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G Winneke

Publications and source records attributed to G Winneke.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1996

Determination of polychlorinated biphenyls and chlorinated pesticides in human body fluids and tissues.

A fast and reliable method for the determination of polychlorinated biphenyls (PCBs) and chlorinated pesticides in human body fluids and tissues is presented. Sample clean-up and selective enrichment of analytes are carried out by liquid column chromatography without a prior solvent extraction step. Analytes are determined either by high-resolution capillary gas chromatography with mass spectrometric detection, or by dual-column GC followed by electron-capture detection. A procedure is described for the simultaneous determination of environmental levels of the PCB congeners 28, 52, 101, 138, 153 and 180 in human cord serum. The method allows the simultaneous determination of chlorinated pesticides such as aldrin, DDT, DDE, BHC and HCB and is also applicable to other biological matrices, such as bone marrow or tissues.

Bone Marrow↗
PubMed1996

The neurobehavioural toxicology and teratology of lead.

When comparing neurobehavioural observations from occupational lead-exposure of adults on the one hand, and environmental lead exposure of children on the other, it appears that the developing relative to the mature brain is more at risk. Neurobehavioural toxicity in occupational lead-exposure has typically not been observed at blood lead-concentrations (PbBs) below 400 micrograms/l, whereas ih environmentally exposed children such deficit has been reported to occur down to PbB of 100-150 micrograms/l and, perhaps, even below this range. Both cross-sectional and prospective studies have arrived at similar conclusions in this respect. The preferred endpoint in most such studies has been the IQ-measure, which has good psychometric qualities, is sufficiently well standardized to be comparable across studies, and exhibits attractive simplicity for the regulator in a public health context. At the same time, however, this IQ-focus has also interfered with systematic efforts to identify more specific lead-induced functional deficits by means of more detailed neurobehavioural analyses (Bellinger 1995). Metanalyses on both cross sectional and prospective studies in lead-exposed children have concluded that a typical doubling of PbB from 100 to 200 micrograms/l is associated with an average IQ-loss of 1-3 points (Pocock et al. 1994; WHO 1995), and no threshold has as yet been identified. Since, however, cause-effect contingencies necessarily remain doubtful in epidemiological studies if the observed effects are as subtle as these, experimental studies in animals have become helpful in supporting the causative role of lead to produce neurobehavioural deficit at steady-state PbB down to about 150 to 200 micrograms/l. Such deficit has been demonstrated by means of a variety of learning/memory models with positive and negative reinforcement contingencies in the rat--and in primates as well. It has also been shown in such studies that neurobehavioural deficit subsequent to early developmental exposure extends long into adulthood after cessation of exposure at weaning. It, therefore, appears that the neurobehavioural teratology of lead has more convincingly been demonstrated in animal models than in human exposure conditions, so far. A coherent theory to explain the particular vulnerability to lead of the developing brain is still lacking. Recent data do suggest, however, that Pb-induced disruption of calcium homeostasis in the immature brain might interfere with normal brain development.

Abnormalities, Drug-Induced↗
PubMed1996

Glial fibrillary acidic protein and RNA expression in adult rat hippocampus following low-level lead exposure during development.

The astroglial cytoskeletal element, glial fibrillary acidic protein (GFAP), is a generally accepted sensitive indicator for neurotoxic effects in the mature brain. We used GFAP as a marker for structural changes in rat hippocampus related to chronic low level lead exposure during different developmental periods. Four groups of rats were investigated: a control group, a perinatal group, which was exposed during brain development (E0-P16), a permanent group, exposed during and after brain development (E0-P100), and a postweaning group, exposed after brain development (P16-P100). Sections were processed for light microscopy (hematoxylin-eosin, Nissl, periodic acid Schiff (PAS) and GFAP-specific immunohistology), for electron microscopy, and for in-situ hybridization (GFAP). Sections were prepared from animals tested for active avoidance learning (AAL) and long-term potentiation (LTP). Chronic lead exposure did not affect glial and neuronal functions, as assessed by LTP and AAL, when lead exposure started after brain development (postweaning group). In this group, astrocytes displayed increased GFAP and GFAP gene transcript levels. However, lead exposure affected neuronal and glial function when the intoxication fell into the developmental period of the brain (perinatal and permanent groups). In these groups, LTP and AAL were impaired, and astrocytes failed to react to the toxic exposure with an adequate increase of GFAP and GFAP gene transcripts. Although GFAP is an accepted marker for neurotoxicity, our data suggest the marker function of GFAP to be restricted to postnatal toxic insult.

