Toxicological Sciences 55, 116-123 (2000)
Copyright © 2000 by the Society of Toxicology
Neurotoxicology |
1-Bromopropane, an Alternative to Ozone Layer Depleting Solvents, Is Dose-Dependently Neurotoxic to Rats in Long-Term Inhalation Exposure
* Department of Occupational and Environmental Health, Graduate School of Medicine, and
Institute for Laboratory Animal Experiments, School of Medicine, Nagoya University, Nagoya, Japan;
National Institute of Industrial Health, Kanagawa, Japan;
§ Safety Assessment Laboratory, Sanwa Kagaku Kenkyusho Co. Ltd., Mie, Japan; and
¶ Department of Medical Technology, School of Health Sciences, Nagoya University, Nagoya, Japan
Received September 13, 1999; accepted December 22, 1999
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1-Bromopropane has been newly introduced as an alternative to ozone layer-depleting solvents. We aimed to clarify the dose-dependent effects of 1-bromopropane on the nervous system. Forty-four Wistar male rats were randomly divided into 4 groups of 11 each. The groups were exposed to 200, 400, or 800 ppm of 1-bromopropane or only fresh air 8 h per day for 12 weeks. Grip strength of forelimbs and hind limbs, maximum motor nerve conduction velocity (MCV), and distal latency (DL) of the tail nerve were measured in 9 rats of each group every 4 weeks. The other 2 rats of each group were perfused at the end of the experiment for morphological examinations. The rats of the 800-ppm group showed poor kicking and were not able to stand still on the slope. After a 12-week exposure, forelimb grip strength decreased significantly at 800 ppm and hind limb grip strength decreased significantly at both 400 and 800 ppm or after a 12-week exposure. MCV and DL of the tail nerve deteriorated significantly at 800 ppm. Ovoid or bubble-like debris of myelin sheaths was prominent in the unraveled muscular branch of the posterior tibial nerve in the 800-ppm group. Swelling of preterminal axons in the gracile nucleus increased in a dose-dependent manner. Plasma creatine phosphokinase (CPK) decreased dose-dependently with significant changes at 400 and 800 ppm. 1-Bromopropane induced weakness in the muscle strength of rat limbs and deterioration of MCV and DL in a dose-dependent manner, with morphological changes in peripheral nerve and preterminal axon in the gracile nucleus. 1-Bromopropane may be seriously neurotoxic to humans and should thus be used carefully in the workplace.
Key Words: 1-bromopropane; neurotoxicity; alternative to chlorofluorocarbons; neuropathy; motor nerve conduction velocity; distal latency; tibial nerve; Wallerian-like degeneration; preterminal; gracile nucleus; creatine phosphokinase.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1-Bromopropane was recently introduced as an alternative to chlorofluorocarbons and 1,1,1-trichloroethane, which have the potential to destroy the ozone layer. This new alternative has less ozone depleting potential, yet has the high volatility and nonflammability required for a cleaning agent. It has come to be a very important solvent, especially after 2-bromopropane was phased out after its reproductive and hematopoietic toxicity to humans were revealed (Ichihara et al., 1999a
; Kim et al., 1996; Park et al., 1997) and rats (Ichihara et al., 1996, 1997; Kamijima et al., 1997a,b; Lim et al., 1997; Nakajima et al., 1997a,b; Yu et al., 1997, 1999b). Following these studies, we clarified the neurotoxicity of 2-bromopropane in rats because polyneuropathy was also reportedly found in Korean workers (Yu et al., 1999a). At the same time, we did a preliminary examination of the neurotoxicity of 1-bromopropane at 1000 ppm, and we unexpectedly found that, after 4 weeks of exposure (Yu et al., 1998), 1-bromopropane induced severe paralysis of hind limbs, decreased maximum motor nerve conduction velocity (MCV), and increased distal latency (DL). The same concentration of 2-bromopropane did not induce paralysis and caused little change in MCV or DL (Yu et al., 1999a). These studies suggested that 1-bromopropane might have more potent neurotoxicity than 2-bromopropane. However, our preliminary experiment (Yu et al., 1998) on neurotoxicity of 1-bromopropane had a limitation, i.e., the exposure was done only at a single concentration of 1000 ppm and was discontinued after 4–7 weeks because of rat debilitation. The present experiment aimed to clarify the concentration- and exposure period-dependent neurotoxicity of 1-bromopropane and its morphological characteristics.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animals and Exposure
