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PubMedDate not supplied

Developmental neurotoxicity after toluene inhalation exposure in rats.

Rats were exposed to 1200 ppm or 0 ppm toluene (CAS 108-88-3) for 6 h per day from day 7 of pregnancy until day 18 postnatally. Developmental and neurobehavioral effects in the offspring were investigated using a test battery including assessment of functions similar to those in the proposed OECD TG for Developmental Neurotoxicity Study, i.e., physical development, reflex ontogeny, motor function, motor activity, sensory function, and learning and memory. The exposure did not cause maternal toxicity or decreased viability of the offspring. Lower birth weight, delayed ontogeny of reflexes, and increased motor activity in the open field was registered in the exposed offspring. Impaired cognitive function was revealed in the exposed female offspring at the age of 3.5 months, i.e., they used more time to locate the hidden platform in the Morris water maze after platform relocation. The difference was not related to poorer swimming capabilities, because swim speeds were similar to control values. The results show that exposure to 1200 ppm toluene during brain development caused long-lasting developmental neurotoxicity in rats.

Administration, Inhalation↗
PubMedDate not supplied

Alteration of pulmonary macrophage intracellular pH following inhalation exposure to sulfuric acid/ozone mixtures.

Recent studies have demonstrated that additive and synergistic effects on rabbit pulmonary macrophages (PM phi) function can occur after combined exposures to acid aerosols and ozone. This study investigated intracellular pH (pHi) homeostasis and H+ extrusion mechanisms of PM phi from rabbits exposed to sulfuric acid, ozone, and their mixtures. Animals were exposed for 3 h to 125 micrograms/m3 sulfuric acid, 0.1, 0.3, 0.6 ppm ozone, or combinations of acid with each concentration of ozone, and the pHi was determined by a fluorescent dye ratioing technique. Exposure to 125 micrograms/m3 acid reduced pHi and exposure to ozone resulted in a concentration-dependent reduction in pHi. Ozone generally tended to mitigate the effect of the acid aerosol on pHi. Other groups of rabbits were exposed to 50 micrograms/m3 sulfuric acid, 0.6 ppm ozone, or their mixture, for 3 h, and PM phi were again harvested. The pHi of PM phi following exposure to each of the pollutant atmospheres was not different from control. However, H+ extrusion with an imposed internal acid load was found to be significantly depressed following exposure to either sulfuric acid or ozone alone, while the mixture produced a significant interaction.

Administration, Inhalation↗
PubMed1989

Effects of selected chelating agents on organ distribution and excretion of manganese after inhalation exposure to 54MnCl2. I. Injection of chelating agents.

The effect of 1,2-cyclohexylene-aminotetraacetic acid (CDTA), diethylenetriaminepentaacetis acid (DTPA) and 2,3-dimercaptol-1-propanesulphonic acid, sodium salt (DMPS) on Mn distribution and excretion in rats was examined after 1 hr exposure to 54MnCl2 (approximately 0.1 microgram Mn/m3). All complexing agents were injected i.p., 0.32 mM/kg/day, for 7 days, starting either immediately after exposure (day 0, group I), or 1 week after exposure (day 7, group II). The controls were injected i.p. with 4 ml/kg of 0.9% saline. Activity of 54Mn was determined in lung, liver, kidney, and brain, 24 hrs after the last treatment and in urine and feces collected for 24 hrs on days 1-7 and 8-14 respectively. CDTA and DTPA administered immediately after Mn exposure appeared to be most effective, resulting in a two-fold decrease of 54Mn in brain and kidney, and a statistically significant decrease in lung (DTPA) and liver (CDTA). In group II a two-fold decrease of 54Mn in kidney and liver was observed with CDTA. There was also a decrease after DTPA administration. DMPS was not effective in these experiments. On the first day after exposure, 54Mn levels in urine were more than 15 and 25 times higher for CDTA and DTPA, respectively than for saline, in the early treatment group. Excretion of Mn in feces was not affected. Our data show that the effectiveness of removing inhaled Mn depends both on the complexing agent and the time of its administration.

