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Biomedical subjects

G Ostergaard

Publications and source records attributed to G Ostergaard.

At least 19 recordsLinked to original sources
PubMed2000

Toxicity study of di(2-ethylhexyl)phthalate (DEHP) in combination with acetone in rats.

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.

Acetone↗
PubMed2000

Four weeks' inhalation exposure of Long Evans rats to 4-tert-butyltoluene: effect on evoked potentials, behaviour, and brain neurochemistry.

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.

Acetylcholinesterase↗
PubMed1999

Distribution of dearomatised white spirit in brain, blood, and fat tissue after repeated exposure of rats.

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.

Adipose Tissue↗
PubMed1998

The applicability of the ADI (Acceptable Daily Intake) for food additives to infants and children.

Children are not little adults. Children may respond differently from adults because they are in a state of growth and development; or because of differences in toxicokinetics or toxicodynamics. Infants and children are often assumed to be more susceptible to toxic effects, but this generalization is founded on assumptions rather than on facts. Available data are mostly concerned with toxicity and therapeutic effects of pharmaceuticals, while the effects in children of industrial chemicals are less well documented. Childhood is characterized by growth and development. Toxicants may interfere with these processes, and therefore toxic exposure may have more serious consequences for children than for adults, irrespective of sensitivity. Immature physiological functions of the foetus and young child theoretically make these age groups more vulnerable to toxicants, at least up to 1 year of age. The existing data on effects of chemical exposure in children point in the direction that susceptibility depends on the substance and on the exposure situation. For a particular compound children may be more sensitive than adults, or they may be less sensitive. Further, the sensitivity of children to a particular substance varies greatly with age. It is necessary to view premature neonates, neonates, infants, and children of different ages as separate risk groups. The long-term studies used as the basis for establishing ADIs cover lifetime for laboratory animals. Methods which have special emphasis on reproductive cells, on the foetus, and on the immature organism are used. Taken together, these studies cover exposure during all life stages. However, some specific types of effects, and delayed effects of perinatal exposure are not always included in standard toxicity test protocols. Exposure may also differ between children and adults. The food intake of children is qualitatively and quantitatively different form that of adults, and the EU Scientific Committee for Food has recommended that intake assessment of children be considered separately from that of adults because patterns of consumption are different. The ADI should cover the entire population including children. Special considerations regarding the use of food additives do apply to infants below the age of 12 weeks, who depend entirely on infant formula for nutrition.

Adult↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: III. Results of proficiency studies. Steering Group.

The goal of the IPCS Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The first phase of the Collaborative Study involved training the participants: evidence of training was then evaluated using positive-control compounds. The positive-control studies required the laboratories to identify, using the FOB, specific neurotoxic syndromes produced by acute exposure to p,p'-DDT, parathion, and by short-term repeated dosing with acrylamide. For the sake of expediency, only one dose of each chemical was used instead of collecting dose-response data. Motor activity test chambers were not of uniform design. The laboratories were therefore required to demonstrate adequate sensitivity by the ability to detect statistically-significant activity increases and decreases produced by triadimefon and chlorpromazine, respectively, following acute administration of a range of doses. The resulting FOB and motor activity data showed variability in the magnitude of effects obtained: some of these differences were attributed to miscommunications, difficulties with the techniques or protocol, or the limitations of having only one dose. All laboratories, however, successfully met the criteria set forth by the Study Steering Committee.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: IV. Control data. Steering Group.

The goal of the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories worldwide. The control data were crucial to the outcome of the studies in terms of sensitivity and reliability of the test measures, which in turn impact on the between-laboratory comparisons of chemical effects. In addition, analyses of control data can aid in determining endpoints that may require modification to improve their sensitivity and reliability. The control data from the eight laboratories were examined in terms of the following parameters: 1) control variability within studies for each laboratory; 2) within-laboratory replicability of control values across studies; 3) within-laboratory stability of control values over the course of testing for a given study; and 4) between-laboratory comparisons of parameters (1), (2), and (3). The analyses indicated considerable differences across endpoints, wherein some measures showed high variability and little replicability, while others were extremely reproducible. Generally, there were similar ranges of variability and replicability of control data across laboratories, although in some cases one or two laboratories were markedly different from the others. The physiological (weight, body temperature) and neuromuscular (grip strength, landing foot splay) endpoints exhibited the least variability, whereas the subjective assessments of reactivity varied the most. These data indicate a reasonable degree of comparability in the data generated in the participating laboratories.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: V. Results of chemical testing. Steering Group.

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. Following the training phase and the conduct of proficiency studies in all laboratories, participants proceeded to test the effects of seven chemicals in both single dose and four-week repeated dosing scenarios. The chemicals studied were acrylamide, bisacrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples from a common source. In order to judge the general utility of these procedures in a diversity of testing situations, laboratories conducted the studies under their standard conditions, using their choice of rat strain and test equipment. Chemical does and time of peak effect for acute testing were determined by each laboratory: these parameters were quite similar for some chemicals, but varied greatly for others. The results of the chemical tests indicated that while there was some variability in the data on specific endpoints, all laboratories detected and characterized the effects of all but one of the known neurotoxicants. The one exception (toluene) was probably due to other factors (e.g., dose level, route of administration) rather than lack of sensitivity of the test methods. This study provides extensive data regarding the use of neurobehavioral screening methods over a range of laboratory conditions as well as the reliability, sensitivity, and robustness of the tests to detect neurotoxic potential of chemicals.

Animals↗
PubMed1996

Four weeks' inhalation exposure of rats to p-cymene affects regional and synaptosomal neurochemistry.

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.

Administration, Inhalation↗
PubMed1996

Neuronal loss in hippocampus in rats exposed to toluene.

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 1500 ppm of toluene, six hours per day, five days per week for six months. This was followed by a four-month-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.

Animals↗
PubMed1995

Changes in markers of oxidative status in brain, liver and kidney of young and aged rats following exposure to aromatic white spirit.

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.

Aging↗
PubMed1995

Three weeks' and six months' exposure to aromatic white spirit affect synaptosomal neurochemistry in rats.

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.

Acetylcholinesterase↗
PubMed1994

Three weeks' exposure of rats to dearomatized white spirit modifies indices of oxidative stress in brain, kidney, and liver.

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.

Animals↗
PubMed1993

Effects of six months' white spirit inhalation exposure in adult and old rats.

In two separate experiments in rats the irreversible effects of six months' exposure to white spirit (0, 400 p.p.m., and 800 p.p.m.) were studied. In one experiment the exposure started at the age of three months, in the other the rats were 15 months at the beginning of the exposure. After an exposure-free period of several months neurobehavioural, pathological, and neurochemical examinations were performed. A marked difference in motor activity between young and aged animals was found. A slight effect on kidney function was seen at 800 p.p.m. No macroscopic or histopathological changes related to dosing were found. The concentrations of noradrenaline, dopamine, and 5-hydroxytryptamine in various brain regions and in whole brain were irreversibly changed. In conclusion, the study revealed different changes within the CNS, but failed to demonstrate neurobehavioural white spirit-induced neurotoxicity.

Administration, Inhalation↗
PubMed1991

Irreversible effects in rats of toluene (inhalation) exposure for six months.

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.

Administration, Inhalation↗
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↗
PubMedDate not supplied

Inhalation exposure to white spirit causes region-dependent alterations in the levels of glial fibrillary acidic protein.

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.

Administration, Inhalation↗
PubMedDate not supplied

Effect on the content of n-acetylaspartate, total creatine, choline containing compounds, and lactate in the hippocampus of rats exposed to aromatic white spirit for three weeks measured by NMR spectroscopy.

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.

Animals↗