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B M Kulig

Publications and source records attributed to B M Kulig.

At least 19 recordsLinked to original sources
PubMed2006

Model studies for evaluating the acute neurobehavioral effects of complex hydrocarbon solvents I. Validation of methods with ethanol.

As a preliminary step to evaluating the acute neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, joint neurobehavioral/toxicokinetic studies were conducted which involved administering ethanol to rats and volunteers. The specific objectives of the present studies were to evaluate the acute central nervous system (CNS) effects of ethanol in rats and humans and to assess relationships between internal levels of exposure and behavioral effects. A more general objective was to validate a battery of neurobehavioral tests that could be used to carry out comparative studies in both species. Accordingly, a range of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute CNS effects. Groups of rats were given ethanol at levels of approximately 0.5, 1.0 or 2.0g/kg, with blood level measurements to verify internal doses. In a volunteer study, 12 healthy male subjects were given 0.65g/kg ethanol, a level approximating the limit for motor vehicle operation in The Netherlands, and neurobehavioral effects were measured prior to and 1 and 3h after ethanol administration, with a computerized neurobehavioral test battery. Blood and air measurements were made to quantify internal doses. Results of the behavioral tests in rats provided evidence of ethanol-induced changes in neuromuscular, sensori-motor, and activity domains. There were also significant changes in visual discrimination, particularly in the areas of general measures of responding and psychomotor speed. In humans there were small but statistically significant effects on learning and memory, psychomotor skills and attention. However, the effects were subtle and not all parameters within given domains were affected. These studies demonstrated a qualitative similarity in response between rats and humans.

Adult↗
PubMed2001

Beneficial effects of TCP on soman intoxication in guinea pigs: seizures, brain damage and learning behaviour.

Poisoning with the potent nerve agent soman produces a cascade of central nervous system (CNS) effects characterized by severe convulsions and eventually death. In animals that survive a soman intoxication, lesions in the amygdala, piriform cortex, hippocampus and thalamus can be observed. In order to examine the mechanisms involved in the effects of soman and to evaluate possible curative interventions, a series of behavioural, electrophysiological and neuropathological experiments were carried out in the guinea pig using the NMDA antagonist N-[1-(2-thienyl)cyclohexyl] piperidine (TCP) in conjunction with atropine and pyridostigmine. The NMDA antagonist TCP appeared to be very effective in the treatment of casualties who suffered from soman-induced seizures for 30 min: (i)Seizures were arrested within minutes after the TCP injection, confirmed by quantitative electroencephalogram (EEG), after fast Fourier analysis. Three hours after TCP the quantitative EEGs were completely normal in all frequency bands and remained normal during the entire 3-week intoxication period. The power shift to the lower (delta) frequency bands, indicative for neuropathology and found in control animals intoxicated only by soman, was not observed in the soman-TCP group. (ii)The gross neuropathology found in soman control animals within 48 h after soman was prevented in soman-TCP animals and was still absent in 3-week survivors. Instead, ultrastructural changes were observed, indicative of defense mechanisms of the cell against toxic circumstances. (iii)Twenty-four hours after soman, soman-TCP animals were able to perform in the shuttle box and Morris water maze. The beneficial effects of TCP on the performance in these tests during the 3-week intoxication period were very impressive, notwithstanding (minor) deficits in memory and learning. (iv)The increase in excitability after TCP was confirmed by an increase in the acoustic startle response. Taken together, these results confirmed the involvement of NMDA receptors in the maintenance of soman-induced seizures and the development of brain damage. They underline the current hypothesis that cholinergic mechanisms are responsible for eliciting seizure activity after soman and that, most likely, the subsequent recruitment of other excitatory neurotransmitters and loss of inhibitory control are responsible for the maintenance of seizures and the development of subsequent brain damage.

Animals↗
PubMed2001

Simultaneous exposure to ethyl benzene and noise: synergistic effects on outer hair cells.