Animals↗
PubMed1993

Inhalation exposure to a hepatocarcinogenic concentration of methylene chloride does not induce sustained replicative DNA synthesis in hepatocytes of female B6C3F1 mice.

We have used methylene chloride as a model to study cellular and molecular processes responsible for liver tumor induction by chlorinated hydrocarbons. Because of current interest in the role of enhanced cell proliferation in tumor induction, measurement of S-phase hepatocytes was incorporated into recently conducted toxicity and carcinogenicity studies. In prechronic studies, female B6C3F1 mice were exposed to 0, 1000, 2000 or 8000 p.p.m. methylene chloride by inhalation, 5 days per week, for up to 4 weeks followed by a 1 and 2 week recovery period. Mice exposed to concentrations of 2000, 4000 or 8000 p.p.m. methylene chloride had sustained increased liver weight commencing after 1 week of exposure and returning to normal after the 1 or 2 week recovery period. The increased liver weight was attributed to hepatocellular hypertrophy secondary to intracellular glycogen accumulation. Tritiated thymidine was administered by osmotic minipumps to label S-phase hepatocytes over a 6 day period. At most intervals examined there was decreased hepatocyte labeling in mice exposed to methylene chloride. However, there was a transitory increased number of S-phase hepatocytes observed at the 2 week interval in the 1000, 4000 and 8000 p.p.m. methylene chloride groups. In a chronic study, female mice were exposed to 2000 p.p.m. methylene chloride for up to two years. Following labeling with BRDU using 6 day minipumps, a statistically significant decrease in S-phase hepatocytes was observed after 13 weeks of methylene chloride exposure. A minor increased labeling index (LI) observed at 52 weeks was not considered to be a methylene chloride treatment-related effect. Retrospective immunohistochemical staining for proliferating cell nuclear antigen (PCNA) in liver sections containing foci of cellular alteration allowed demonstration of S-phase hepatocytes in these clonally expanded preneoplastic lesions. While foci frequently had higher LI's than surrounding normal hepatocytes, there was no difference in the mean LI of foci from methylene chloride-treated mice versus foci occurring spontaneously in control mice. The absence of a sustained increase in S-phase hepatocytes in female B6C3F1 mice suggests that enhanced cell proliferation is not a major mechanistic factor associated with the observed hepatocarcinogenicity of methylene chloride.

Administration, Inhalation↗
PubMed1999

Acute symptoms during non-inhalation exposure to combinations of toluene, trichloroethylene, and n-hexane.

OBJECTIVES: To study the acute effect of exposure to a mixture of three commonly used solvents in humans using a route of exposure not involving the nose and lungs, in this case a gastrointestinal application. METHODS: In a 2(3)-factorial experiment eight healthy male volunteers were exposed to the eight combinations of toluene (1. 5 and 4 mg. min(-1)) trichloroethylene (1.5 and 4 mg. min(-1)), and n-hexane (0.3 and 1.0 mg. min(-1)) for 60 min given into the stomach via a feeding tube. The body burden was measured by the exhaled solvent concentrations and the urinary excretion of metabolites during and after exposure. The subjective ratings of tiredness, sleepiness, headache, nausea, feeling of intoxication, and dizziness were estimated by continuous linear analogue rating scales before and 30, 90, and 240 min after the start of exposure. RESULTS: Concentrations of the three solvents in the end exhaled air varied between 0 and 46 mg. min(-3). The ratings of symptoms were generally low and there was no difference between the high and low doses. Neither was there any correlation between the concentration of solvents in the exhaled air and the ratings. CONCLUSIONS: The study show no effects at levels in end exhaled air of mixtures of solvents which in inhalation studies have given signs of a possible neurotoxic effect. The lack of symptoms using this alternative route supports the hypothesis that "neurotoxic" symptoms in relation to exposure to very low air concentrations of solvents are mainly indirect, mediated by irritation or smell.

