Biomedical subjects

V C Moser

Publications and source records attributed to V C Moser.

At least 19 recordsLinked to original sources

PubMed1998

Age- and gender-related differences in the time course of behavioral and biochemical effects produced by oral chlorpyrifos in rats.

It is well known that young animals are generally more sensitive to lethal effects of cholinesterase-inhibiting pesticides, but there are sparse data comparing less-than-lethal effects. We compared the behavioral and biochemical toxicity of chlorpyrifos in young (postnatal Day 17; PND17) and adult (about 70 days old) rats. First, we established that the magnitude of the age-related differences decreased as the rat matures. Next, we evaluated the time course of a single oral dose of chlorpyrifos in adult and PND17 male and female rats. Behavioral changes were assessed using a functional observational battery (with age-appropriate modifications for pre-weanling rats) and an evaluation of motor activity. Cholinesterase (ChE) activity was measured in brain and peripheral tissues and muscarinic receptor binding assays were conducted on selected tissues. Rats received either vehicle (corn oil) or chlorpyrifos (adult dose: 80 mg/kg; PND17 dose: 15 mg/kg); these doses were equally effective in inhibiting ChE. The rats were tested, and tissues were then taken at 1, 2, 3.5, 6.5, 24, 72, 168, or 336 h after dosing. In adult rats, peak behavioral changes and ChE inhibition occurred in males at 3.5 h after dosing, while in females the onset of functional changes was sooner, the time course was more protracted and recovery was slower. In PND17 rats, maximal behavioral effects and ChE inhibition occurred at 6.5 h after dosing, and there were no gender-related differences. Behavioral changes showed partial to full recovery at 24 to 72 h, whereas ChE inhibition recovered markedly slower. Blood and brain ChE activity in young rats had nearly recovered by 1 week after dosing, whereas brain ChE in adults had not recovered at 2 weeks. Muscarinic-receptor binding assays revealed apparent down-regulation in some brain areas, mostly at 24 and 72 h. PND17 rats generally showed more receptor down-regulation than adults, whereas only adult female rats showed receptor changes in striatal tissue that persisted for 2 weeks. Thus, compared to adults (1) PND17 rats show similar behavioral changes and ChE inhibition although at a five-fold lower dose; (2) the onset of maximal effects is somewhat delayed in the young rats; (3) ChE activity tended to recover more quickly in the young rats; (4) young rats appear to have more extensive muscarinic receptor down-regulation, and (5) young rats show no gender-related differences.

Age Factors↗

PubMed1998

Gestational exposure to chlorpyrifos: apparent protection of the fetus?

Previous studies have shown that, in general, young, postnatal animals are more sensitive than adults to the toxic effects of anticholinesterase (antiChE) pesticides. Paradoxically, often fetal brain cholinesterase (ChE) is less inhibited than maternal brain after gestational exposure to an antiChE, presumably due to placental and fetal detoxification of the antiChE. The present investigation was designed to study selected toxicokinetic and toxicodynamic factors surrounding the toxicity of chlorpyrifos (CPF; [O,O'-diethyl O-3,5,6-trichloro-2-pyridyl] phosphorothionate) in pregnant rats dosed repeatedly or singly during late gestation. Dams were dosed daily (po) with CPF in corn oil (0 or 7 mg/kg) on gestational days (GD) 14 to 18. Animals were euthanized at 2 to 120 h after the last dose and tissues were collected for enzyme analysis. Using this dosing regimen, we found that (1) the time of maximal ChE inhibition was the same (i.e., 5-10 h after dosing) for both maternal and fetal brain, (2) the degree of fetal brain ChE inhibition was 4.7 times less than maternal brain inhibition, and (3) the detoxification potential (i.e., carboxylesterase and chlorpyrifos-oxonase) of the fetal tissues was very low compared to the maternal tissues. A separate group of experiments showed that if pregnant dams received only one oral dose of 7 or 10 mg/kg CPF on GD18, the degree of ChE inhibition in the fetal brain was comparable to the maternal brain ChE inhibition. Taking into consideration the net increase (more than fourfold) in fetal brain ChE activity from GD14 to 18 in control animals, and the fact that maternal brain ChE was inhibited more than fetal brain ChE only in a repeated-dosing regimen, we conclude that the fetus is not genuinely protected from the toxic effects of a given dose of CPF. We propose that fetal brain ChE is simply able to recover more fully between each dose as compared to maternal brain ChE, giving the illusion that the fetal compartment is less affected than the maternal compartment.

