MacPhail RC

References (14)

Title : Carbaryl and 1-naphthol tissue levels and related cholinesterase inhibition in male brown norway rats from preweaning to senescence - Moser_2013_J.Toxicol.Environ.Health.A_76_1151
Author(s) : Moser VC , Phillips PM , McDaniel KL , Zehr RD , Macmillan DK , MacPhail RC
Ref : J Toxicol Environ Health A , 76 :1151 , 2013
Abstract : Studies incorporating both toxicokinetic and dynamic factors provide insight into chemical sensitivity differences across the life span. Tissue (brain, plasma, liver) levels of the N-methyl carbamate carbaryl, and its metabolite 1-naphthol, were determined and related to brain and RBC cholinesterase (ChE) inhibition in the same animals. Dose-response (3, 7.5, 15, or 22.5 mg/kg, 40-45 min postdosing) and time course (3 or 15 mg/kg at 30, 60, 120, or 240 min postdosing) of acute effects of carbaryl (oral gavage) in preweanling (postnatal day [PND] 18) and adult male Brown Norway rats from adolescence to senescence (1, 4, 12, 24 mo) were compared. At all ages there were dose-related increases in carbaryl and 1-naphthol in the dose-response study, and the time-course study showed highest carbaryl levels at 30 min postdosing. There were, however, age-related differences in that the 1- and 4-mo rats showed the lowest levels of carbaryl and 1-naphthol, and PND18 and 24-mo rats had similar, higher levels. The fastest clearance (shortest half-lives) was observed in 1- and 4-mo rats. Carbaryl levels were generally higher than 1-naphthol in brain and plasma, but in liver, 1-naphthol levels were similar to or greater than carbaryl. Brain ChE inhibition closely tracked brain carbaryl concentrations regardless of the time after dosing, but there was more variability in the relationship between RBC ChE and plasma carbaryl levels. Within-subject analyses suggested somewhat more brain ChE inhibition at lower carbaryl levels only in the PND18 rats. These findings may reflect maturation followed by decline in kinetic factors over the life span.
ESTHER : Moser_2013_J.Toxicol.Environ.Health.A_76_1151
PubMedSearch : Moser_2013_J.Toxicol.Environ.Health.A_76_1151
PubMedID: 24279816

Title : Acute administration of dopaminergic drugs has differential effects on locomotion in larval zebrafish - Irons_2013_Pharmacol.Biochem.Behav_103_792
Author(s) : Irons TD , Kelly PE , Hunter DL , MacPhail RC , Padilla S
Ref : Pharmacol Biochem Behav , 103 :792 , 2013
Abstract : Altered dopaminergic signaling causes behavioral changes in mammals. In general, dopaminergic receptor agonists increase locomotor activity, while antagonists decrease locomotor activity. In order to determine if zebrafish (a model organism becoming popular in pharmacology and toxicology) respond similarly, the acute effects of drugs known to target dopaminergic receptors in mammals were assessed in zebrafish larvae. Larvae were maintained in 96-well microtiter plates (1 larva/well). Non-lethal concentrations (0.2-50 muM) of dopaminergic agonists (apomorphine, SKF-38393, and quinpirole) and antagonists (butaclamol, SCH-23390, and haloperidol) were administered at 6 days post-fertilization (dpf). An initial experiment identified the time of peak effect of each drug (20-260 min post-dosing, depending on the drug). Locomotor activity was then assessed for 70 min in alternating light and dark at the time of peak effect for each drug to delineate dose-dependent effects. All drugs altered larval locomotion in a dose-dependent manner. Both the D1- and D2-like selective agonists (SKF-38393 and quinpirole, respectively) increased activity, while the selective antagonists (SCH-23390 and haloperidol, respectively) decreased activity. Both selective antagonists also blunted the response of the larvae to changes in lighting conditions at higher doses. The nonselective drugs had biphasic effects on locomotor activity: apomorphine increased activity at the low dose and at high doses, while butaclamol increased activity at low to intermediate doses, and decreased activity at high doses. This study demonstrates that (1) larval zebrafish locomotion can be altered by dopamine receptor agonists and antagonists, (2) receptor agonists and antagonists generally have opposite effects, and (3) drugs that target dopaminergic receptors in mammals appear, in general, to elicit similar locomotor responses in zebrafish larvae.
ESTHER : Irons_2013_Pharmacol.Biochem.Behav_103_792
PubMedSearch : Irons_2013_Pharmacol.Biochem.Behav_103_792
PubMedID: 23274813