Adult↗
PubMedDate not supplied

Induction of cytochrome P450 isozymes by simultaneous inhalation exposure of hens to n-hexane and methyl iso-butyl ketone (MiBK).

Chickens were exposed simultaneously to the industrial hexacarbon solvents n-hexane and methyl iso-butyl ketone (MiBK). n-Hexane has been shown to be neurotoxic in both humans and other vertebrates. While MiBK is not neurotoxic, it has been shown to greatly synergize the clinical appearance of neurotoxicity in animals exposed to both of these solvents. Groups of hens were exposed for 29 days in inhalation chambers to 1000 ppm n-hexane in combination with 10, 100, 250, 500, or 1000 ppm MiBK. Other groups received either 1000 ppm n-hexane, 1000 ppm MiBK, or ambient air and served as controls. A dose-dependent decrease in body weight and an increase in clinical effects were noted for the highest exposure groups (1000 ppm n-hexane combined with 1000, 500 or 250 ppm MiBK). There was an MiBK dose-dependent increase in cytochrome P450 content and benzphetamine N-demethylase activity, but there was no distinct pattern for ethoxyresorufin O-deethylase or cytochrome c reductase activities. Mixed-function oxidase levels and activities (cytochrome P450 content and benzphetamine N-demethylase) were elevated significantly (P less than 0.05) over controls even in the lowest MiBK group (10 ppm), although there were no clinical signs of neurotoxicity. Four different isozymes of cytochrome P450 were measured immunologically. There was a dose-dependent increase in three of the isozymes, two of which were phenobarbital inducible and one of which was induced by beta-napthoflavone. Quantitatively, the largest increase was in the PB-A isozyme, a phenobarbital-inducible isozyme which accounted for approximately 70% of the cytochrome P450 present in animals treated with MiBK. The results suggest that MiBK selectively induces cytochrome P450 isozymes leading to the metabolic activation of the weak neurotoxicant n-hexane to the potent neurotoxicant 2,5-hexanedione (2,5-HD).

Administration, Inhalation↗
PubMed1977

Effects of lead inhalation exposures alone and in combination with carbon monoxide in nonpregnant and pregnant rats and fetuses. I. Distribution of lead in blood and liver.

Nonpregnant and pregnant rats were continuously exposed for 3 weeks to an aerosol containing 1, 3 and 10 mg lead/m3 air and to a combination of 3 mg Pb/m3 and 500 ppm carbon monoxide. At the two lower lead doses, fetal blood lead levels exceeded those of the mothers. Active transport mechanisms were discussed to be responsible for these differences. A decrease of the fetal blood lead level below the maternal level in the high exposure group was explained by an increasing storage capacity of the fetal livers with increasing lead doses. Lead concentrations of the maternal livers exceeded the nonpregnant values at all 3 doses, probably caused by a higher ventilation and altered pharmacokinetics of lead in pregnancy. Additional CO-inhalation lowered the storage capacity of the livers of the adult animals and raised the blood concentration. In the fetuses additional CO-inhalation raised liver lead concentrations.

Air Pollutants↗
PubMed1999

Effect of inhalation exposure to 2-bromopropane on the nervous system in rats.

Exposure to 2-bromopropane (2-BP) is suspected to have adverse effects on the nervous system. The aim of this study was to investigate whether the exposure of rats to 2-BP had neurotoxic effects using histological and electrophysiological studies. Wistar strain male rats were exposed daily to either 100 or 1000 ppm 2-BP or to fresh air for 8 h a day for 12 weeks. Body weight was measured before exposure and every 2 weeks. Motor nerve conduction velocity (MCV) and distal latency (DL) were measured before exposure and every 4 weeks during exposure. Histological examination of the nervous system was also performed. Exposure of rats (n = 9) to 1000 ppm resulted in suppression of body weight gain and a significant decrease in brain weight compared to the control (n = 9). Electrophysiological measurements showed a significant decrease in MCV in 1000 ppm exposed rats at 8 weeks and significant prolongation of DL at 8 and 12 weeks. Abnormalities of the myelin sheath were detected in the common peroneal nerves. In 100-ppm exposed rats (n = 9), no significant changes were noted in body weight and the peripheral nerve. In conclusions, long-term exposure to 1000 ppm of 2-BP may result in peripheral neuropathy in rats.

