed that only 1-3% of the total delivered dose was found in the cells, with the remainder in the media and adhering to the culture plates. For the dose-response study in vivo, male Fischer rats were dosed with a single i.p. injection of various concentrations of PCB77 (0.1-50 mg/kg body wt) and euthanized on Day 3. PCB77-derived radioactivity and EROD induction in vivo were measured. When EROD activity and PCB77-derived radioactivity in the rat hepatoma cells and in the rat liver were compared on an equivalent weight basis, there was a significant correlation (r2 = 0.985) between them. Prior to this study, no information on quantitative dosimetry and EROD activities of PCB77 has been reported to validate the in vitro assay with in vivo data.

Evaluating human variability in chemical risk assessment: hazard identification and dose-response assessment for noncancer oral toxicity of trichloroethylene.

Human variability can be addressed during each stage in the risk assessment of chemicals causing noncancer toxicities. Noncancer toxicities arising from oral exposure to trichloroethylene (TCE) are used in this paper as a case study for exploring strategies for identifying and incorporating information about human variability in the chemical specific hazard identification and dose-response assessment steps. Toxicity testing in laboratory rodents is the most commonly used method for hazard identification. By using animal models for sensitive populations, such as developing fetuses, testing can identify some potentially sensitive populations. A large variety of reproductive and developmental studies with TCE were reviewed. The results were mostly negative and the limited positive findings generally occurred at doses similar to those causing liver and kidney toxicity. Physiologically based pharmacokinetic modeling using Monte Carlo simulation is one method for evaluating human variability in the dose-response assessment. Three strategies for obtaining data describing this variability for TCE are discussed: (1) using in vivo human pharmacokinetic data for TCE and its metabolites, (2) studying metabolism in vitro, and (3) identifying the responsible enzymes and their variability. A review of important steps in the metabolic pathways for TCE describes known metabolic variabilities including genetic polymorphisms, enzyme induction, and disease states. A significant problem for incorporating data on pharmacokinetic variability is a lack of information on how it relates to alterations in toxicity. Response modeling is still largely limited to empirical methods due to the lack of knowledge about toxicodynamic processes. Empirical methods, such as reduction of the No-Observed-Adverse-Effect-Level or a Benchmark Dose by uncertainty factors, incorporate human variability only qualitatively by use of an uncertainty factor. As improved data and methods for biologically based dose-response assessment become available, use of quantitative information about variability will increase in the risk assessment of chemicals.

A trichloroethylene risk assessment using a Monte Carlo analysis of parameter uncertainty in conjunction with physiologically-based pharmacokinetic modeling.

A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10(-6) lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10(-6) risk.

Oncogenic potential of inhaled hydrazine in the nose of rats and hamsters after 1 or 10 1-hr exposures.

Hydrazine (N2H4) is used as a fuel for missiles and standby power systems of operational military aircraft. Maintenance of missiles and aircraft may result in accidental human exposure to high concentrations for brief periods of time. The purposes of this study were to assess the oncogenic potential of N2H4 in rats and male hamsters exposed to a high concentration of N2H4 for repeated short exposures and to investigate the relationships of acute and subchronic effects of N2H4 to nasal tumorigenesis. In phase 1 (acute and subchronic) and Phase 2 (lifetime experiments, groups of male and female Fischer 344 rats and male Syrian golden hamsters were exposed by inhalation to 0, 75 (Phase 2 only), or 750 ppm N2H4 for 1 (acute) or 10 (subchronic) 1-hr weekly exposures. Rodents were euthanized 24 hr after exposures 1 and 10 and 24 to 30 months poststudy initiation. Significant reductions in body weight were observed in N2H4-treated rodents compared to controls during the exposure interval. No hydrazine-induced mortality was detected. Histopathologic examination after the acute and subchronic exposures revealed degeneration and necrosis of transitional, respiratory, and olfactory epithelia in the anterior nose and, in rats exposed subchronically, squamous metaplasia of the transitional epithelium. Minimal to mild rhinitis resulted from N2H4 exposures. Apoptosis was observed in olfactory and squamous metaplastic transitional epithelium. Lesions occurred at sites reportedly having high air-flow and generally appeared to be more severe in the anterior portion of the nose. By 24 months, the squamous metaplastic transitional epithelium reverted back to normal-appearing transitional epithelium. By 24+ months, low incidences (sexes combined) of hyperplasia (5/194, 2.6%) and neoplasia (11/194, 5.7%) were detected, principally in the transitional epithelium of the 750 ppm N2H4-treated rats. A similar incidence of hyperplasia (2/94, 2%) and neoplasia (5/94, 5.3%) was detected in the high-exposure group of hamsters. The location and type of N2H4-induced proliferative lesions were similar to those reported in a chronic N2H4-exposure study (5.0 ppm x 6 hr/day x 5 days/week for 1 year) conducted in our laboratory, but the chronic study had much higher incidences (rats, sexes combined: hyperplasia 15.5% vs 2.6% and polypoid adenoma 44.6% vs 5.2%). The product (CD) of concentration + time was the same (750 ppm hours) for the high-dose groups for both studies, but the duration of exposure was 150 x longer and the concentration was 150 x lower in the chronic study.(ABSTRACT TRUNCATED AT 400 WORDS)