Animals↗
PubMed1996

Impairment of schedule-controlled behavior by pre- and postnatal exposure to hexachlorobenzene in rats.

Hexachlorobenzene (HCB) is still frequently found at elevated levels in human adipose tissue and breast milk. As intoxication with HCB causes neurological disturbance in human beings, the purpose of the present study was to examine neurobehavioral functions in rats after pre- and postnatal exposure. Female rats were fed diets with 0, 4, 8, or 16 mg HCB/kg diet. Exposure started 90 days prior to mating and was continued throughout mating, gestation, and lactation. Thereafter, the offspring were given the same diets as their respective mothers. HCB levels were determined in the brain, the liver, and in the adipose tissue from virgin rats, dams, and the offspring. Concentrations on a lipid basis were found to decline in the order adipose > liver > brain. The exposure levels chosen did not cause gross toxic effects in dams or offspring. There were dose-related increases in liver-to-body-weight ratios in exposed dams, but not in unmated females treated alike. Behavioral testing was conducted in the offspring. Examination of open-field activity on PND 21, and of active avoidance learning on PND 90 failed to reveal significant differences between groups. Training of operant behavior started at the age of 150 days in the offspring from the control, the 8-mg group, and the 16-mg group. Animals were trained on a fixed interval schedule of 1 min (FI-1). On this schedule, responses were reinforced by a food pellet every time 1 min had elapsed after the preceding reinforcement. There were dose-dependent reductions in the post-reinforcement pause, e.g. the time between each reinforcement and the first reaction emitted after it. In addition, the index of curvature, which describes the efficiency of performance on the FI-1 schedule, was decreased in a dose-dependent fashion.

Adipose Tissue↗
PubMed1995

Endpoints of developmental neurotoxicity in environmentally exposed children.

An overview is given of endpoint measures used or to be used in studying developmental neurotoxicity in environmentally exposed children. A variety of neurodevelopmental assessment methods is available covering either more general or rather sepcific aspects of the neuromotor or the neurobehavioral development, respectively. The available assays, not covered in any exhaustive manner, are classified into (1) neurodevelopmental assays for neonates, (2) neurodevelopmental assays for infants and older children, and (3) assays for cognitive development. Illustrative examples are given to demonstrate the use of several such assays in prospective cohort studies on neurodevelopmental effects of inorganic lead and of polychlorinated biphenyls (PCBs). Using these case studied crucial problems of the causative interpretation of findings due to interactions and confounding are discussed.

Behavior↗
PubMed1994

Persistent increases in scotopic B-wave amplitudes after lead exposure in monkeys.

The electroretinogram (ERG) of rhesus monkeys was re-examined more than 2 years after termination of lead exposure when mean blood lead levels had declined to values below 10 micrograms dl-1. Amplitude of the b-wave was increased by lead exposure at scotopic conditions, while there were no changes in photopic signals. The lead-induced effects were similar to alterations detected during the treatment phase and, thus, are not dependent on current exposure. Taking into account, that dopamine antagonists cause similar changes in the ERG, it is suggested that the observed effects may be mediated by a permanent change of dopaminergic processes since immunoreactivity also revealed adverse effects on the dopaminergic system in the retinae of these monkeys.

Animals↗
PubMed1994

The effects of control on stress-induced gastric erosions: the use of active shuttle-box avoidance learning with yoked controls.

The aim of the present study was to investigate effects of instrumental control on the development of stress-induced gastric erosions by using a shuttle-box paradigm with yoked controls. In Experiment 1 the learning conditions had a reinforcement ratio of only 70% to increase stress during the short-term learning session. No significant differences of the mean cumulative length of gastric erosions between active avoiding and yoked groups were found. Experiment 2 tested three different reinforcement conditions (70%, 90%, 100%) with yoked groups. Again, no significant differences of the mean cumulative length of erosions between active avoiding and yoked control groups were obtained. Instead, the length of erosions decreased with increasing reinforcement. Taken together, the data show that the frequency of unavoided noxious stimuli as a function of the reinforcement schedule can be seen as a major influence on the development of gastric erosions in a shuttle-box paradigm.

