Biomedical subjects

K L McDaniel

Publications and source records attributed to K L McDaniel.

10 recordsLinked to original sources

PubMed2001

Dopamine transporter binding in the rat striatum is increased by gestational, perinatal, and adolescent exposure to heptachlor.

Heptachlor is a persistent cyclodiene pesticide that affects GABAergic function. Recent reports indicate that heptachlor exposure also alters dopamine transporter (DAT) expression and function in adult mice. The aim of this study was to determine whether gestational, perinatal, and/or adolescent heptachlor exposure in rats altered dopamine-receptor and DAT binding. Adolescent exposure to dieldrin was included to evaluate the generality of the findings. Sprague-Dawley rats received doses (po) ranging from 0 to 8.4 mg/kg/day of heptachlor, or dieldrin, 3 mg/kg/day, during different developmental periods. There were dose-related decreases in maternal weight gain and pup survival, as well as delayed righting reflex, at heptachlor doses > or =3 mg/kg/day. There were no changes in striatal dopamine receptor-D1 ([(3)H]SCH-23390) and -D2 ([(3)H]spiperone) binding in preweanling pups exposed perinatally to heptachlor, and no differences in the response of adult rats to the motor activity-increasing effects of d-amphetamine. However, there were significant (27-64%) increases in striatal DAT binding of [(3)H]mazindol in preweanling rats exposed only gestationally. In rats exposed perinatally and/or during adolescence, there were also increases (34-65%) in striatal DAT binding at postnatal days (PND) 22, 43, and 128. Adolescent exposure to dieldrin also increased DAT binding. In other rats exposed perinatally and throughout adolescence, even the lowest dose of heptachlor 0.3 mg/kg/d increased DAT binding on PND 130. The DAT affinity for mazindol was unchanged in heptachlor-exposed striata. In vitro binding studies indicated that heptachlor (> or =10 microM) displaced mazindol binding. Thus, gestational, perinatal, and/or adolescent exposure to heptachlor produced an increase in DAT binding as early as PND 10, and this change persisted into adulthood.

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: VI. Agreement and reliability of the data.

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. The effects of seven chemicals (acrylamide, bis-acrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin) were studied during two dosing regimens: single-dose and four-week repeated dosing. All participating laboratories generally could detect and characterize the effects of known neurotoxicants, even though there were some differences in outcome on specific endpoints. The results were further evaluated to assess the agreement across laboratories in the dose-response data at the expected times of maximal effect (time of peak effect for the single-dose studies, and during or at the end of dosing for repeated-exposure studies). Percent agreement was calculated as the percentage of laboratories agreeing on an outcome (whether it be a significant dose effect or not). As an alternative approach, slopes of the dose-response functions were calculated, and reliability of those slope estimates across laboratories and chemicals was determined. Reliability was defined as the degree of agreement across laboratories (intraclass correlation coefficient) of the dose-response slopes within and between chemicals. These reliability estimates were calculated for each domain and for each endpoint. Relative reliability of the endpoints was evaluated, and hypotheses concerning the influence of outlying data were tested. The data clearly showed that reliability was not influenced by the objectivity or subjectivity of the test measure. Thus these data provide additional information regarding the reliability and robustness of the tests across the participating laboratories.

Animals↗

PubMed1997

The influence of dosing volume on the toxicity of p,p'-DDT.

In the IPCS Collaborative Study on Neurobehavioral Screening Methods, the "Top Dose" (TD) of p,p'-DDT (oral gavage, in corn oil) was determined to be different depending on the volume of administration: TD = 87 mg/kg when delivered in 1 ml/kg (i.e., 87 mg/ml) vs. TD = 130.5 mg/kg when given at 5 ml/kg (26.1 mg/ml). Two acute dose-response studies were conducted, the only difference being the doses used (pre-established percentages of the TD) and dosing volume (1 and 5 ml/kg); a third study was conducted using a single dose and varying the dosing volume (1 and 5 ml/kg). In the higher-volume study, dose-response curves for almost all the affected endpoints were shifted to the right, and the effects of the highest dose were less severe compared to the lower-volume study. For example, tremors were observed in all rats dosed with 43.5 mg/kg at 1 ml/kg, but only in 40% of the dose group given 65.3 mg/kg at 5 ml/kg. The highest dose groups (100% TD) showed myoclonus in both studies, but the incidence was 100% at 87 mg/kg (1 ml/kg) compared to 60% at 130.5 mg/kg (5 ml/kg). The dose-response curves indicated that the effective doses were generally 2-5 times higher, i.e., less potent, using a volume of 5 ml/kg. In general, the profiles of effect were similar in that the Sensorimotor and Convulsive domains were significantly altered in both studies, but again the dose-response curves were shifted; these domains were affected by both 43.5 and 87 mg/kg at 1 ml/kg, but only by 130.5 mg/kg at 5 ml/kg. The Neuromuscular domain, however, was only affected in the 1 ml/kg study (at 87 mg/kg). These differences in outcome could be due to higher partitioning of DDT into the oil, or increased gut motility, both of which could be due to the larger volume of oil delivered. The findings illustrate the importance of knowing the pharmacokinetic properties of the compound in question, as well as standardization of such variables whenever direct comparisons of dose levels are conducted.

Animals↗

PubMed1991

Rat strain and stock comparisons using a functional observational battery: baseline values and effects of amitraz.

