PubMed Health⌕ Search

Biomedical subjects

B M Kulig

Publications and source records attributed to B M Kulig.

At least 19 recordsLinked to original sources
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↗
PubMed1986

Attenuation of phenobarbital-induced deficits in coordinated locomotion during subacute exposure.

The effects of phenobarbital on coordinated locomotion were measured in rats trained to criterion to avoid electric shock by running treadmill fashion along a motor driven belt. Two phenobarbital groups (35 and 50 mg/kg) and saline controls were injected for 29 consecutive days. Testing was carried out on Drug Days 1, 15, and 29. On Drug Day 1, disturbances in gait and balance were reflected by an increased time off belt for the phenobarbital groups. In addition, both groups demonstrated a significant improvement in performance over the three 2-min trial test sessions. Deficits were further reduced on Drug Day 15, and by Drug Day 29, the performance of rats treated with 35 mg/kg was equivalent to control values while that of the 50 mg/kg group had improved by more than 90%. There was no corresponding change in plasma levels of phenobarbital during subacute dosing. After a one month drug withdrawal period, treatment with phenobarbital again produced coordination deficits which were equivalent to those seen on Drug Day 1. These data demonstrate that an attenuation of the effects of phenobarbital on coordination can begin within minutes of the initial test session and is most likely due to behavioral processes (i.e., acute functional tolerance). In addition, results suggest that further drug exposure may play a role in the carry-over of functional tolerance from one drug test session to the next.

Analysis of Variance↗
PubMed1985

The automated analysis of coordinated hindlimb movement in rats during acute and prolonged exposure to toxic agents.

The effects of CNS-active drugs and neurotoxic agents on motor coordination in the rat were studied using a newly developed, automated technique. In this test, a tv/microprocessor-based system was utilized to detect and describe the movement and placement characteristics of one of the rat's hindpaws as the rat placed its paw from one rung to another while walking in a rotating wheel. In studies employing a wheel speed of 8.2 cm/sec and a single 90-sec trial, significant deficits in coordinated hindlimb movement could be detected following the acute ip administration of a variety of compounds, including acrylamide (0, 50, and 100 mg/kg), diazepam (0, 0.5, 1.0, and 2.0 mg/kg), ethyl alcohol (0, 600, 900, and 1200 mg/kg), and tremorine (0, 2.5, 5.0, and 10.0 mg/kg). Further, results from a subacute study involving the oral administration of 2,5-hexanedione (2,5-HD; 0, 250, and 600 mg/kg) indicated that rats treated with 600 mg/kg, 2,5-HD were significantly impaired after 1 week of treatment and those treated with 250 mg/kg 2,5-HD, after 2 weeks of treatment. Although both groups improved during the recovery period, the performance of the 600 mg/kg group 5 weeks post-treatment was still inferior to controls. Taken together, these studies indicate that the coordinated hindlimb placement test provides a reliable, sensitive, and rapid technique for quantifying deficits in motor coordination in the rat during acute and prolonged exposure to neurotoxic substances.

Acrylamide↗
PubMed1977

Effect of di-n-propylacetate on the 'binding of GABA to synaptosome-enriched fraction of rat cerebral cortex.

The effect of di-n-propylacetate (DPA) on the 'binding' of gamma-aminobutyric acid (GABA) to a synaptosome-enriched fraction of rat cerebral cortex has been examined using differential centrifugation and double-isotope liquid scintillation spectrometry. DPA at 10(-4) M caused a slight decrease in GABA binding. This effect could explain in part the in vivo anticonvulsant and behavioral effects of this drug when administered to animals in high systemic doses.

Aminobutyrates↗