A total of 44 Wistar male rats (specific pathogen-free, 9 weeks old) were purchased from Shizuoka Laboratory Animal Center, Japan. They were housed and acclimated to their new circumstances for 1 week. Eight rats were randomly selected and divided into 4 groups of 2 each for morphological studies. These rats were exempted from measurement of electrophysiological indices of the tail nerve or grip strength, because physiological stimulation of the tail or limbs might cause morphological artifacts of the axons in the gracile nucleus. The remaining 36 rats were randomly divided into 4 groups of 9 each with a stratified sampling method based on body weight and motor nerve conduction velocity (MCV). These rats were used for evaluation of grip strength, maximum motor nerve conduction velocity (MCV), distal latency (DL), organ weights, and blood biochemical indices. The 4 groups of 11 each, which consisted of 2 rats for morphological examination and 9 rats for quantiative evaluation, were exposed to 200, 400, or 800 ppm 1-bromopropane or fresh air, respectively in stainless steel chambers (884 x 884 x 1000 mm). The highest concentration used was 800 ppm because our previous study showed that the rats exposed to 1000 ppm 1-bromopropane were debilitated after 4 weeks (Yu et al., 1998
). 1-Bromopropane exposure lasted from 1400 h to 2200 h, 8 h a day, for 12 weeks. The internal size of a cage was 260 x 380 x 180 mm. Food and water was provided ad libitum. The environment was kept on a 12-h light-dark cycle (lighting on at 0900 h and off at 2100 h) and was held at 23–25°C and 57–60% humidity. Body weight was measured between 10:00 and 11:00 A.M. once a week. The inhalation exposure system used in the present study was described elsewhere (Ichihara et al., 1997; Takeuchi et al., 1989). In brief, the regulated volume of solvents was evaporated at room temperature and mixed with a larger volume of clean air to achieve the desired concentration. The vapor concentrations were measured every 10 s by gas chromatography and controlled to within ± 5% of the target concentration by means of a personal computer. Rectification boards, which had numerous small holes, were positioned at the entrance to the chamber for the vapor to be distributed uniformly. The concentrations at 9 points were within ± 3% of the value of the central point in the chambers. 1-Bromopropane (99.81% purity in the chart area of a capillary gas chromatograph with flame ionization detector [FID]) was kindly supplied by Tosoh Co., Japan. The structure of 1-bromopropane was confirmed with proton nuclear magnetic resonance (NMR). All of the 1-bromopropane used was from the same lot. Repeated gas chromatographic analyses showed no change in the composition of 1-bromopropane in storage bottle or its vapor in the chambers throughout the experiments. Japanese law concerning the protection and control of experimental animals and the "Guide of Animal Experimentation," Nagoya University School of Medicine, were followed throughout the experiments.
Walking Status of Rats
After 11 weeks, the walking status of the rats on the horizontal plane and a slope of 25° was observed and videotaped. The surfaces of the plane and slope were covered with coarse-textured cloth so that the control rats could walk or climb easily.
Forelimb and Hind Limb Grip Strength
Forelimb and hind limb grip strength was measured from 9:00 A.M. to 11:00 A.M. before the start of exposure and every 4 weeks. The grip strength was measured using a push-pull scale (Imada Co., Ltd., Japan) according to Meyer's method (Meyer et al., 1979).
Electrophysiological Examination of Tail Nerve of Rats
MCV and DL were measured in the rats' tails every 4 weeks, in accord with our previous studies (Ichihara et al., 1998a; Ono et al., 1979; Takeuchi et al., 1980; Yu et al., 1999a; Yu et al., 1998). The rats were wrapped in a towel to keep them immobilized without anesthesia. Stainless steel electrodes 0.34 mm in diameter were used. Electrode A was located 3 cm distal from the anus, electrode C was 3–4 cm proximal from the end of the tail, and electrode B was 5 cm proximal from electrode C. The electrodes were inserted tangentially into the subcutanea to prevent injury to the nerve trunks. The tail was immersed in a paraffin bath kept at 37.0 to 37.5°C. The nerve conduction velocity was measured no sooner than 4 min and no later than 20 min after immersion. The tail nerve was stimulated at electrode A or B by a square pulse of 0.3-ms duration and supramaximal strength, using an electrostimulator equipped with an electroisolator (SEN-7103, Nihon Kohden). The biopotentials were observed at electrode C with an Addscope (ATAC-350, Nihon Kohden). MCV (AB/latency time [AC-BC]) and DL (latency time [BC]) were measured before the start of exposure and every 4 weeks during exposure. Conduction velocities were measured more than 10 h after the end of the exposure to remove the acute effects of inhalation.