Administration, Inhalation↗
PubMed1999

Mutagenicity of the racemic mixtures of butadiene monoepoxide and butadiene diepoxide at the Hprt locus of T-lymphocytes following inhalation exposures of female mice and rats.

The purpose of this study was to determine if Hprt mutant frequency (Mf) data from rodents exposed directly to individual epoxy metabolites of 1,3-butadiene (BD) can be used to identify the relative significance of each intermediate in the mutagenicity of BD in mice vs. rats. To this end, the relative contributions of the racemic mixtures of BD monoepoxide (BDO) and BD diepoxide (BDO(2)) to BD-induced mutagenicity was investigated by exposing mice and rats to selected concentrations of BDO and BDO(2) (i.e., 2.5 and 4.0 ppm, respectively) and comparing the mutagenic potency of each intermediate to that of BD (at 62.5 ppm) when comparable blood levels of metabolites are achieved (in the mouse). Female B6C3F1 mice and F344 rats (4-5 weeks old) were exposed to rac-BDO (0, 2.5, or 25 ppm) or (+/-)-BDO(2) (0, 2, 4 ppm) by inhalation for 4 weeks (6 h/day, 5 days/week), and then groups of control and exposed animals (n=3-12/group) were necropsied at multiple time points post-exposure for measuring Hprt Mfs in splenic lymphocytes (via the T-cell cloning assay) and estimating mutagenic potencies (represented by the difference in the areas under the mutant T-cell 'manifestation' curves of treated vs. control animals). The resulting Mf data, along with the extant metabolism data, suggest that at lower BD exposures (</=62.5 ppm) (+/-)-BDO(2) is a major contributor to the mutagenicity of BD in mice, whereas other metabolites and stereochemical configurations are responsible for mutations in BD-exposed rats and for the incremental mutagenic effects at higher BD exposures in mice. These studies indicate that additional work is needed to determine more definitively the relative contributions of these and other metabolites and stereochemical forms to BD-induced mutagenicity. Also, the novel approach of measuring mutagenic potencies as the change in Hprt Mfs over time in T-cells of exposed vs. control animals, as used in this study, can be valuable for predicting the potential role of these intermediates in each species.

Administration, Inhalation↗
PubMed1999

Effects of a thirteen-week inhalation exposure to ethyl tertiary butyl ether on fischer-344 rats and CD-1 mice.

The 1990 Clean Air Act Amendments require that oxygenates be added to automotive fuels to reduce emissions of carbon monoxide and hydrocarbons. One potential oxygenate is the aliphatic ether ethyl tertiary butyl ether (ETBE). Our objective was to provide data on the potential toxic effects of ETBE. Male and female Fisher 344 rats and CD-1 mice were exposed to 0 (control), 500, 1750, or 5000 ppm of ETBE for 6 h/day and 5 days/wk over a 13-week period. ETBE exposure had no effect on mortality and body weight with the exception of an increase in body weights of the female rats in the 5000-ppm group. No major changes in clinical pathology parameters were noted for either rats or mice exposed to ETBE for 6 (rats only) or 13 weeks. Liver weights increased with increasing ETBE-exposure concentration for both sexes of rats and mice. Increases in kidney, adrenal, and heart (females only) weights were noted in rats. Degenerative changes in testicular seminiferous tubules were observed in male rats exposed to 1750 and 5000 ppm but were not seen in mice. This testicular lesion has not been reported previously for aliphatic ethers. Increases in the incidence of regenerative foci, rates of renal cell proliferation, and alpha2u-globulin containing protein droplets were noted in the kidneys of all treated male rats. These lesions are associated with the male rat-specific syndrome of alpha2u-globulin nephropathy. Increases in the incidence of centrilobular hepatocyte hypertrophy and rates of hepatocyte cell proliferation were seen in the livers of male and female mice in the 5000-ppm group, consistent with a mitogenic response to ETBE. These two target organs for ETBE toxicity, mouse liver and male rat kidney, have also been reported for methyl tertiary butyl ether and unleaded gasoline.