Reproductive toxicity screen of ammonium dinitramide administered in the drinking water of Sprague-Dawley rats.

The Department of Defense is currently considering replacing ammonium perchlorate with ammonium dinitramide (ADN), a class 1.1 explosive oxidizer to be used in solid rocket propellant mixtures and explosives. This study was intended to evaluate the potential of ADN to produce alterations in paternal fertility, maternal pregnancy and lactation, and growth and development of offspring. Male and female rats received drinking water containing 0.0, 0.2, 1.0, or 2.0 g ADN/liter throughout the study. Mating occurred following 14 days of treatment. All dams, one-half the males, and representative pups were maintained for a total of 90 days of treatment. No mortality occurred in parental animals during the study. Treatment with ADN resulted in no adverse effects on mating; 92-100% of the animals mated. No treatment-related effects were seen in parental animals clinically or histopathologically. Adverse treatment-related effects were noted in maternal and paternal fertility indices, gestational indices, and live birth indices in both the mid- and high-dose groups. Litter sizes in the mid- and high-dose groups were significantly smaller than those of the low-dose and control groups. Mean pup weights showed no statistically significant differences between ADN-treated pups and controls. Gross and histopathological examination of the animals failed to identify the cause for the decrease in litter production in the mid- and high-dose dams. This study indicates that ADN is a reproductive toxicant. The no-observable-effect level (NOEL) is 29 mg/kg/day, the median dose of the low level female rats.

The effects of JP-8 jet fuel on male Sprague-Dawley rats after a 90-day exposure by oral gavage.

The U.S. Air Force is converting from JP-4 jet fuel to the less volatile JP-8 jet fuel, which is similar to commercial Jet Fuel A. Our previous 90-day inhalation study with JP-8 vapor, using F-344 rats and C57BL/6 mice, resulted in no treatment-related adverse effects other than alpha 2-microglobulin nephropathy in male rats (Mattie et al., 1991). In the present study, male rats were dosed with neat JP-8 (0, 750, 1500, 3000 mg/kg) daily by gavage for 90 days in an effort to characterize the kidney lesion and assess further any additional adverse effects associated with prolonged oral exposure to this fuel. Results of this study revealed a significant dose-dependent decrease in body weights of rats exposed to JP-8. Male rat-specific alpha 2-microglobulin nephropathy was observed by histopathologic examination. A number of significant changes were also seen in blood and urine that were not dose-dependent. Additional treatment-related effects were a gastritis and a perianal dermatitis. Although there were no histopathological or weight changes in the livers of exposed rats, there was an increase in the liver enzymes AST and ALT. The elevated enzymes did not increase with increasing dose of JP-8.

Reproductive toxicity screen of 1,3,5-trinitrobenzene administered in the diet of Sprague-Dawley rats.