Brain Weights and Blood Biochemical Indices
After 12 weeks of exposure to 1-bromopropane, 9 rats of each group were killed under pentobarbital anesthesia by collecting all blood with heparinized syringe through the abdominal aorta. The cerebrum, cerebellum, and brainstem were dissected out and weighed. Plasma was separated by centrifugation at room temperature, and stored at –80°C until analysis. Plasma GOT (glutamic-oxaloacetic transaminase), GPT (glutamic-pyrubic transaminase), LDH (lactate dehydrogenase), ALP (alkaline phosphatase), CPK (creatine phosphokinase), BUN (blood urea nitrogen), creatinine, uric acid, total bilirubin, glucose, triglyceride, free fatty acid, total cholesterol, phospholipid, total protein, albumin, globulin, Ca (calcium), and Pi (inorganic phosphate) were measured with a Hitachi model 736–10 Auto Analyzer.
Morphological Examination of Peripheral Nerve, Central Nerves and Muscles
Two rats from each group were perfused from the left ventricle with two different kinds of fixatives after the 12-week exposure, one with 10% buffered formalin (pH 7.2) and the other with Zamboni's solution. Muscular branches of the posterior tibial nerve, the brain, and the lumbar enlargement of the spinal cord were dissected out from the rat perfused with buffered formalin. Muscular nerves were dissected out for unraveled specimens because we observed a remarkable weakness of muscle. They were post-fixed in 0.5% osmium tetroxide for 15 min, immersed in 30% ethanol for 60 min, and then transferred into 50% glycerin. Specimens were loosened and unraveled by needles in the 50% glycerin under a binocular dissection microscope. The brain was cut transversely at the level of the optic chiasma, the caudal margin of the mamillary body, the paraflocculus of the cerebellum (corresponding to caudal pole of the pons), and the gracile nucleus of the medulla oblongata. The blocks of the brain and the spinal cord were embedded in paraffin, and several serial sections were made around the levels mentioned above. The sections were stained by the Klüver-Barrera method for light-microscopic observation. Small tissue blocks of tibial nerve, brain, and soleus muscle perfused with Zamboni's solution were embedded in epoxy resin and cut into semi-thin or ultra-thin sections for light or electron microscopic observation. The tibial nerve and its branches were dissected out with their neighboring muscle tissue to prevent physical damage from the dissection process.
Statistical Analysis
Multiple comparisons were made between the exposure groups and the control in the means of body weights, organ weights, grip strength, MCVs, and DLs using Dunnett's method following one-way analysis of variance (ANOVA). A probability (p) of < 0.05 was accepted as statistically significant.
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RESULTS |
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The concentrations of 1-bromopropane in the 3 chambers were 208 ± 15, 412 ± 24, and 821 ± 38 (mean ± SD) ppm, respectively. One rat in the control for evaluation of quantitative indices was excluded because it showed serious splenoma with histopathological change of erythroblast hyperplasia in red pulp. The blood biochemical data of another rat in the 200-ppm group were excluded because of hemolysis due to mechanical injury during blood collection failure.
The rats of the 800-ppm group showed weak kicking on the floor with their hind limbs, poor extension, and poor outspreading of pedal digits, turning up their planta when landing on the plane (up-and-down landing). They could not stand still on the slope, while the control rats could easily do so on the same slope. Every rat of the 800-ppm group showed more or less similar findings to those mentioned above. The rats of the 400- or 200-ppm groups did not show clear abnormality in walking status. Body weight gain was suppressed dose-dependently, but there was no suppression at 200 ppm (Table 1). Grip strength of forelimb and hind limb decreased dose-dependently and progressively with exposure period (Table 1). Forelimb grip strength decreased progressively at 400 ppm or more. Hind limb grip strength significantly decreased at 200 ppm or more after 4 weeks of exposure, but after 8 weeks of exposure, the decrease was significant only in the 800-ppm group. After 12 weeks the decrease was significant only at 400 ppm or more. MCV decreased and DL increased progressively at 800 ppm, but not at 400 or 200 ppm (Table 2).