Animals↗

PubMed1998

Age- and gender-related differences in sensitivity to chlorpyrifos in the rat reflect developmental profiles of esterase activities.

Young rats are more sensitive than adults to a single oral dose of chlorpyrifos, an organophosphorus pesticide. A direct comparison of chlorpyrifos effects in young (postnatal day 17; PND17), adolescent (PND27), and adult (70 days) Long-Evans rats was conducted to determine quantitative and possibly qualitative differences in sensitivity in terms of behavioral changes and cholinesterase (ChE; total cholinesterase activity) inhibition at these three ages. Male and female rats were administered chlorpyrifos orally at one of two doses (PND17, 5 or 20 mg/kg; PND27, 20 or 50 mg/kg; adult, 20 or 80 mg/kg) and tested at either 3.5 or 6.5 h after dosing. Behavioral testing included observational evaluations and measurements of motor activity and was followed immediately by tissue collection for ChE determination in brain and blood. For both behavioral changes and ChE inhibition, peak effects occurred at 3.5 h in adult male and PND27 rats (both sexes) and at 6.5 h in adult female and PND17 rats (both sexes). Comparisons of the 20 mg/kg dose across ages showed generally less ChE inhibition and fewer behavioral effects with increasing age, except that the adult females were similar to the PND27 rats. The high dose used for each age group produced similar brain ChE inhibition (80-90%) and generally similar behavioral effects. Interestingly, a few end-points in the young rats were less affected than in adults at this level of ChE inhibition. The degree of ChE inhibition in the brain more closely paralleled the blood inhibition in the younger rats, compared to the adults. Carboxylesterase (CaE) and A-esterase are known to play an important role in the detoxification of organophosphates and may be partially responsible for these sensitivity differences. Liver and plasma CaE and A-esterase activities were measured in untreated male rats on PND1, 4, 7, 12, 17, and 21 and in adults of both sexes (82-92 days old). Preweanling rats had considerably less activity of both enzymes, and adult females had less liver CaE activity than males. These differences in detoxifying enzymes correlate with the age-related differences in behavioral and biochemical effects, as well as the gender differences seen in adult rats, and thus may be a major influence on the differential sensitivity to chlorpyrifos.

Age Factors↗

PubMed1998

Carbon disulfide neurotoxicity in rats: VII. Behavioral evaluations using a functional observational battery.

The neurobehavioral consequences of inhalational exposure to carbon disulfide (CS2) were evaluated as part of a joint project between the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency. Behavioral changes in rats were measured using a functional observational battery (FOB), which is a series of observations and manipulations designed to assess the neuronal integrity of autonomic, motor, sensory, and integrative functions. Young adult male and female Fischer-344 rats were exposed to one of four CS2 concentrations (0, 50, 500, or 800 ppm, six hours/day, five days/week) and tested at the end of one of several exposure durations (two, four, eight, or 13 weeks). All rats were also tested before exposure began to obtain baseline values. Neuromuscular deficits which were more pronounced in the hindlimbs, e.g., decreased strength and gait alterations, were detected in rats of both sexes. These changes were closely related to CS2 concentration and exposure duration, with mild gait changes evident after only two weeks of exposure. Other effects, mostly observed at 13 weeks, included decreased responsiveness to a visual stimulus and mild tremors. Reactivity in response to handling was generally increased, and excitability in the open field was decreased, in rats tested after the shorter exposures (two and four weeks). Thus, the exposure-concentration and -duration characteristics of the neuromotor syndrome produced by CS2 were detected and defined using the FOB. These studies provide a more complete evaluation of rats under these CS2 exposure conditions, which can then be used to compare with other mechanistic-related endpoints from this collaborative study.

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 effects of perinatal/juvenile methoxychlor exposure on adult rat nervous, immune, and reproductive system function.