Animals↗
PubMed1994

Developmental delay of astrocytes in hippocampus of rhesus monkeys reflects the effect of pre- and postnatal chronic low level lead exposure.

Rhesus monkeys were pre- and postnatally exposed to lead-acetate at 0, 350, or 600 ppm in diet for nine years, followed by a period of lead-free diet for 32 months. During this time blood lead levels declined to normal, but still showed dose-related differences. In behavioral and neurophysiological studies the rhesus monkeys exhibited dose-related cognitive and functional deficits. After sacrifice hippocampal sections were processed for immunohistological staining. GFAP, introduced as a marker of neurotoxicity and Vimentin, which is expressed by immature or reactive astrocytes were investigated. A dose-dependent increase of GFAP due to prenatal and chronic low level lead exposure was not observed. We found a dose-related increase of GFAP-positive radial glia and star-shaped Vimentin-positive astrocytes in the high lead group. We consider these findings as indication of immature astrocytes, which are not able to react with gliosis in respond to pre- and postnatal low level lead exposure. The lack of pronounced glial response due to low level lead exposure may result in a delay of astrocytic differentiation, shown by persistence of radial glia.

Animals↗
PubMed1994

Neurobehavioral and neurophysiological observations in six year old children with low lead levels in East and West Germany.

Within a larger comparative environmental health screening program in East and West Germany neurobehavioral and neurophysiological measures were taken in 367 six year old children in Leipzig (N = 179), Gardelegen (N = 68), and Duisburg (N = 120). Lead concentrations from venous blood samples (PbB) and from deciduous teeth (PbT) were measured as markers of environmental lead exposure by electrothermal AAS. Dependent variables included four subtests from NES1 (tapping, reaction time, pattern comparison, and Benton visual retention), as well as VEP-latencies (N2, P100, N3) evoked by checkerboard patterns of different size and contrast. The overall median blood lead-concentration was 5 micrograms/dl (range: 1.3-19.0 micrograms/dl), and the corresponding tooth lead-concentration was 2 micrograms/g (0.2-14 micrograms/g). The 95-percentile of the overall frequency distribution for PbB was below 10 micrograms/dl. Associations between markers of lead-exposure and neurobehavioral or neurophysiological outcome were assessed by means of multiple linear or logistic regression analyses. After adjusting for relevant confounders/covariates significant (p < 0.05) Pb-related deficit was found for tapping and pattern recognition with respect to PbB but not PbT. No such associations could be established for VEP-latencies. These results are compatible with the hypothesis that subtle neurobehavioral dysfunction in children may be associated with very low PbB.

Child↗
PubMed1993

Chronic prenatal and postnatal Pb2+ exposure increases [3H]MK801 binding sites in adult rat forebrain.

We have measured the binding of [3H]MK801 to the N-methyl-D-aspartate (NMDA) receptor-ion channel in membrane preparations from adult rat forebrain exposed to lead (Pb2+) during gestation, lactation, and postweaning. Our results indicate a 30.9% increase in the number of [3H]MK801 binding sites in Pb2+ exposed animals relative to controls. No significant changes in the affinity constant were observed. The level of blood Pb2+ for which such changes were measured was 13.9 +/- 2.8 micrograms/dl. These results indicate that alterations in the NMDA receptor-ion channel complex are present at blood Pb2+ levels which are environmentally relevant and suggest that chronic Pb2+ exposure during development can influence the NMDA receptor complex in the adult rat brain.

Animals↗
PubMed1993

Impairment of long-term potentiation and learning following chronic lead exposure.

Chronic lead exposure during brain development is known to affect functions of the central nervous system. We exposed rats chronically to low levels of lead at different developmental stages in order to determine the most sensitive periods of exposure. Active avoidance learning and hippocampal long-term potentiation were tested in the same animals. If the exposure period comprised the prenatal and the early postnatal phase and was continued into adulthood, learning as well as long-term potentiation were impaired. Starting the exposure not before 16 days postnatally, however, neither affected learning nor hippocampal potentiation. These results reflect the higher vulnerability of the immature as compared to the mature hippocampus to lead-induced functional deficits.