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Light microscopic observation of the unraveled specimens (Fig. 1
) and epoxy resin-embedded sections (Fig. 2) of the peripheral nerve showed ovoid or bubble-like debris of myelin sheaths in the 800-ppm group, but not in the 400-ppm or 200-ppm group. Electron microscopic observation of the tibial nerve of the 800-ppm group showed swelling of the axon, in which we observed lamellar bodies, bubble-like vesicular condensation, amorphous material involving mitochondria, fine filament tangles, and vesicular debris. Light-microscopic observation on the semi-thin epoxy resin sections of the gracile nucleus showed light (Fig. 3, arrows) and dark (Fig. 3, arrowheads) preterminal swellings with thinned myelin. Under the electron microscope, an accumulation of mitochondria (Fig. 4A), myelin-like debris (Fig. 4A), various sized vesicles (Fig. 4B), vacuolated mitochondria (Figs. 4B and 4C) and amorphous dense materials (Fig. 4C) were found. The light preterminal swelling profiles under light microscopy (Fig. 3, arrows) seem to represent electron microscopic profiles with abundant mitochondria (Fig. 4A) or vesicular debris (Fig. 4B), while the dark preterminal swelling profiles (Fig. 3, arrowheads) show accumulations of amorphous dense materials (Fig. 4C).
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No degeneration was found in either gray matter or white matter at the examined transverse sections of the brain through the optic chiasma, caudal margin of the mamillary body, or caudal pole of the pons.
Irregular bandings of the striated muscle fibers were found in the soleus muscle of the 800-ppm group under light microscopy (Fig. 5). Electron microscopic observations revealed a loss of regular linearity in the Z line and zigzag arrangement of the myofilaments (Fig. 6).
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The weight of the cerebrum decreased significantly at 800 ppm compared to the control, whereas weights of the cerebellum and brainstem did not change significantly (Table 3
). Plasma CPK activity decreased dose-dependently, but the activity of LDH, ALP, ChE, GOT, and GPT enzymes did not change (Table 4). Total cholesterol decreased dose-dependently, and total protein, albumin and globulin increased dose-dependently. The former 3 parameters changed significantly at 400 ppm and 800 ppm, but globulin changed significantly only at 800 ppm. No other laboratory data showed any significant changes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All the rats in the exposed groups showed less severe debilitation and weight loss than the rats exposed to 1-bromopropane at 1000 ppm in our previous study (Yu et al., 1998
), which showed a great decrease in body weight after 4–5 weeks. Walking status, such as up-and-down landing on a plane and inability to stand still on a slope, showed the lack of muscle strength of hind limbs in the 800-ppm group. This was supported quantitatively by the dose-dependent decrease in the grip strength of hind limbs, which indicated the strength of the flexor musculature there.
Decrease in grip strength at 400 ppm and transiently at 200 ppm could not be explained by deterioration of MCV and DL or morphological abnormalities, both of which were found only at 800 ppm. Since the grip strength examination could reflect total vital factors involved with the functions of limbs, they might be more sensitive than morphological examination or measurement of MCV or DL. Decrease in grip strength at lower concentrations might be due to some factors detectable only by the biochemical method. Plasma CPK activity decreased specifically and dose-dependently with a significant change at 400 ppm or more. This showed that plasma CPK activity was more sensitive than MCV, DL, or histopathological signs. We could not determine whether the decrease in CPK activity was involved with low muscle strength. However, the decrease in CPK activity might indicate some biochemical changes involved with toxic effects induced by 1-bromopropane or its metabolites. This may also be suggested by the fact that administration of acrylamide, a neurotoxicant, specifically decreased CPK activity in plasma or brain as well as increasing landing-foot spread (Matsuoka et al., 1996).
The earlier change in DL than in MCV might indicate earlier degeneration of myelin and axon in distal nerves. However, we cannot disprove the possibility that it might indicate a delay in the neuromuscular junction, since DL includes not only the duration of distal nerve conduction but also that of chemical transduction. A degenerative change of irregular banding of the muscle fibers showed adverse effects of 1-bromopropane on muscle fiber. However, it was unknown whether the degeneration was neurogenic or myogenic.