The effects on hearing of simultaneous exposure to the ototoxic organic solvent ethyl benzene and broad-band noise were evaluated in rats. The effects of three ethyl benzene concentrations (0, 300 or 400 ppm) and three noise levels (95 or 105 dB(lin) SPL or background noise at 65 dB(lin) SPL) and all their combinations were investigated for a 5 day exposure at 8 h/day. Distortion product otoacoustic emissions and compound action potentials were affected after 105 dB noise alone, and after 105 dB noise in combination with ethyl benzene (300 and 400 ppm). However, the amount of loss for these combinations did not exceed the loss for 105 dB noise alone. Outer hair cell (OHC) loss after exposure to 300 ppm ethyl benzene was located in the third row of OHCs. At 400 ppm, the loss spread out to the second and first row of OHCs. Noise alone hardly affected the OHC counts except for a minor loss in the first row of OHCs after 105 dB SPL. Noise at 105 dB in combination with ethyl benzene at 300 and 400 ppm, however, showed OHC loss greater than the sum of the losses induced by noise and ethyl benzene alone.

Action Potentials↗
PubMed1999

The ototoxic effects of ethyl benzene in rats.

Exposure to organic solvents has been shown to be ototoxic in animals and there is evidence that these solvents can induce hearing loss in humans. In this study, the effects of inhalation of the possibly ototoxic solvent ethyl benzene on the cochlear function and morphology were evaluated using three complementary techniques: (1) reflex modification audiometry (RMA), (2) electrocochleography and (3) histological examination of the cochleas. Rats were exposed to either ethyl benzene (800 ppm, 8 h/day for 5 days) or to control conditions. The RMA threshold increased significantly by about 25 dB, 1 and 4 weeks after the exposure, irrespective of the stimulus frequency tested (4-24 kHz). Electrocochleography was performed between 8 and 11 weeks after exposure to the organic solvent. The threshold for the compound action potential increased significantly by 10-30 dB at all frequencies tested (1-24 kHz). Histological examination of the cochlea showed outer hair cell (OHC) loss, especially in the upper basal and lower middle turns (corresponding to the mid-frequency region) to an extent of 65%. We conclude that exposure to 800 ppm ethyl benzene for 8 h/day during 5 days induces hearing loss in rats due to OHC loss.

Administration, Inhalation↗
PubMed1997

The IPCS collaborative study on neurobehavioral screening methods.

The International Programme on Chemical Safety sponsored a collaborative study to evaluate the utility of neurobehavioral test methods for identifying neurotoxic chemicals. The protocol consisted of a functional observational battery and automated assessment of motor activity. The study involved four laboratories in the United States and four in Europe, each of which evaluated the dose- and time-related effects of seven prototypic chemicals following both single and 4-week repeated exposures. The protocol was designed to assess the general utility and reliability of neurobehavioral screening procedures in a diversity of testing situations. The results of chemical testing indicated that all participating laboratories generally could detect and characterize the effects of known neurotoxicants, despite some differences on specific endpoints. These data provide important information regarding the reliability and sensitivity of neurobehavioral screening methods over a range of laboratory conditions. The purpose of this workshop was to describe the background and study design of the collaborative effort, present the data (including comparison of results across laboratories), and discuss issues regarding the conduct and interpretation of these behavioral tests, as well as future directions for neurotoxicity screening.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening. I. Background and genesis.

Numerous events over several years culminated in recognition of the need to explicitly evaluate the nervous system as a potential target for environmental chemicals. Based on recommendations from several international expert panels, the International Programme on Chemical Safety (IPCS) sponsored the Collaborative Study on Neurobehavioral Screening Methods. A Steering Committee was created to oversee the project, develop the testing protocol, recruit participating laboratories and review and analyze the data. The protocol specified the tests, the chemicals (supplied from a common source) and the exposure conditions (acute and repeated dosing). Test methods were based upon existing practices in toxicological screening as well as recent advances in neurotoxicity screening. Chemicals were selected to produce different profiles of neurobehavioral effects. Considerable latitude was afforded the participating laboratories in the choice of several key variables (e.g., strain of rat, testing device for motor activity assessment) that could potentially affect the results of the experiments. The approach therefore provided a standardized yet flexible protocol for evaluating the reproducibility of neurobehavioral screening data in diverse laboratory settings.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: II. Protocol design and testing procedures.