Animals↗
PubMed1992

Structure and determinants of psychophysiological response to odorant/irritant air pollution.

From a psychophysiological point of view, acute effects of indoor air pollution with odorant/irritant properties can be evaluated in terms of sensory/perceptual factors, in terms of objective eye/mucous membrane irritation or systemic responses of the orienting reflex, as well as in terms of either specific or systemic psychological responses. Formaldehyde and hydrogen sulfide are used to illustrate sensory evaluation in terms of detection (absolute thresholds), suprathreshold intensity, and hedonic tone. Dose-response contingencies are exemplified for ETS-induced eye irritation in terms of eyeblinks and lacrymal flow. Orienting responses to odorant stimuli are illustrated using peripheral vasoconstriction and pupil dilation as outcome measures. Specific (descriptive statements and symptoms) as well as systemic psychological responses (annoyance) exhibited clear-cut dose-response association in chamber studies using ETS and hydrogen sulfide exposures. It is, furthermore, shown that environmental annoyance to different environmental stressors exhibits both trait and state characteristics, and that age, perceived health, and (to a smaller degree) gender moderate the response. Based on this information proposals for research needs are given.

Air Pollution↗
PubMed1992

Extrapolation from animals to humans: scientific and regulatory aspects.

The necessity to protect humans from the adverse effects of chemicals on structure and function of the developing and/or mature nervous system is increasingly recognized among regulatory bodies throughout the world. Whereas structural changes dominated much of neurotoxicological research in the past, functional markers of neurotoxicity are gaining acceptance as early signs of insult. Among the more ambitious protective efforts are legal requirements of premarket testing for "behaviour-disrupting properties" of chemicals. Assumed or proven validity of cross species extrapolation underlies the use of animals in primary or secondary screening schemes. Two steps must be distinguished here. The first step is endpoint-base or qualitative, whereas the second one is dose-based or quantitative. Species comparisons in terms of endpoints is typically done within a framework of broad functional categories, such as sensory, motivational, cognitive, motor or social functions. Dose-based extrapolation requires knowledge about species differences in terms of toxicokinetics or metabolism in order to arrive at valid translations of dose-response contingencies. Principles of cross-species extrapolation in neurotoxicology will be exemplified by means of representative neurobehavioural and neurophysiological findings for neurotoxic chemicals of environmental concern, for which an adequate data base is available for comparative purposes, such as inorganic lead and polychlorinated biphenyls (PCB).

Animals↗
PubMed1992

Cross species extrapolation in neurotoxicology: neurophysiological and neurobehavioral aspects.

The theory of phylogenetic continuity of animal species is the basis of any comparative or extrapolative endeavour (Calabrese, 1983). Cross species extrapolation is also a prerequisite for hazard identification in general and developmental neurotoxicology. Two steps must be distinguished: The first step is endpoint-based or qualitative, whereas the second is dose-based or quantitative. Comparison of different species, typically rodents, nonhuman primates and humans, in terms of endpoints is preferentially done within a framework of broad functional categories, such as sensory, motivational, cognitive, motor, and social variables. Within each category specific neurobehavioral as well as electrophysiological measures need to be considered; typically the degree of comparability is higher for electrophysiological than for most behavioral measures. For some frequently used behavioral endpoints in human neurotoxicology, such as psychometric IQ, there is no direct animal counterpart. Once the neural substrate of a particular neurotoxic effect has been identified, as is true for several chemicals such as the pyrethroid insecticides, the organophosphates, most nerve gases or MPTP, or if interspecies comparability in terms of endpoints has proven satisfactory, an effort towards quantitative, dose-based extrapolation is needed. Here species-specific differences in toxicokinetics and metabolism must be taken into consideration in order to arrive at valid translations of dose-response contingencies. If at all possible internal rather than external doses should serve as the frame of reference here. Neurotoxic chemicals of environmental concern for which an adequate data base is available for comparative purposes include alcohol, carbon monoxide, lead, methylmercury and polychlorinated biphenyls (PCB). Principles of cross species extrapolation in neurotoxicology will be illustrated by means of representative neurobehavioral and electrophysiological findings.

Animals↗