Administration, Inhalation↗
PubMed1990

Neurotoxicologic evaluation of rats after 13 weeks of inhalation exposure to dichloromethane or carbon monoxide.

Male and female Fischer 344 rats were exposed to dichloromethane (methylene chloride, DCM) or carbon monoxide (CO) for 6 hr/day, 5 days/week, for 13 weeks. Since oxidative metabolism of DCM to CO and CO2 is a saturable process, DCM exposure concentrations were selected clearly below saturation (50 ppm), just below saturation (200 ppm), and well above saturation (2000 ppm). At saturation of metabolism, metabolic CO causes about 10% carboxyhemoglobinemia (COHb). Therefore, as a control for CO effects, a separate group of rats was exposed to 135 ppm CO to induce approximately 10% COHb. Postexposure functional tests included an observational battery, hindlimb grip strength, and a battery of evoked potentials (flash, auditory brainstem, somatosensory, caudal nerve). After functional tests were completed, rats from all groups were perfused with fixative and a comprehensive set of nervous tissues from the high DCM exposure group and from controls were examined by light microscopy. Although some miscellaneous functional and morphologic variations were recorded, none were related to treatment. Thus, subchronic exposures as high as 2000 ppm DCM or 135 ppm CO had no deleterious effects on any of the measures of this study.

Action Potentials↗
PubMedDate not supplied

Dearomatized white spirit inhalation exposure causes long-lasting neurophysiological changes in rats.

Exposure for 6 h per day, 5 days per week, during a period of 6 months to the organic solvent dearomatized white spirit (0, 400, and 800 ppm) was studied in rats that were 3 months old when the repeated exposure was initiated. After an exposure-free period of 2-6 months duration, neurophysiological, neurobehavioral, and macroscopic pathologic examinations were performed. The study revealed exposure-related changes in sensory evoked potentials and a decrease in motor activity during dark (no light) periods but no white spirit-induced changes in learning and memory functions. The measurements of the flash evoked potential (FEP), somatosensory evoked potential (SEP), and auditory brain stem response (ABR) all demonstrated dose-dependent increases of the amplitudes of the early latency peaks of the sensory evoked potentials (EPs). Furthermore, an increase of the dose showed that the measurements of FEP and SEP revealed changes in the later-latency peaks, which reflect the more associative aspects of sensory processing. The results demonstrated that 6 months of exposure to dearomatized white spirit induced long-lasting and possible irreversible effects in the nervous system of the rat.

Administration, Inhalation↗
PubMed1999

Neurotoxicity evaluation of rats after subchronic inhalation exposure to isobutanol.

The subchronic neurotoxic effects of isobutanol were studied by exposing Sprague-Dawley rats to isobutanol vapor concentrations of 0, 250, 1000, and 2500 ppm for 6 hrs/day, 5 days/wk, for 3 months. A comprehensive set of neurotoxicity tests (functional observational battery, motor activity, perfusion fixation neuropathology, and schedule-controlled operant behavior) including an assessment of complex behavior dependent on learning and memory was conducted. In addition, full histopathology and blood chemistry evaluations were conducted in order to assess any potential functional/behavioral effects in the context of other possible systemic toxicities. There were no morphological or behavioral effects indicative of a specific, persistent or progressive effect of isobutanol on the nervous system at exposure concentrations up to 2500 ppm. A slight decrease in response to external stimuli was observed during exposures at all concentrations. These effects are likely transient effects of acute exposure to isobutanol.