The morphological features of the degenerated peripheral nerve were quite different from the axonal swelling, with masses of neurofilament in a case of hexane intoxication (Spencer and Schaumburg, 1977b), but rather similar to those of Wallerian degeneration (Chaudhry et al., 1992; Griffin et al., 1996; Johnson, 1997) or morphological change in rats administered acrylamide (Fullerton and Barnes, 1966; Schaumburg et al., 1974).
The preterminal axonal swelling in the gracile nucleus was also observed in rats exposed to hexane or acrylamide (Spencer et al., 1977a), and, on fewer occasions, also in non-treated rats (Lampert et al., 1964). Their common change was an accumulation or increase of neurofilaments (Lampert et al., 1964; Spencer et al., 1977a) under electron microscopy, although accumulations of mitochondria (Lampert et al., 1964; Spencer et al., 1977a), electron dense material (Lampert et al., 1964), or other substances were also observed. The present experiment did not show a predominant accumulation of neurofilaments, but did reveal various degenerated materials. This might characterize 1-brompropane intoxication, but also might be possibly due to the difference in the level or part of the nerve, the period of exposure, the concentration of chemicals, and so on.
Zhao et al. (1999) reported no difference between 1-bromopropane and 2-bromopropane in the effects of their subcutaneous injections on MCV or motor latency. However, the present study and our preliminary study (Yu et al., 1998) showed more potent neurotoxicity of 1-bromopropane, than with 2-bromopropane (Yu et al., 1999a). In the present study, 1-bromopropane significantly decreased MCV at 800 ppm after 8 weeks (15.1%) and 12 weeks (22.4%) and increased DL after 4, 8, and 12 weeks (25.9%, 24.8%, and 51.4%, respectively, compared to the control). On the other hand, exposure to 2-bromopropane, even at 1000 ppm, did not significantly decrease MCV after 12 weeks nor did it change DL after 4 weeks (Yu et al., 1999a). It increased DL after 8 weeks and 12 weeks at 1000 ppm, but the degree was almost equal to (26.4% after 8 weeks) or less than (36.7% after 12 weeks) exposure to 1-bromopropane at 800 ppm. 2-Bromoproane exposure did not increase preterminal axonal swelling in the gracile nucleus, but induced only ball or balloon-like swelling of the myelin sheath near Ranvier's node in the peripheral nerve at 1000 ppm (Yu et al., 1999a).
Ohnishi et al. (1999) exposed rats to 1-bromopropane at a single concentration of 1500 ppm for 4 weeks and found ataxic gait in rats. We could not define cerebellular ataxia in rats, since the 4-footed walking rat was quite different from a bipedal walking human in terms of cerebellular ataxia expression. Although pyknotic degeneration of cerebellular Purkinje cells was found in the rats exposed to 1-bromopropane at 1000 ppm for 4–5 weeks (Yu et al., 1998) and at 1500 ppm for 4 weeks (Ohnishi et al., 1999), the present study did not show such change at 800 ppm and lower for 12 weeks.
In addition to the neurotoxicity of 1-bromopropane, we have recently revealed its reproductive toxicity in male rats (Ichihara et al., 1998b, 1999b, 2000).
In conclusion, 1-bromopropane weakened the muscle strength of rat limbs and deteriorated MCV and DL, in a concentration-dependent and exposure period-dependent manner. 1-Bromopropane was revealed to have a more potent neurotoxicity than 2-bromopropane. Histopathological studies showed ovoid or bubble-like debris of myelin in the peripheral nerve, preterminal swelling in the gracile nucleus, and irregular banding of muscle fibers in soleus muscle. 1-Bromopropane should be used carefully in the workplace, because it may be seriously neurotoxic to humans in addition to its reproductive toxicity.
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ACKNOWLEDGMENTS |
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This study was partly supported by Grants 10470106 and 11670367 from the Ministry of Education, Science, Sports, and Culture, Japan.
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NOTES |
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1 To whom correspondence should be addressed at the Department of Occupational and Environmental Health, 65 Tsurumai-cho, Showa-ku, Nagoya University Graduate School of Medicine, Nagoya, Japan. Fax: (81) (52) 744-2126. E-mail: gak{at}med.nagoya-u.ac.jp.
Parts of this study on the neurotoxicity of 1-bromopropane were presented in the 71st and 72nd Annual Meetings of the Japan Society for Occupational Health (Ichihara et al., 1998b, 1999b) and the 9th Annual Meeting for the study of the peripheral nerve (Ichihara et al., 1998c).
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