Six dose groups of 8 male and female rats respectively received a daily dose equivalent to 0, 0.15, 0.006, 0.03, 0.15 or 0.3 mg/kg b.w./day chlorpyrifos (groups 1–6) and the last four dose groups (groups 3–6) received in addition daily doses equivalent to 18 mg/kg b.w./day alphacypermethrin, 30 mg/kg b.w./day bromopropylate, 45 mg/kg b.w./day carbendazim and 12.5 mg/kg b.w./day mancozeb for 28 days. Plasma acetylcholinesterase was significantly decreased in the groups 2, 5 and 6 males. Total white blood cell count was significantly lower in females of group 6. Total red blood cell count, haematocrite and haemoglobin concentration was significantly reduced in both male and female rats of groups 5 and 6. Relative liver weight was significantly increased in groups 3–6 male and female rats. Absolute thyroid gland weight was significantly increased in groups 3, 5 and 6 male rats and of groups 3–6 female rats, and relative thyroid gland weight was significantly increased in groups 2–6 male rats and of groups 3–6 female rats. Absolute thymus weight of groups 3–6 male and female rats and relative thymus weight of groups 3–6 male rats and groups 3 and 4 female rats was significantly decreased. A mild degree of centrilobular cell hypertrophy of the liver was seen in all male rats and of three female rats of group 6. In the thyroid gland follicular cell hypertrophy was present in one female in the control group and in six females and seven males of group 6. It was concluded that inhibition of acetylcholinesterase activity in plasma and brain by chlorpyrifos was not enhanced by co-administration of the other four pesticides. Effects were seen in liver, thyroid, thymus and blood in the combination groups. However, identification of the pesticide(s) responsible for these changes would require further studies of the individually pesticides as well as various combinations of the pesticides.

The purpose of the study was to investigate the potential developmental neurotoxicity of the widely used organic solvent, white spirit. Rats (Mol:WIST) were exposed to 0 or 800 ppm dearomatized white spirit for 6 hr per day on gestation days 7-20. Developmental and neurobehavioural effects in the offspring were investigated using a test battery including assessment of physical development, reflex ontogeny, motor function, motor activity and, learning and memory. No significant effects were recorded on motor function and the activity in Open Field. In the initial learning period (age 1 month), the performance in a Morris water maze was similar in exposed and control animals. When testing for memory at the age of 2 months, the exposed male offspring used more time to locate the hidden platform. After platform relocation, impaired cognitive function was revealed in the exposed females. At the age of 5 months, learning and memory deficits were observed in exposed offspring. The differences were not related to poorer swimming capabilities. because swim speeds were similar to control values. The results show that prenatal exposure to 800 ppm white spirit caused longlasting learning and memory deficits in rats.

Long-lasting central nervous system (CNS) neurotoxicity of 4-tert-butyltoluene (TBT) has been investigated using electrophysiology, behaviour, and neurochemistry in Long Evans rats exposed by inhalation to 0, 20, or 40 p.p.m. TBT 6 hr/day, 7 days/week for 4 weeks. Flash evoked potentials and somatosensory evoked potentials were not affected by TBT. In Auditory Brain Stem Response there was no shift in hearing threshold, but the amplitude of the first wave was increased in both exposed groups at high stimulus levels. Three to four months after the end of exposure, behavioural studies in Morris water maze and eight-arm maze failed to demonstrate any TBT induced effects. Exposure was followed by a 5 months exposure-free period prior to gross regional and subcellular (synaptosomal) neurochemical investigations of the brain. TBT reduced the NA concentration in whole brain minus cerebellum. Synaptosomal choline acetyltransferase activity increased and acetylcholinesterase activity was unchanged suggesting increased synaptosomal ability for acetylcholine synthesis. The relative and total yield of synaptosomal protein was reduced suggesting reduced density and total number of synapses in situ, respectively. We hypothesise that a reduced yield of synaptosomal protein reflects a more general effect of organic solvent exposure on the software of the brain. The synaptosomal concentration per mg synaptosomal protein and the total amount of 5-hydroxytryptamine were not affected whereas the total amount of synaptosomal noradrenaline decreased. The concentration and the total amount of synaptosomal dopamine decreased. The noradrenergic and dopaminergic parts of CNS may be more vulnerable to TBT than the serotonergic, and these long-lasting effects may cause or reflect TBT-compromised CNS function.