Title : Rearing conditions differentially affect the locomotor behavior of larval zebrafish, but not their response to valproate-induced developmental neurotoxicity - Zellner_2011_Neurotoxicol.Teratol_33_674
Author(s) : Zellner D , Padnos B , Hunter DL , MacPhail RC , Padilla S
Ref : Neurotoxicology & Teratology , 33 :674 , 2011
Abstract : Zebrafish (Danio rerio) are widely used in developmental research, but still not much is known about the role of the environment in their development. Zebrafish are a highly social organism; thus exposure to, or isolation from, social environments may have profound developmental effects. Details of rearing conditions are often sparse in the zebrafish literature. This study compared (1) the activity of larval zebrafish that were raised individually vs in groups, and (2) the effect of the developmental neurotoxicant valproate. We randomly assigned embryos to single- or group-reared social environments from 0 to 5days post fertilization (dpf), while treating them with or without valproate (final concentration 48muM) from 0 to 2dpf, resulting in a total of four groups (group control, group treated, single control, single treated). At 5dpf all embryos were transferred to singly-housed environments where they remained for locomotor activity testing (alternating periods of light and dark) conducted on day 6. Larvae that had been reared in groups had higher levels of activity in the dark period compared to larvae that had been raised individually. Valproate increased activity in both the singly-reared and group-reared larvae during periods of darkness but not light. Further analyses of dark activity indicated that rearing condition did not differentially affect larval responses to valproate. These results indicate that rearing conditions affected the locomotion of zebrafish larvae, but did not alter the effect of the developmental neurotoxicant valproate.
ESTHER : Zellner_2011_Neurotoxicol.Teratol_33_674
PubMedSearch : Zellner_2011_Neurotoxicol.Teratol_33_674
PubMedID: 21767635

Title : Assessing locomotor activity in larval zebrafish: Influence of extrinsic and intrinsic variables - Padilla_2011_Neurotoxicol.Teratol_33_624
Author(s) : Padilla S , Hunter DL , Padnos B , Frady S , MacPhail RC
Ref : Neurotoxicology & Teratology , 33 :624 , 2011
Abstract : The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. We are exploring methods to detect developmentally neurotoxic chemicals using zebrafish behavior at 6 days of age. The behavioral paradigm simultaneously tests individual larval zebrafish under both light and dark conditions in a 96-well plate using a video tracking system. We have found that many variables affect the level or pattern of locomotor activity, including age of the larvae, size of the well, and the presence of malformations. Some other variables, however, do not appear to affect larval behavior including type of rearing solution (10% Hank's vs. 1:3 Danieau vs 60 mg/kg Instant Ocean vs 1x and 1:10x EPA Moderately Hard Water). Zebrafish larval behavior using a microtiter plate format may be an ideal endpoint for screening developmentally neurotoxic chemicals, but it is imperative that many test variables be carefully specified and controlled.
ESTHER : Padilla_2011_Neurotoxicol.Teratol_33_624
PubMedSearch : Padilla_2011_Neurotoxicol.Teratol_33_624
PubMedID: 21871562

Title : The dynamics of successive induction in larval zebrafish - Staddon_2010_J.Exp.Anal.Behav_94_261
Author(s) : Staddon JE , MacPhail RC , Padilla S
Ref : J Exp Anal Behav , 94 :261 , 2010
Abstract : Charles Sherrington identified the properties of the synapse by purely behavioral means-the study of reflexes-more than 100 years ago. They were subsequently confirmed neurophysiologically. Studying reflex interaction, he also showed that activating one reflex often facilitates another, antagonistic one: successive induction, which has since been demonstrated in a wide range of species, from aphids to locusts to dogs and humans. We show a particularly orderly example in zebrafish (Danio rerio) larvae; the behavior (locomotion) of larvae is low in dark and intermediate in light, but low in light and substantially higher in dark when dark followed light. A quantitative model of a simple dynamic process is described that readily captures the behavior pattern and the effects of a number of manipulations of lighting conditions.
ESTHER : Staddon_2010_J.Exp.Anal.Behav_94_261
PubMedSearch : Staddon_2010_J.Exp.Anal.Behav_94_261
PubMedID: 21451752