Several Army installations targeted for restoration have measurable quantities of 1,3,5-trinitrobenzene (TNB) in the soil and groundwater. As part of the process of developing environmental and health effects criteria for restoration, a modified Screening Information Data Set (SIDS) reproductive study was performed. Male and female Sprague-Dawley rats received a diet containing approximately 30, 150, or 300 mg TNB/kg diet. Mating occurred following 14 days of treatment. All dams, one-half the males, and representative pups were maintained for a total of 90 days of treatment. No mortality occurred during the study; however, a decrease in mean body weights was noted in both sexes of high-dose rats. A dose-related effect was noted in measurements of sperm function/activity. Sperm depletion and degeneration of the seminiferous tubules were noted histopathologically. Methemoglobinemia and splenic hemosiderosis were common findings in the high- and mid-dose levels of both sexes at necropsy. No adverse effects were noted in mating or fertility indices. No significant treatment-related differences were found in length of gestation, sex ratio, gestation index, or mean number of pups per litter.

General toxicity and reproductive screen of liquid propellant XM46 administered in the drinking water of Sprague-Dawley rats.

Liquid propellant XM46 is being considered as a replacement for solid propellants, both as part of a regenerative injection gun system and as a working fluid in an electrothermal gun system. The XM46 formulation contains hydroxylammonium nitrate, triethanolammonium nitrate, and water. Male and female Sprague-Dawley rats received XM46 in drinking water containing 2.0, 1.0, 0.2, or 0.0 g XM46/liter throughout a 90-day study. Mating occurred following 14 days of treatment. One-half the male rats per group were necropsied after 28 days of treatment; the remaining males and all dams were necropsied following 90 days of treatment. No mortality occurred in any of the parental animals during the study. The study did not demonstrate any adverse effects on reproduction or litter parameters. Hemolytic anemia and methemoglobinemia were common in both sexes of rats. Splenomegaly was found in both sexes; in male rats as early as 28 days. Exposures via drinking water containing XM46 for 90 days did not result in any decrease in reproductive performance in male or female rats, but it did result in clinical signs of hemolytic anemia at doses as low as 17 mg/kg/day.

Reproductive toxicity of butylated triphenyl phosphate and tricresyl phosphate fluids in F344 rats.

The effects of tricresyl phosphate (TCP) and butylated triphenyl phosphate (BTP)-based hydraulic fluid on reproduction were studied in F344 rats using a modification of the National Toxicology Program's Continuous Breeding Protocol. Groups of breeding pairs received single daily oral doses of an equal volume of either 0, 0.6, 1.0 g BTP/kg or 0.4 TCP/kg in sesame oil or 1.7 g neat BTP/kg for up to 135 days. A naive control group allowed to breed, but not dosed or handled daily, demonstrated that daily dosing and handling of the rats had no effect on reproduction. The fertility index and number of litters born were significantly decreased in rats exposed to 1.0 and 1.7 g BTP/kg and 0.4 g TCP/kg. The number of pups per litter was significantly decreased in the TCP group. A crossover mating experiment using 0.4 g TCP/kg/day and 1.0 g BTP/kg/day groups, each mated with vehicle controls, demonstrated that TCP caused 100% infertility in male rats but did not affect reproduction in females. BTP caused a significant decline in reproduction in female rats characterized by low mating and fertility indices, decreased number of litters, and abnormal estrous cycles. Fertility was decreased in the BTP-dosed male rats. Both sexes of rats in the crossover experiment with TCP and BTP had significant decreases in terminal body weights and increases in adrenal gland and liver weights. Only TCP-dosed male rats had significantly decreased testicular and epididymal weights.(ABSTRACT TRUNCATED AT 250 WORDS)

The comparative toxicity of operational Air Force hydraulic fluids.