Enhanced expression of glial fibrillary acidic protein (GFAP) is known to be associated with toxicant-induced gliosis, a homotypic response of the central nervous system to neural injury. A variety of neurochemical and neurophysiological effects have been observed in experimental animals exposed to white spirit, but a linkage of such effects to neural damage has not been established. Here we evaluated the regional levels of GFAP to assess potential sites of CNS damage in the rat, following exposure to dearomatized and aromatic white spirit. Samples from rats exposed to dearomatized white spirit were assayed for GFAP levels in the United States and Denmark. The results were remarkably similar between countries. Small region-dependent increases and decreases in GFAP were observed with the cerebellum showing the most consistent effects (increases). In contrast, samples from rats exposed to aromatic white spirit showed large (as much as 150% of control) increases in regional levels of GFAP; again, the cerebellum showed the most consistent effects. The data are indicative of an aromatic white-spirit-induced astrogliosis in several regions of the rat CNS and suggest that chronic exposure to this solvent may be associated with underlying neural damage.

In two separate studies with exposure duration 9 weeks or 4 weeks, male Wistar rats were dosed with di(2-ethylhexyl)phthalate (DEHP) by gavage and exposed to drinking water with or without acetone (0.5% wt/v in the 9-week study, 1.0% wt/v in the 4-week study). In the 9-week study the doses of DEHP were 0, 125, 250, 500 or 1000 mg/kg b.wt. In the 4-week study the doses of DEHP were increased to 1000, 5000 and 10,000 mg/kg b.wt. In the 9-week study, the relative liver weight was increased in the rats exposed to 500 and 1000 mg/kg b.wt. No interaction of DEHP and acetone was observed in any of the measured parameters. In the 4-week study DEHP, at the highest dose level, resulted in severe general toxicity. The group exposed to DEHP in combination with acetone was more affected. Male fertility was decreased. Body weight was decreased, and the relative weight of the liver, kidney, heart, brain and adrenals increased. The relative weight of the testes decreased in the 5000 and 10,000 mg/kg b.wt. groups. The weight of seminal vesicles and epididymals decreased at 10,000 mg/kg b.wt. In animals exposed to 5000 and 10,000 mg DEHP/kg b.wt. a severe atrophy of the seminiferous tubules and a slight diffuse Leydig's cell hyperplasia was observed. The cellular debris and conglomerates of desquamated cells found in the lumen of the seminiferous tubules were immunostained positive for vimentin. This indicates that Sertoli cell cytoplasm is included in the conglomerates - an interesting finding not previously described. No specific interaction of DEHP and acetone was observed in any of the measured parameters.

Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg/1), or 800 p.p.m. (4.58 mg/l) of dearomatised white spirit, 6 hr/day, 5 days/week up to 3 weeks. Five rats from each group were sacrificed immediately after the exposure for 1, 2, or 3 weeks and 2, 4, 6, or 24 hr after the end of 3 weeks' exposure. After 3 weeks of exposure the concentration of total white spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 p.p.m., respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of exposure. Two hours after the end of exposure the n-decane concentration decreased to about 25% in blood and 50% in brain. A similar pattern of elimination was also observed for n-nonane, n-undecane and total white spirit in blood and brain. In fat tissue the concentrations of n-nonane, n-decane, n-undecane, and total white spirit increased during the 3 weeks of exposure. The time to reach steady-state concentrations is longer than 3 weeks. After the 3 weeks' exposure the fat tissue concentration of n-nonane, n-decane, n-undecane, and total white spirit decreased very slowly compared with the rate of decrease in blood and brain suggesting that long-lasting redistribution from fat to brain may occur. One week of exposure at 800 p.p.m. caused a statistically significant increase in whole brain dopamine concentration while the noradrenaline concentration was unaffected. Exposure at both exposure levels for 1 week caused a statistically significantly decreased concentration of 5-hydroxytryptamine in whole brain. The reduction was related to the exposure concentration. These changes in neurotransmitter concentrations were normalised after 2 and 3 weeks' exposure. In conclusion, after 3 weeks of exposure the fat:brain:blood concentration coefficients for total white spirit were approximately 250:3:1, and redistribution from fat to brain is possible. As total white spirit behaved similarly to the n-alkanes in blood, brain, and fat tissue, we suggest that the non-n-alkane white spirit components possess toxicokinetic properties similar to the n-alkanes.