This paper describes the development of the protocol for the International Programme on Chemical Safety (IPCS)-sponsored Collaborative Study on Neurobehavioral Screening Methods, including background on the methods and chemicals selected, as well as details concerning the conduct of the collaborative study, including proficiency testing, range-finding and main study. Participating laboratories in the collaborative study received training in the conduct and scoring of the behavioral tests and each laboratory received a video training film to train additional personnel as needed. Each of the eight laboratories that chose to participate in the study completed proficiency testing and assessed seven representative chemicals using a functional observational battery and automated motor activity assessment. The seven chemicals studied were acrylamide, bis-acrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples of the chemicals from a common source. Each laboratory derived doses for single and repeated administration based on the determination of a within-laboratory acute "top dose." Animal strains were not standardized and laboratory conditions were standardized to a limited degree in order to judge the general utility and robustness of these procedures in a diversity of testing situations.

Animals↗
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↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: VII. Summary and conclusions.

In the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods, eight participating laboratories used a standard battery of behavioral tests to determine, in rats, the effects of seven representative chemicals following acute and repeated dosing. The results of the collaborative study indicate good agreement across laboratories with regard to the data collected in vehicle controls. It was clear, however, that some behavioral measures had significantly more variability than other tests. The laboratories also demonstrated the ability to detect known neurotoxic chemicals and identify profiles of effects that differed from non-neurotoxic agents. The results of the study suggest that appropriate training of personnel is crucial to ensure the reliability of the test battery. The results also underscore the importance of dose selection in behavioral screening studies, since it is sometimes difficult to determine the specificity of behavioral changes in animals receiving high doses of some chemicals. The collaborative study also emphasizes the need to utilize a battery of tests in screening a wide range of potential neurotoxic agents. Analysis of data from such studies poses unique challenges due to the large number of tests and test times, and the consequent possibility of false positives. Some statistical concerns may be alleviated by grouping the results from tests that measure similar functions into neurobiological domains. Although this approach improves confidence in the biological relevance of chemical-induced changes in behavior, it may also lead to false negatives. The exploration of other statistical approaches to analyze data from experiments using a test battery is encouraged. Nevertheless, results of the collaborative study strongly support the use of behavioral tests in hazard identification.

Animals↗
PubMed1997

Multivariate time of peak effects assessment for use in selecting time of testing in acute neurotoxicity studies.

One of the aims of conducting observational assessments shortly following administration of a test compound is to provide information regarding the profile of acute neurotoxic effects. By limiting the time of peak effects (TOPE) determination to a time range-finding study using only gait and arousal as the end-points for determining time of peak effects, as was proposed in the IPCS/WHO Collaborative Study on Neurobehavioral Screening Methods protocol, it is possible that the time of testing selected for the acute study proper may underestimate other neurotoxic effects which show a different time course. We explored the feasibility of including measures of autonomic activity as well as clonic/tonic movements in the TOPE determination in two experiments using chlorpyrifos and carbaryl as test compounds. A scoring system based on the original operational definitions provided in the IPCS/WHO protocol was devised. Results indicated that there were considerable differences in the time course for autonomic effects and convulsive behavior in comparison to effects on gait and arousal. It is concluded that the use of a multivariate approach for TOPE determination may provide a more comprehensive empirical basis for selecting a testing time for studies designed to profile acute neurotoxic effects.

Animals↗
PubMed1996

Comprehensive neurotoxicity assessment.