The subchronic (26 day) oral toxicities of two AF hydraulic fluids (MIL-H-5606 [H5], MIL-H-83282 [H8]), a commercial phosphate ester (PE), and two candidate hydraulic fluids (low temperature version of MIL-H-83282 [LT] and chlorotrifluorethylene oligomers [polyCTFE]) were compared in male F-344 rats. Oral dosing was used in order to quickly compare these fluids to PolyCTFE, the only fluid at the time to have been tested in a 90-day inhalation study. Rats were initially dosed with 1.0 g/kg/day of each fluid. H8 increased alkaline phosphatase (ALKP) while LT produced an anemia and leukocytosis. Exposure to H5 fluid resulted in lymphocytopenia and persistent diuresis. Due to their greater toxicity, resulting in lethality in the first dosing study, only 0.5 g/kg/day of PE and PolyCTFE were administered in the second study. Exposure to PE (0.5 g/kg) resulted in an anemia and decreases in BW (day 10 until day 25), spleen/BW ratio, blood urea nitrogen (BUN), and creatinine (CREAT). PolyCREAT (0.5 g/kg) decreased BW (day 11 to the end of the study) and testicular weight. PolyCTFE (0.5 g/kg) increased relative spleen weights, various clinical chemistry parameters, and triggered a reversible diuresis. PolyCTFE (0.5 g/kg), PE (0.5 g/kg), and H5 produced an increase in absolute and relative liver weights compared to control livers. Peroxisomal beta oxidation, an indicator of peroxisomal proliferation, was significantly increased above control levels in the livers of all rats except the PE (0.5 g/kg) group, where the increase was not significant. Hydrocarbon nephropathy, indicated by increased levels of hyaline droplets in kidney tubules, was severe in H5, mild in H8, LT, and PolyCTFE (0.5 g/kg), and minimal in PE (0.5 g/kg). The MIL-H-83282 fluids (H8 and LT) were the least toxic hydraulic fluids. PolyCTFE and PE were the most toxic, with H5 intermediate.

Variability of physiologically based pharmacokinetic (PBPK) model parameters and their effects on PBPK model predictions in a risk assessment for perchloroethylene (PCE).

When used in the risk assessment process, the output from physiologically based pharmacokinetic (PBPK) models has usually been considered as an exact estimate of dose, ignoring uncertainties in the parameter values used in the model and their impact on model predictions. We have collected experimental data on the variability of key parameters in a PBPK model for tetrachloroethylene (PCE) and have used Monte Carlo analysis to estimate the resulting variability in the model predictions. Blood/air and tissue/blood partition coefficients and the interanimal variability of these data were determined for tetrachloroethylene (PCE). The mean values and variability for these and other published model parameters were incorporated into a PBPK model for PCE and a Monte Carlo analysis (n = 600) was performed to determine the effect on model predicted dose surrogates for a PCE risk assessment. For a typical dose surrogate, area under the blood time curve for metabolite in the liver (AUCLM), the coefficient of variation was 25% and the mean value for AUCLM was within a factor of two of the maximum and minimum values generated in the 600 simulations. These calculations demonstrate that parameter uncertainty is not a significant potential source of variability in the use of PBPK models in risk assessment. However, we did not in this study consider uncertainties as to metabolic pathways, mechanism of carcinogenicity, or appropriateness of dose surrogates.

Evaluation of the promotion potential of chlorotrifluoroethylene trimer acid in male Sprague-Dawley rats.

The promoting effect of chlorotrifluoroethylene trimer acid (TRA), a metabolite of the 6-carbon oligomer of Halocarbon 3.1 oil, was investigated using a bioassay designed to detect enzyme-altered foci. These oligomers, as well as their carboxylic acid metabolites, have been shown to cause hepatomegaly and an increased rate of hepatic peroxisomal fatty acid beta-oxidation following administration by oral and inhalation routes. Groups of 2/3 partially hepatectomized male Sprague-Dawley rats were initiated with a single dose of diethylnitrosamine (10 mg/kg). Two weeks later phenobarbital (0.5% in the drinking water) was provided to animals in the positive control group. At the same time, three other groups received an initial dose of TRA by intraperitoneal injection (98, 9.8 and 0.98 mg/kg). Biweekly intraperitoneal injections of TRA (12.3, 1.2, and 0.12 mg/kg) were continued for 9 months. Quantitative sterological analysis revealed that TRA exposure resulted in a significant dose-dependent increase in the number of gamma-glutamyltranspeptidase-positive foci.