Administration, Inhalation↗
PubMed1996

Reproductive and developmental toxicity studies of toluene. II. Effects of inhalation exposure on fertility in rats.

Male and female Sprague-Dawley rats were exposed to toluene vapor at 600 and 2000 ppm for 6 h/day, and effects on their fertility were investigated. Females were exposed from 14 days before mating until day 7 of gestation. Males were exposed for a total of 90 days, including the mating period; treatment was begun 60 days before pairing, and toxicity with respect to testicular and reproductive functions was examined. In females of the 2000 ppm-treated group, salivation and lacrimation that may have been caused by CNS depression were observed starting 20 days after exposure. Although no abnormalities were seen in mating behavior or fertility, fetal mortality and the number of dams with dead fetuses increased in the 2000 ppm group. In the males exposed to 2000 ppm toluene for 90 days, an increase in kidney weights and a decrease in thymus weights were observed. Basophilic changes and necrosis of kidney tubules were greater at the higher exposure level. Additionally, decreases in the weights of the epididymides and spermatic count were observed, indicating toxicity of toluene to the male reproductive system in vivo for the first time. In conclusion, embryo-fetal toxic effects were apparent in female rats exposed to toluene before and during the early stage of pregnancy. Subacute exposure to a high level (2000 ppm) of toluene vapor elicited mild toxic changes in the kidneys, thymus, and reproductive organs of males. Toxic effects on fertility and reproduction were thus demonstrated not only in females but also in males exposed to toluene vapor in the present study.

Administration, Inhalation↗
PubMed1996

Pattern of inhalation exposure: blood levels and acute subnarcotic effects of toluene and acetone in rats.

Solvent blood concentrations and subnarcotic effects (inhibition of electrically evoked seizures) were measured in rats exposed to constant or fluctuating air concentrations of toluene or acetone. A 4 hour exposure of resting rats to toluene at an air concentration of 1 and 2 mg/l, or to acetone at 4 and 10 mg/l, led to blood levels of 6.7 and 12.8 mg/l of toluene, or 183 and 520 mg/l of acetone: seizure inhibition amounted to 18% and 40+, or 10% and 50%, respectively. Blood level and effect attained 1/2 of the final values after 40 min and 60 min of exposure to 2 mg/l toluene, respectively, and dropped to 1/2 70 min and 90 min after exposure cessation: respective values for acetone 10 mg/l were 80 and 120 min, and more than 4 hours. A steep rise and a rapid drop was characteristic also for the course of blood level and effect during an exposure to fluctuating concentrations of toluene: ten minute fivefold jump in the air concentration induced a shortlasting seizure inhibition by more than 80%; the curves for acetone were flat.

Acetone↗
PubMed1991

Globin adducts of benzo[a]pyrene: markers of inhalation exposure as measured in F344/N rats.

We have explored methods for determining benzo[a]pyrene (BaP) dosimetry by measuring adduction levels to F344/N rat blood hemoglobin, and have refined and validated an assay that measures the in vivo binding of the 7,8-diol 9,10-epoxide metabolite of BaP to globin. The assay for BaP-globin adducts was based on the release of tetrahydroxy-BaP (BaP-tetrols) from globin by mild acid hydrolysis. After extensive isolation, BaP-tetrols were quantitated by high-pressure liquid chromatography using fluorescence detection. BaP-tetrol levels were measured in rats dosed intraperitoneally with 242, 71 and 24 mumol BaP kg-1 body weight in corn oil. The formation of BaP-tetrols was not linear with dose. The lowest dose yielded adduct levels that represented the limits of sensitivity for the method, as performed in this laboratory. Once this limit of sensitivity was established, the potential use of the assay was assessed by measuring the radiochemical binding of inhaled [14C]BaP or its metabolites to the globin of F344/N rats. Rats were exposed for 4 h per day, 1 day per week, for 12 weeks to pure aerosols of [14C]BaP at a level of 2 mg m-3. At the conclusion of exposure, rats were sacrificed and globin was isolated. The extent of [14C]BaP binding to the globin was determined by liquid scintillation spectrometry. Rats exposed to aerosols of [14C]BaP had statistically increased levels of binding to globin, and the levels were comparable to those observed previously after intragastric administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1979

Comparative effects of repeated and prolonged inhalation exposure of beagle dogs and Cynomolgus monkeys to anaesthetic and subanaesthetic concentrations of enflurane and halothane.