Male Wistar rats were dosed with 0, 1250, 3750 or 5000 mg/l of phenylglyoxylic acid (PGA) (CAS no. 611-73-4) in the drinking water ad libitum for 3 months. During the entire treatment period, there were no gross signs of toxicity related to PGA. No changes in neurobehavior were found after using a functional observational battery or radial arm maze. An increased relative kidney weight was seen in the highest dose-group (Controls: 0.504 +/- 0.031 g/100 g b. wt.; 5000 mg PGA/I: 0.579 +/- 0.033 g/100 g b.wt.; p<0.01). No other organ weights were affected. Histopathology revealed no change in kidney structure. No changes in clinical biochemistry. in the highest dose-group three animals out of ten showed reduction in peripheral nerve myelin sheath thickness. No such changes were seen in the control group. The study revealed no changes in auditory brain stem response but minor changes in electroretinography. The noradrenaline (NA) concentration decreased in pens and thalamus whereas it increased in medulla oblongata and whole brain. The dopamine (DA) concentration increased in cerebellum, hippocampus, pens, and whole brain. The most marked DA increase was seen in hippocampus (Controls: 0.56 +/-0.10 nmol/g tissue; 5000 mg/l: 1.04 +/- 0.11 nmol/g tissue; p<0.001). The 5-hydroxytryptamine (5-HT) concentration decreased in cerebellum, cerebral cortex, hippocampus, and medulla oblongata, whereas it increased in thalamus. The yield of synaptosomal protein, synaptosomal NA, DA, and 5-HT concentrations, and DA uptake rate were not affected. When dosed males were mated with naive females, there were no differences between groups in the pregnancy rate, number of corpora luteae, implantations, live or dead fetuses, resorptions, preimplantation loss, or postimplantation loss. It is concluded that a part of the effects on kidney, peripheral nerves, and vision, which have previously been reported after exposure to styrene, might be induced by the styrene metabolite, PGA. If PGA has ototoxic effects in rats, the dosing in the present study is not sufficient to induce the necessary ototoxic concentration in blood. Alternatively, the ototoxicity of styrene, like toluene, may be caused the parent compound itself and not by a metabolite like PGA. (C) 1998 Inter Press, inc.

Long-lasting effects of inhalation exposure to p-cymene (p-isopropyl-toluene; CAS No. 99-87-6) on regional and subcellular brain neurochemistry were studied. Male Long-Evans rats were exposed to 0, 50, or 250 p.p.m. p-cymene 6 hr/day, 5 days/week for four weeks followed by an exposure-free period of 8 weeks. Synaptosomes were isolated from whole brain minus cerebellum and used as an ex situ model for in situ conditions at the level of the presynaptic nerve terminal. There was no persistent effect on wet weight (regional) or regional noradrenaline (NA), dopamine (DA), or 5-hydroxytryptamine (5-HT) concentrations owing to exposure. Yield of synaptosomal protein was statistically significantly reduced in an exposure concentration-related manner (Control: 16.6 +/- 3.1; 50 p.p.m.: 9.2 +/- 2.1; 250 p.p.m.: 8.6 +/- 1.7 mg protein/g tissue, mean +/- I.S.D.). Synaptosomal NA and DA concentrations and acethycholinesterase, butyrylcholinesterase, and lactate dehydrogenase activities were statistically significantly increased when expressed relative to synaptosomal protein. It is hypothesized that a reduced density and number of synapses in situ are functionally compensated for by increased NA and DA release from noradrenergic and dopaminergic presynaptic nerve terminals. The applicability of the synaptosome as an ex situ neurochemical research model for the presynaptic CNS nerve terminal in situ for the study of solvent neurotoxicity in rats was further supported.

Both clinical and epidemiological studies of the effects of exposure to toluene have shown that long-term exposure may result in chronic toxic encephalopathy, where one of the major symptoms is memory deficits. We have attempted to identify the structural basis of the toxic effects of toluene in the hippocampus, a region of the brain known to be involved in learning and memory processes and well suited for stereological analysis. Rats were exposed to 1 500 ppm of toluene, six hours per day, five days per week for six months. This was followed by a tb ur-mon th-period without exposure prior to sacrifice. The total number of neurons in each of the five subdivisions of hippocampus of six exposed and six control rats was estimated with the optical fractionator. A statistically significant neuron loss of 16% was found in regio inferior (CA3 and CA2) of the exposed rats. (C) 1996 Intox Press, Inc.