The toxicologic and oncogenic potential of JP-4 jet fuel vapors in rats and mice: 12-month intermittent inhalation exposures.

Three-hundred Fischer 344 rats and 300 C57BL/6 mice of each sex were divided into three treatment groups and exposed intermittently (6 hr/day, 5 days/week) to JP-4 jet fuel vapors at concentrations of 0, 1000, and 5000 mg/m3 for 12 months. At exposure termination, 10% of the animals were killed and those remaining were held for a 12-month postexposure tumorigenesis observation period. Pathologic findings in male rats revealed treatment-related renal toxicity and neoplasia consistent with the male rat unique alpha 2 mu-globulin nephropathy syndrome. Distinct JP-4-induced respiratory toxicity was not observed, and pulmonary neoplasms were not significantly increased in any treatment group. Benign hepatocellular adenomas were slightly increased in high-dose female mice, but the trend was reversed in male mice. Other pathologic findings were regarded as equivocal or compatible with expected biologic variation. The study did not demonstrate target organ toxicity or carcinogenesis which could be extrapolated to other species.

Comparative hepatotoxicity of two polychlorotrifluoroethylenes (3.1 oils) and two chlorotrifluoroethylene (CTFE) oligomers in male Fischer 344 rats.

Polychlorotrifluoroethylene (3.1 oil) is a nonflammable hydraulic fluid composed of chlorotrifluoroethylene (CTFE) oligomers of different carbon chain lengths (C5 to C9), primarily six (trimer) and eight (tetramer) carbons. Four test groups of Fischer 344 rats (16 rats/group) were orally gavaged daily over a 2-week period at doses of 1.25 g/kg with 3.1 oil containing a 55:45 ratio of trimer and tetramer (3.1 oil-C6:C8), 3.1 oil composed of 95% trimer (3.1 oil-C6), pure tetramer, and pure trimer. Four rats per treatment group were terminated after 1, 3, 7, and 14 doses. Rats dosed with either 3.1 oil-C6:C8 or pure tetramer demonstrated significant weight losses, increased liver weights, increased rates of liver fatty acid beta-oxidation, pronounced hepatomegaly and altered hepatocellular architecture, and elevated serum liver-associated enzymes. Rats dosed with either 3.1 oil-C6 or only pure trimer demonstrated significant increase in liver weight and moderate liver histopathologic changes. Compositional analyses of the ratio percentage of trimer to tetramer present in 3.1 oil-C6:C8 (55:45) were found to be altered when measured in the liver (32:68). Differential CTFE oligomer toxicity was indicated by effects on liver, body weight, and peroxisomal beta-oxidation and may allow for less toxic formulations of 3.1 oil to be generated by reducing or eliminating the tetramer component.

Repeated-dose gavage studies on polychlorotrifluoroethylene acids.

C8 polychlorotrifluoroethylene (pCTFE) oligomers accumulate preferentially in the liver during long-term oral exposure and appear to be more hepatotoxic than C6 oligomers. A repeated-dose gavage study was initiated to determine the relative contributions of the corresponding C6 (trimer) and C8 (tetramer) acid metabolites to the toxicity of pCTFE in the male Fischer 344 rat. Test animals were dosed once per week for various time periods up to one year. A depression (p less than 0.05) in mean body weight occurred in the highest dose tetramer acid (2.16 mg/kg) group. An increase in hepatic peroxisomal beta-oxidation activity was found in the 2.16 mg pCTFE tetramer acid/kg dose group at the 3-, 6-, and 9-month sacrifice periods. An increase in relative liver weight was seen at all sacrifice periods in this dose group. Hepatocellular cytomegaly was a common finding in the higher dose tetramer acid groups but not in the trimer-treated rat groups.

Effects of a 13-week chloropentafluorobenzene inhalation exposure of Fischer 344 rats and B6C3F1 mice.