Significant progress has been made in recent years in terms of both the conceptualization of neurotoxicity assessment strategies as well as in the development of behavioral techniques for evaluating neurotoxic exposures. A tiered approach, for example, has been advocated as an assessment strategy in which testing would proceed in a stepwise fashion from general screening using simple behavioral methods and neuropathology (tier 1) to the characterization of effects (tier 2) using more specific testing techniques. With respect to tier-1 testing, behavioral observational methods have been standardized for screening purposes, and these technically simple techniques, together with automated methods for motor activity assessment, are being increasingly incorporated into chemical and drug safety evaluations for regulatory purposes. With respect to tier-2 testing, more technically sophisticated techniques and behavioral paradigms are available for characterizing the behavioral effects of chemical exposures on motor, sensory, and cognitive processes. Paradigms involving learned and unlearned behavior, for example, have been described for quantifying a variety of clinical signs of motor impairment including paretic gait disorders, tremor, and coordination deficits. Likewise, robust noninvasive behavioral methods capable of tracking changes in visual, auditory, and somatosensory thresholds during the course of exposure are also available. With respect to cognitive testing, numerous maze and operant techniques and paradigms measuring different aspects of performance, learning, and memory have been elaborated. This paper presents an overview of behavioral techniques currently used to assess neurotoxicity in adult laboratory animals and discusses their application to hazard identification and other areas of risk assessment.

Behavior↗
PubMed1994

The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study.

4-Aminopyridine (4-AP) has a favorable effect on the disability of certain patients with MS. We investigated the effect of 4-AP on neuropsychological performance in 20 MS patients using a randomized, double-blind, placebo-controlled, crossover design. Although there was a trend for improved performance with 4-AP for two of the tests, we could not demonstrate significant effects of 4-AP on cognitive function.

4-Aminopyridine↗
PubMed1991

Evaluating the effects of chemical exposures on adaptive functioning.

1. Although morphological and classical toxicological data have typically served as criteria for judging the effects of chemicals on the nervous system, there has been increasing interest in the use of behavioral end-points for examining the adverse effects of chemicals on nervous system function. 2. The present paper describes the current use of behavioral methods in neurotoxicity assessment and surveys some of the recent developments in the use of specialized methods for examining motor, sensory and cognitive changes following chemical exposures.

Adaptation, Physiological↗
PubMed1988

Experimental exposure to alcohol as a model for the evaluation of neurobehavioural tests.

The performance characteristics of 4 computerized psychological tests were studied using alcohol as a model compound. Subjects received alcohol (0.5 ml/kg) or placebo in a cross-over design and performance was assessed using the Simple Reaction Time test, the Switching Attention test, the Hand/Eye Coordination test and the Color-Word Vigilance test. Analyses indicated an overall significant effect of alcohol at blood-alcohol levels of 0.03% with response speed on the Color-Word Vigilance test being the most sensitive parameter.

Adult↗
PubMed1987

An automated technique for the evaluation of coordinated movement deficits in rats.

The effects of CNS-active drugs and neurotoxic agents are often expressed as changes in coordinated movement. In order to quantitate such changes during prolonged chemical exposures, an automated technique for the routine measurement of coordinated hindlimb movement in the rat was developed. In this test, a color tv/microprocessor-based system was used to detect and analyze the movement of one of the rat's hindpaws as the rat placed its paw from one rung to another while walking in a rotating, motor-driven wheel. Test length was 90 sec and a wheel speed of 8.2 cm/sec was employed. Results from a 12 week study involving the ip administration of acrylamide (0, 3.6, 7.2 and 14.4 mg/kg) indicated that acrylamide produced a progressive decline in coordinated hindlimb movement beginning in Wk 6 of exposure. Although some recovery was evident following the termination of exposure, the performance of the highest dose group was still inferior to controls at the end of the 6 week recovery period. These results indicate that a video-based system for the measurement of coordinated movement can provide a rapid and reliable method for the study of prolonged neurotoxic exposures.

Acrylamides↗