Several epidemiological studies of workers occupationally exposed to white spirit show that neuropsychiatric disorders are a frequent cause of early disability pension in this population compared with non-exposed controls. In the rat, we have demonstrated that exposure to different kinds of white spirit induces changes in neurotransmitter concentrations, indices of oxidative stress, and electrophysiological parameters. Others have confirmed that acute behavioural effects can be induced by short-term high-level exposure. With NMR spectroscopy technique it is possible to study neurochemical parameters in vivo, and to examine the same subjects repeatedly over time. NMR spectroscopy was used to study the effects of organic solvents in rats. Rats were exposed to 0, 400 ppm, or 800 ppm of aromatic white spirit 6 hr/day, 7 days/week for 3 weeks. During the first week, the rats showed signs of irritation of mucous membranes, and appeared to be sedated. Both types of effect gradually diminished during the second week. The rats were examined by single volume of interest (VOI) NMR spectroscopy. N-acetylaspartate, creatinine and phosphocreatinine, and choline containing compounds were measured in the hippocampus and surrounding regions. The concentration of N-acetylaspartate for the three groups was found to be in the range of 8.2-8.5 mM with a standard deviation of 0.6-0.9. There was no difference between the three groups. In a previous study no change in the number of astrocytes in hippocampus was found following exposure to white spirit for six months. Since N-acetylaspartate is thought to be a marker for neurons, the results of these two studies indicate that white spirit does not produce a marked neuronal loss. However, it was not possible to show effect of trimethyltin. In this study trimethyltin was used as a "positive control'. The NMR technique can be applied to the rat, and it is possible to obtain reasonable signal-to-noise ratios.

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.

Levels of glutathione and activity of glutamine synthetase were assayed in organs of rats following inhalation of a heterogeneous solvent mixture containing both aliphatic and aromatic hydrocarbons. This mixture was administered for 3 weeks (6 h daily) at two levels in the inhaled air (400 and 800 ppm) to young adult (5-month-old) and aged (14-month-old) rats. Depression of levels of glutamine synthetase in the P2 fraction of kidney was observed, which was more severe in aged than young adult rats. Glutamine synthetase is a cytosolic enzyme especially susceptible to oxidative damage. A parallel depression of this enzyme was also seen in the corresponding hepatic fractions. However, levels of glutamine synthetase in the hippocampus were elevated by this exposure. Glutathione levels were depressed in P2 fractions of livers of exposed rats, and also in the corresponding renal fraction. Glutathione concentration was unchanged in cerebral fractions. Overall results were interpreted to imply that pro-oxidant events were elevated in kidney and liver following prolonged inhalation of the solvent mixture. The changes found in brain tissue did not reveal evidence of oxidative stress but, however, suggested that glial activation was taking place.

The effects of 3 weeks' or 6 months' inhalation exposure of rats to aromatic white spirit 6 h/day, 5 days/week at 0, 400, or 800 ppm were studied. Synaptosomal neurochemistry was investigated as index of the in situ conditions in the presynaptic nerve terminal. In both studies, the relative and absolute yield of synaptosomal protein were significantly reduced in the two exposed groups. Both studies demonstrated increased synaptosomal noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) concentrations, high-affinity 5-HT uptake rate and uptake capacity. It is hypothesized that a reduced density and total number of synapses in situ may be functionally compensated by increased NA, DA, and 5-HT neurotransmitter release, or by increased activity of corresponding neurons. The increased synaptosomal 5-HT uptake rates and uptake capacities may explain the previously demonstrated increased global and regional neurotransmitter concentrations and the present finding of increased synaptosomal 5-HT concentrations. These changes are interpreted as an indication of toxic effect on the CNS function and are considered supportive of recent findings of electrophysiological changes and affected motor activity following 6 months' exposure to dearomatized white spirit followed by an exposure-free period.

The present study was undertaken in order to investigate whether dearomatized white spirit induces indices of oxidative stress in subcellular fractions of hemisphere, hippocampus, kidney and liver tissue of rats exposed to 0, 400 and 800 ppm 6 hr/day, 7 days a week for 3 weeks. The results show that white spirit is a strong in vivo inducer of oxidative stress in subcellular fractions of brain, kidney and liver. In the liver there was a statistically significant increase in the rate of reactive oxygen species (ROS) generation and a decrease in glutamine synthetase activity. In the kidney there was a statistically significant decrease in the rate of ROS generation. In the hemisphere there was a statistically significant increase in the level of reduced glutathione. In the hippocampus there was a statistically significant increase in the rate of ROS generation. However, in vitro addition of dearomatized white spirit had no effect on the rate of cerebrocortical P2 fraction ROS generation. The results suggest that cumulative oxidative damage may be an underlying mechanism of dearomatized white spirit-induced neurotoxicity and that various regions of the brain may respond differently.