A functional observational battery (FOB) was utilized to assess the effects of 3-day exposure to the formamidine pesticide amitraz in outbred Sprague-Dawley-derived and inbred Fischer-344-derived (F344) rats (both from Charles River Laboratories) and in outbred Long-Evans rats obtained from two commercial suppliers (Charles River Breeding Laboratories and Blue Spruce Farms). Significant strain and stock differences were obtained in baseline values for one-third of the FOB measures. In most cases, F344 rats were different from the others. Characteristic signs of amitraz exposure consisting of increased excitability, hyper-reactivity, and physiological and autonomic changes were evident in all treated rats. These effects increased with repeated dosing, and many were still present 6 days after dosing. On individual measures, there were differences between the strains and stocks in terms of sensitivity and time course of amitraz effects. In general, Blue Spruce Long-Evans rats displayed more effects of amitraz and F344 rats recovered more quickly than others. Although Sprague-Dawley rats showed the least effect overall, they displayed the largest increases in the sensorimotor responses to stimuli. These data indicate that although some behavioral and physiological parameters showed strain and supplier differences, in both baseline values and the effects of amitraz, conclusions concerning its neurotoxic potential in a screening context would be similar.

Animals↗

PubMed1990

Microinjection of dynorphin into the hippocampus impairs spatial learning in rats.

The effect of hippocampal dynorphin administration on learning and memory was examined in spatial and nonspatial tasks. Bilateral infusion of dynorphin A(1-8) (DYN; 10 or 20 micrograms in one microliters) into the dorsal hippocampus resulted in a dose-related impairment of spatial working memory in a radial maze win-stay task. Subsequent experiments found that acquisition of a reference memory task in the water maze was impaired by DYN injections (20 micrograms/microliters) in the dorsal hippocampus, but not in the ventral hippocampus, and that this impairment could be blocked by naloxone. In a nonspatial task, posttraining DYN injections in the dorsal hippocampus had no effect on retention of step-through passive avoidance. These results suggest that dynorphin specifically interferes with spatial learning and memory, and that this effect is mediated by opioid receptors in the dorsal hippocampus.

Animals↗

PubMedDate not supplied

Utility of a neurobehavioral screening battery for differentiating the effects of two pyrethroids, permethrin and cypermethrin.

The ability of a neurobehavioral screening battery to differentiate the effects of two pyrethroids, permethrin and cypermethrin, was assessed in this experiment. Although the structures of these pesticides differ only in the alpha-cyano group, the behavioral syndromes associated with the Type I and II pyrethroids are quite different. The tests included a functional observational battery which is a series of subjective and quantitative measures of neurological function and behavior, and an automated measure of motor activity. Our results verified previous reports in the literature describing these different syndromes, i.e., aggressive sparring behavior, fine to whole-body tremor, hyperthermia, and decreased motor activity for the Type I pyrethroid permethrin, and pawing, burrowing, salivation, whole body tremor to choreoathetosis, hypothermia, and lowered motor activity for the Type II pyrethroid cypermethrin. In addition, we report that permethrin produced decreased grip strengths, increased resistance to capture, increased reactivity to a click stimulus, and induced head and forelimb shaking and agitated behaviors, whereas cypermethrin produced pronounced neuromuscular weakness and equilibrium changes, retropulsion, lateral head movements, alterations in responses to various stimuli, and increased urination. Although there were similarities in some effects (e.g., decreased motor activity), the pesticides differed sufficiently in their overall behavioral profiles, and severity and time course of effects, to discriminate these two compounds. Thus, this type of screening approach is sensitive enough to differentiate these pyrethroids for hazard identification purposes.

Animals↗

PubMedDate not supplied

Behavioral evaluation of the neurotoxicity produced by dichloroacetic acid in rats.

Dichloroacetic acid (DCA) is commonly found in drinking water as a by-product of chlorination disinfection. It is a known neurotoxicant in rats, dogs, and humans. We have characterized DCA neurotoxicity in rats using a neurobehavioral screening battery under varying exposure durations (acute, subchronic, and chronic) and routes of administration (oral gavage and drinking water). Studies were conducted in both weanling and adult rats, and comparisons were made between Long-Evans and Fischer-344 rats. DCA produced neuromuscular toxicity comprised of limb weakness and deficits in gait and righting reflex; altered gait and decreased hindlimb grip strength were the earliest indicators of toxicity. Other effects included mild tremors, ocular abnormalities, and a unique chest-clasping response (seen in Fischer-344 rats only). Neurotoxicity was permanent (i.e., through 2 years) following a 6-month exposure to high dose levels, whereas the effects of intermediate dose levels with exposures of 3 months or less were slowly reversible. The severity, specificity, and recovery of neurological changes were route, duration, and strain dependent. Fischer-344 rats were more sensitive than Long-Evans rats, and weanling rats may be somewhat more sensitive than adults. Oral gavage produced significantly less toxicity compared to the same intake level received in drinking water. Neurotoxicity was progressive with continued exposure, and was observed at exposure levels as low as 16 mg/kg/day (lowest dose level tested) when administered via drinking water in subchronic studies. The data from these studies characterize the neurotoxicity produced by DCA, and show it to be more pronounced, persistent, and occurring at lower exposures than has been previously reported. Further research should take into account these marked route, age, and strain differences.

Administration, Oral↗