In order to address data gaps identified by the NAS report Pesticides in the Diets of Infants and Children, a study was performed using methoxychlor (MXC). Female rats were gavaged with MXC at 0, 5, 50, or 150 mg/kg/day for the week before and the week after birth, whereupon the pups were directly dosed with MXC from postnatal day (pnd) 7. Some dams were killed pnd7 and milk and plasma were assayed for MXC and metabolites. For one cohort of juveniles, treatment stopped at pnd21; a modified functional observational battery was used to assess neurobehavioral changes. Other cohorts of juveniles were dosed until pnd42 and evaluated for changes to the immune system and for reproductive toxicity. Dose-dependent amounts of MXC and metabolites were present in milk and plasma of dams and pups. The high dose of MXC reduced litter size by approximately 17%. Ano-genital distance was unchanged, although vaginal opening was accelerated in all treated groups, and male prepuce separation was delayed at the middle and high doses by 8 and 34 days, respectively. In the neurobehavioral evaluation, high-dose males were more excitable, but other changes were inconsistent and insubstantial. A decrease in the antibody plaque-forming cell response was seen in males only. Adult estrous cyclicity was disrupted at 50 and 150 MXC, doses which also showed reduced rates of pregnancy and delivery. Uterine weights (corrected for pregnancy) were reduced in all treated pregnant females. High-dose males impregnated fewer untreated females; epididymal sperm count and testis weight were reduced at the high, or top two, doses, respectively. All groups of treated females showed uterine dysplasias and less mammary alveolar development; estrous levels of follicle stimulating hormone were lower in all treated groups, and estrus progesterone levels were lower at 50 and 150 MXC, attributed to fewer corpora lutea secondary to ovulation defects. These data collectively show that the primary adult effects of early exposure to MXC are reproductive, show that 5 mg/kg/day is not a NO(A)EL in rats with this exposure paradigm (based on changes in day of vaginal opening, pubertal ovary weights, adult uterine and seminal vesicle weights, and female hormone data) and imply that the sites of action are both central and peripheral.

Animals↗

PubMed1997

The relationship of oral chlorpyrifos effects on behavior, cholinesterase inhibition, and muscarinic receptor density in rat.

Behavioral changes and tissue cholinesterase (ChE) inhibition were examined in animals treated with the commonly used insecticide chlorpyrifos. Adult male rats were dosed by gavage with 0, 10, 30, 60, or 100 mg/kg chlorpyrifos. Rats (n = 20/dose group) were evaluated using a functional observational battery (FOB) and an automated measure of motor activity. All rats were tested the day before dosing and at 3.5 h (the time of peak effect) after dosing; half of these (n = 10/dose) were sacrificed immediately after testing for tissue collection. The remaining rats were tested again at 24 h, followed by sacrifice. The following tissues were collected from each animal: half brain, individual brain areas from the other half of the brain (frontal cortex, hippocampus, striatum, hypothalamus, cerebellum, pons/medulla), retina, liver, heart, diaphragm, quadriceps femoris muscle, and blood (separated into whole blood, plasma, and erythrocytes). ChE activity was measured in all tissues, and muscarinic receptor density was assessed as quinuclidinyl benzilate (QNB) binding in all brain regions, heart, and retina. The lowest dose produced no behavioral effects but did produce significant ChE inhibition in most tissues at 3.5 h. Higher doses produced more ChE inhibition and cholinergic signs of toxicity. Partial recovery from behavioral effects was evident at 24 h, with little or no corresponding recovery of ChE activity. Apparent downregulation of muscarinic receptor density was noted only in striatum and pons/medulla of rats treated with the highest dose of chlorpyrifos. Correlations for behavioral and biochemical effects were generally poor because: a) the low-dose effects on ChE inhibition were not reflected in behavioral signs, and b) behavioral signs showed recovery at 24 h, whereas ChE activity did not. Examination of data for individual rats indicated that > 60% of brain ChE inhibition was reached before neurobehavioral effects were evident.

Animals↗

PubMed1997

Persisting learning deficits in rats after exposure to Pfiesteria piscicida.

Pfiesteria piscicida and other toxic Pfiesteria-like dinoflagellates have been implicated as a cause of fish kills in North Carolina estuaries and elsewhere. Accidental laboratory exposure of humans to P. piscicida has been reported to cause a complex syndrome including cognitive impairment. The current project was conducted to experimentally assess the possibility of cognitive effects of P. piscicida exposure in rats. Samples of water from aquaria in which P. piscicida zoospores were killing fish were frozen, a procedure that has been found to induce encystment. Thawed samples were injected into albino Sprague-Dawley rats. A significant learning impairment was documented in rats administered samples of P. piscicida that were recently frozen. Prolonged storage of Pfiesteria samples diminished the effect. No effect was seen in the recall of a previously learned task, but when the rats were called upon to learn a new task, the Pfiesteria-treated animals showed a significant learning deficit. This effect persisted up to at least 10 weeks after a single injection of Pfiesteria. The Pfiesteria-induced learning deficit did not seem to be associated with any obvious debilitation or health impairment of the exposed rats. Deficits in habituation of arousal and rearing behavior were detected using a functional observational battery. No Pfiesteria-induced effects on blood count and white cell differential or in a standard pathological screening of brain, liver, lung, kidney, and spleen tissue were seen at 2 months after exposure. These studies document a persistent learning impairment in rats after exposure to the dinoflagellate P.piscicida in otherwise physically well-appearing rats. This effect may partially model the symptoms of cognitive impairments that humans have shown after Pfiesteria exposure.