Male and female Beagle dogs and Cynomolgus monkeys were exposed to anaesthetic (1.5 MAC) and subanaesthetic (1/100 MAC) levels of enflurane and halothane for 3 hours on alternate days for 4 weeks. One-half of the animals were killed following the last exposure and the remainder after 4 weeks of recovery. The animals' condition was assessed during anaesthetic periods by measuring respiration, ECG, blood pressure, temperature and EEG. Haematology, urinalysis and clinical chemistry parameters were evaluated. Gross and microscopic pathological examinations were conducted at the end of the exposure and recovery periods. Two female monkeys in the mid- and high-dose halothane groups died during the study. No deaths were observed in the enflurane group. No quantitative differences were observed in respiration rate, heart rate, blood pressure and EEG activity of animals anaesthetized with enflurane or halothane. Muscle twitches were observed in some mid- and high-dose dogs inhaling enflurane, but not in monkeys. A number of liver function tests became abnormal in mid- and high-dose halothane-treated dogs and high-dose halothane-treated monkeys. This was not observed with enflurane. Histopathologic alterations were confined to the liver of animals exposed to halothane. In dogs, the lesions were characterized by centrilobular hepatocyte degeneration and/or necrosis, fibroblastic proliferation, hepatocyte enlargement, fat deposition and glycogen depletion; and in mid- and high-dose monkeys by moderate to marked hepatocyte vacuolation and fat deposition. Except for one high-dose dog, these lesions were not seen in animals killed after 4 weeks of recovery. No histopathologic alterations were observed with enflurane.

Alanine Transaminase↗
PubMed1990

Olfactory and hepatic changes following a single inhalation exposure of 3-trifluoromethyl pyridine in rats: concentration and temporal aspects.

The effects of a single exposure to 3-trifluoromethyl pyridine (3FMP), were investigated in two studies. In the first study, rats were exposed nose only to 0, 50 or 800 ppm 3FMP for periods of 15 min to 4 h. Half were sacrificed on day 3 and the remainder on day 10. In the second study, rats were exposed whole body to 0, 0.1, 1.0, 10 or 50 ppm 3FMP for 6 h, with sacrifices immediately after exposure (6 h), 24 h and on days 3 (48 h after exposure started) 5, 8, 11, 35, 70 and 157. Effects were seen in the olfactory epithelium at concentrations of 1 ppm and above and in the liver at concentrations of 50 ppm and above. In the olfactory epithelium the earliest changes were seen immediately after exposure and by 24 h this progressed to extensive necrosis with sloughing of the epithelium. By day 3, the epithelium was replaced by undifferentiated basophilic cells, considered to reflect early regeneration. Regeneration progressed to complete recovery between days 70 and 157, no changes were seen in the nasal respiratory epithelium, an olfactory function test on rats exposed for 6 h to 50 or 10 ppm 3FMP showed a reduced sense of olfaction at days 3 and 5 with complete recovery on subsequent days, indicating functional recovery in advance of histological normality. Single cell necrosis was seen in the liver at day 3 after 30 min exposure and immediately after 6 h exposure to 50 ppm 3FMP. At 24 h after a 6 h exposure to 50 ppm this had progressed to necrosis, haemorrhage and moderate cytoplasmic hepatocyte vacuolation in centrilobular areas. The lesion had completely recovered by day 5.

Administration, Inhalation↗