Chloropentafluorobenzene (CPFB) has been identified as a candidate simulant for nonpersistent chemical warfare agents. Acute toxicity studies have shown that CPFB has limited adverse effects on laboratory animals. A 21-day inhalation study of rats and mice to 2.5, 0.8, and 0.25 mg CPFB/liter resulted in reduced weight gain in male and female rats exposed at the high concentration only and identified the liver as a potential target organ. This multiconcentration inhalation study was designed to detect a no-observable-effect level associated with repeated exposure to CPFB. Male and female rats and mice were exposed to 250, 50, or 10 mg CPFB/m3 (0.25, 0.05, or 0.01 mg CPFB/liter) for 13 weeks. No treatment-related effects on body weight, clinical chemistries, mortality, absolute or relative organ weight or histopathology were noted.

A 90-day continuous vapor inhalation toxicity study of JP-8 jet fuel followed by 20 or 21 months of recovery in Fischer 344 rats and C57BL/6 mice.

The kerosene-type jet fuel, JP-8, consists of a complex mixture of aliphatic and aromatic hydrocarbons. Because of the utility of JP-8, studies have been conducted to identify the potential long-term consequence of occupational inhalation exposure. Fischer 344 rats and C57BL/6 mice of both sexes were exposed to JP-8 vapors at 0, 500, and 1,000 mg/m3 on a continuous basis for 90 days, then followed by recovery until approximately 24 months of age. Occurrence of necrotizing dermatitis associated with fighting resulted in an increase in mortality in mice (male greater than female) during the 2 week to 9 month post-exposure recovery period. The male rat kidney developed a reversible ultrastructural increase in size and propensity for crystalloid changes of phagolysosomal proteinic reabsorption droplets in the proximal convoluted tubular epithelium. A specific triad of persisting light microscopic renal lesions occurred but functional change was limited to a decrease in urine concentration compared to controls that persisted throughout the recovery period. The response is comparable to the chronic effect of lifetime exposure of the male rat to unleaded gasoline, d-limonene, and p-dichlorobenzene, except for the absence of tubular tumorigenesis. The active toxicologic response presumably must occur over a greater proportion of the male rat's life span for the tumor component of this male rat hydrocarbon nephropathy syndrome. The predictiveness for humans must be questioned, since the pathologic response to JP-8 involved only one tissue in one sex of one species, and since the male rat response appears to be linked to an inherent renal protein peculiarity.

The determination of the repeated oral toxicity of halocarbon oil, series 27-S.

Halocarbon 27-S (HC 27-S), a polymer of chlorotrifluoroethylene (CTFE), is used as a lubricating oil for pumps in hyperbaric chambers. Although monomeric CTFE has been shown to produce renal lesions in rats, the toxicity of CTFE polymers have not been investigated. To assess the toxicity of repeated exposure to HC 27-S, three groups (N = 6/group) of male and female Fischer-344 rats were dosed with 2.5 g HC 27-S/kg for 7 or 21 consecutive days. Groups were sacrificed at 7, 21, and 35 days (14 days after the 21-day dosing). Corresponding control groups (N = 6) were dosed with deionized water. Decreased water consumption and urine output were apparent in all test groups. Statistically significant increases in fluoride excretion were noted in 24-hr urine samples assessed periodically during the study. Neurotoxic signs were observed in female rats but not in male rats. Significant increases in liver and kidney weights were seen in all rats, regardless of number of dosing days. The increased fluoride burden in treated animals appeared sufficient to alter bone calcium/phosphate ratios in male rats but not female rats. Gross liver enlargement and hepatocellular cytomegaly indicated that the liver was probably the primary target organ following repeated administration of HC 27-S.

Toxicant distribution in the Thomas Domes.

Measurement of test article concentration distribution for light gases have been made in the Thomas Dome inhalation chambers at Wright-Patterson Air Force Base, using propane as a test agent. The method used to analyze for inhomogeneities in test article spatial distribution deliberately varies the dome operational parameters rather than requiring extreme operational stability. The variation in test article concentration is analyzed by regression to determine which operational parameters most influence the test agent distribution. Unaccounted concentration variability is assumed to be the inherent spatial variation of the test article in the dome. The propane studies indicated that the spatial variation within the dome was 6.4% of the mean and that room air temperature at the top of the dome, propane analyzer baseline stability, and dome pressure were (listed in order of decreasing importance) the variables influencing the test article distribution.