Pharmacology & ToxicologyVolume 75, Issue 5 p. 324-326 The Area under the Plasma Concentration Curve (AUC) of Urethane in Mice and the Influence of Concomitant Administration of Ethanol Eva Kristiansen, Corresponding Author Eva Kristiansen Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkAuthor for correspondence: Eva Kristiansen, Institute of Toxicology, National Food Agency, 19, Mørkhøj Bygade, DK-2860 Søborg, Denmark (fax +45 39 66 01 00).Search for more papers by this authorMartin Vahl, Martin Vahl Institute of Food Chemistry and Nutrition, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this authorOle Ladefoged, Ole Ladefoged Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this authorOtto Meyer, Otto Meyer Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this authorGrete Østergaard, Grete Østergaard Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this authorHenrik Rye Lam, Henrik Rye Lam Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this author Eva Kristiansen, Corresponding Author Eva Kristiansen Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkAuthor for correspondence: Eva Kristiansen, Institute of Toxicology, National Food Agency, 19, Mørkhøj Bygade, DK-2860 Søborg, Denmark (fax +45 39 66 01 00).Search for more papers by this authorMartin Vahl, Martin Vahl Institute of Food Chemistry and Nutrition, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this authorOle Ladefoged, Ole Ladefoged Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this authorOtto Meyer, Otto Meyer Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this authorGrete Østergaard, Grete Østergaard Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this authorHenrik Rye Lam, Henrik Rye Lam Institute of Toxicology, National Food Agency, 19, Morkhøj Bygade, DK-2860 Søborg, DenmarkSearch for more papers by this author First published: November 1994 https://doi.org/10.1111/j.1600-0773.1994.tb00369.xCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References Altmann, H.-J., B. Dusemund, M. Goll & W. Grunow: Effect of ethanol on the induction of lung tumours by ethyl carbamate in mice. Toxicology 1991, 68, 195– 201. Kristiansen, E., S. Clemmensen & O. Meyer: Chronic ethanol intake and reduction of lung tumours from urethane in strain A mice. Fd. Chem. Toxic. 1990, 28, 35– 38. Kurata, N., H. E. Hurst, F. W. Benz, R. A. Kemper & W. J. Waddell: Studies on inhibition and induction of metabolism of ethyl carbamate by acetone and related compounds. Drug Metab. Dispos. 1991, 19, 388– 393. Nomeir, A. A., Y. M. Ioannou, J. M. Sanders & H. B. Matthews: Comparative metabolism and disposition of ethyl carbamate (urethane) in male Fischer 344 rats and male B6C3Fl mice. Toxicol. Appl. Pharmacol. 1989, 91, 203– 215. O'Flaherty, E. J. & S. P. Sichak: The kinetics of urethane elimination in the mouse. Toxicol. Appl. Pharmacol. 1983, 68, 354– 358. Schlatter, J. & W. K. Lutz: The carcinogenic potential of ethyl carbamate (urethane): risk assessment at human dietary exposure levels. Fd. Chem. Toxic. 1990, 28, 205– 211. Uggla, A. & L. Busk: Ethyl carbamate (urethane) in alcoholic beverages and foodstuffs - A Nordic View. Nordiske Seminar og Arbejdsrapporter 1992: 570. Nordic Council of Ministers, Copenhagen. Vahl, M.: A survey of ethyl carbamate in beverages, bread and acidified milks sold in Denmark. Fd. Add. Contam. 1993, 10, 585– 592. Waddell, W. J., C. Marlowe & W. M. Pierce: Inhibition of the localization of urethane in mouse tissues by ethanol. Fd. Chem. Toxic. 1987, 25, 527– 531. Yamamoto, X., W. M. Pierce, H. E. Hurst, D. Chen & W. J. Waddell: Inhibition of the metabolism of urethane by ethanol. Drug Metab. Dispos. 1988, 16, 355– 358. Zimmerli, B. & J. Schlatter: Ethyl carbamate: analytical methodology, occurrence, formation, biological activity and risk assessment. Mutat. Res. 1991, 259, 325– 350. Citing Literature Volume75, Issue5November 1994Pages 324-326 ReferencesRelatedInformation

The irreversible CNS effects of six months' exposure to toluene (0, 500, and 1500 p.p.m.) in rats was studied applying a multi-disciplinary approach. After an exposure-free period, neurobehavioural, morphometric, pathological, and biochemical examinations were performed. No neurobehavioural or gross pathological changes were found. Morphometric measurements did not show loss of neurones. At 500 p.p.m. the mean nuclear volume and mean perikaryonal volume and the variation of the values of these parameters was increased in the exposed groups compared to the controls. Noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) levels were significantly changed in various brain regions. It is concluded that this investigation failed to reveal overt toluene-induced CNS-neurotoxicity, however, certain irreversible effects were found which further add to the accumulating evidence of the chronic CNS-neurotoxicity of toluene.