Animals↗

PubMed1997

Tissue-specific effects of chlorpyrifos on carboxylesterase and cholinesterase activity in adult rats: an in vitro and in vivo comparison.

Organophosphate (OP) pesticides can bind to carboxylesterase (CaE), which may lower the concentration of OPs at the target site enzyme, acetylcholinesterase (ChE). It is unclear from the literature whether it is the CaE's affinity for the OP and/or the number of CaE molecules which is the dominant factor in determining the protective potential of CaE. We undertook a detailed, in vitro and in vivo survey of both CaE and ChE to ascertain if in vitro sensitivity of CaE and ChE predicted the pattern of inhibition seen after in vivo dosing with chlorpyrifos (CPF; 80 mg/kg, p.o.) in male or female adult Long-Evans rats. For the brain, the in vitro sensitivity to CPF-oxon did predict the in vivo patterns of inhibition: In vitro, brain ChE was approximately 25 times more sensitive to the active metabolite, CPF-oxon, than brain CaE, and in vivo brain ChE was more inhibited than brain CaE. In contrast, the in vitro sensitivity of plasma ChE and CaE did not correlate well with the in vivo pattern of inhibition: In vitro, plasma ChE was approximately 6.5 times less sensitive to CPF-oxon than plasma CaE, but in vivo, plasma ChE was more inhibited than CaE. In order to understand the role of CaE in protecting the brain ChE from inhibition by CPF-oxon in vitro, adult rat striatal tissue was incubated in the presence and absence of adult rat liver tissue and IC50s of CPF-oxon were determined. The increase in the striatal CPF-oxon IC50 value noted for ChE in the presence of liver suggested that CaE was binding the CPF-oxon and limiting its access to ChE. Male liver CaE, which has the same affinity for binding CPF-oxon as female liver CaE but has twice as many binding sites, caused a greater increase in the striatal CPF-oxon IC50 than female liver, suggesting that the number of binding sites does play a role in the detoxification potential of a tissue. In summary, we found that (1) there are tissue and gender-related differences for basal ChE and CaE activity; (2) the in vitro sensitivity of CaE or ChE to CPF-oxon is highly tissue-specific; (3) the pattern of ChE and CaE inhibition after in vivo dosing with CPF is not necessarily predictable from the in vitro IC50 for these same enzymes, and (4) the number of CaE molecules may play a role in modifying the toxicity of CPF.

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: 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 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

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↗

PubMed1996

Rat strain- and gender-related differences in neurobehavioral screening: acute trimethyltin neurotoxicity.

Trimethyltin (TMT) produces unique pathological and behavioral changes after a single dose. In this study, TMT was used to examine the ability of a neurobehavioral screening battery (functional observational battery and motor activity) to characterize these behavioral changes in rats. The behavioral profile of TMT was obtained using these tests in male Long-Evans (LE) and Fischer 344 (F344) rats, to assess the influence of rat strain, and in LE males and females to evaluate gender-related differences. All rats were tested before dosing and again at 1, 7, 21, and 42 d after a single dose of either 0, 4, 6, or 8 mg/kg TMT-hydroxide (intravenously). In general, the characteristic syndrome of tremor, increased reactivity, and hyperactivity was observed; however, the magnitude and time course of these effects were much greater in F344 rats. Significant strain- but not gender-related differences were obtained when comparing TMT effects on different domains of neurological function. Comparisons of predosing data between male LE and F344 rats, as well as between male and female LE rats, revealed significant differences in baseline values for about half of the measures of the test battery. These preexisting differences, however, could not account for the observed dissimilarities in treatment effects. Quantitative and qualitative differences were evident to a greater extent when comparing LEs and F344s than between males and females. Therefore, conclusions based on these types of neurobehavioral screening data would be influenced considerably more by the differences between rat strains.

Analysis of Variance↗