Title : Acute neuroactive drug exposures alter locomotor activity in larval zebrafish - Irons_2010_Neurotoxicol.Teratol_32_84
Author(s) : Irons TD , MacPhail RC , Hunter DL , Padilla S
Ref : Neurotoxicology & Teratology , 32 :84 , 2010
Abstract : As part of the development of a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae by assessing the acute effects of prototypic drugs that act on the central nervous system. Initially, we chose ethanol, d-amphetamine, and cocaine, which are known, in mammals, to increase locomotion at low doses and decrease locomotion at higher doses. Wild-type larvae were individually maintained in 96-well microtiter plates at 26 degrees C, under a 14:10 h light:dark cycle, with lights on at 0830 h. At 6 days post-fertilization, ethanol (1-4% v/v), d-amphetamine sulfate (0.1-20.0 microM) or cocaine hydrochloride (0.2-50.0 microM) were administered to the larvae by immersion. Beginning 20 min into the exposure, locomotion was assessed for each animal for 70 min using 10-minute, alternating light (visible light) and dark (infrared light) periods. Low concentrations of ethanol and d-amphetamine increased activity, while higher concentrations of all three drugs decreased activity. Because ethanol effects occurred predominately during the light periods, whereas the d-amphetamine and cocaine effects occurred during the dark periods, alternating lighting conditions proved to be advantageous. These results indicate that zebrafish larvae are sensitive to neuroactive drugs, and their locomotor response is similar to that of mammals.
ESTHER : Irons_2010_Neurotoxicol.Teratol_32_84
PubMedSearch : Irons_2010_Neurotoxicol.Teratol_32_84
PubMedID: 19465114

Title : Locomotion in larval zebrafish: Influence of time of day, lighting and ethanol - MacPhail_2009_Neurotoxicol_30_52
Author(s) : MacPhail RC , Brooks J , Hunter DL , Padnos B , Irons TD , Padilla S
Ref : Neurotoxicology , 30 :52 , 2009
Abstract : The increasing use of zebrafish (Danio rerio) in developmental research highlights the need for a detailed understanding of their behavior. We studied the locomotion of individual zebrafish larva (6 days post-fertilization) in 96-well microtiter plates. Movement was recorded using a video-tracking system. Time of day results indicated locomotion, tested in darkness (infrared), decreased gradually from early morning to a stable level between 13:00 and 15:30 h. All further studies were conducted in early-to-late afternoon and lasted approximately 1 h. Each study also began with a period of darkness to minimize any unintended stimulation caused by transferring the plates to the recording platform. Locomotion in darkness increased initially to a maximum at 4 min, then decreased steadily to a low level by 20 min. Locomotion during light was initially low and then gradually increased to a stable level after 20 min. When 10-min periods of light and dark were alternated, activity was low in light and high in dark; curiously, activity during alternating dark periods was markedly higher than originally obtained during either extended dark or light. Further experiments explored the variables influencing this alternating pattern of activity. Varying the duration of the initial dark period (10-20 min) did not affect subsequent activity in either light or dark. The activity increase on return to dark was, however, greater following 15 min than 5 min of light. Acute ethanol increased activity at 1 and 2% and severely decreased activity at 4%. One-percent ethanol retarded the transition in activity from dark to light, and the habituation of activity in dark, while 2% ethanol increased activity regardless of lighting condition. Collectively, these results show that locomotion in larval zebrafish can be reliably measured in a 96-well microtiter plate format, and is sensitive to time of day, lighting conditions, and ethanol.
ESTHER : MacPhail_2009_Neurotoxicol_30_52
PubMedSearch : MacPhail_2009_Neurotoxicol_30_52
PubMedID: 18952124

Title : A randomization test-based method for risk assessment in neurotoxicology - Bogdan_2001_Risk.Anal_21_107
Author(s) : Bogdan MA , MacPhail RC , Glowa JR
Ref : Risk Anal , 21 :107 , 2001
Abstract : A current trend in risk assessment for systemic toxicity (noncancer) endpoints is to utilize the observable range of the dose-effect curve in order to estimate the likelihood of obtaining effects at lower concentrations. Methods to accomplish this endeavor are typically based on variability in either the effects of fixed doses (benchmark approaches), or on variability in the doses producing a fixed effect (probabilistic or tolerance-distribution approaches). The latter method may be particularly desirable because it can be used to determine variability in the effect of an agent in a population, which is an important goal of risk assessment. This method of analysis, however, has typically been accomplished using dose-effect data from individual subjects, which can be impractical in toxicology. A new method is therefore presented that can use traditional groups-design data to generate a set of dose-effect functions. Population tolerances for a specific effect can then be estimated from these model dose-effect functions. It is based on the randomization test, which assesses the generality of a data set by comparing it to a data set constructed from randomized combinations of single point estimates. The present article describes an iterative line-fitting program that generates such a data set and then uses it to provide risk assessments for two pesticides, triadimefon and carbaryl. The effects of these pesticides were studied on the locomotor activity of laboratory rats, a common neurobehavioral end point. Triadimefon produced dose-dependent increases in activity, while carbaryl produced dose-dependent decreases in activity. Risk figures derived from the empirical distribution of individual dose-effect functions were compared to those from the iterative line-fitting program. The results indicate that the method generates comparable risk figures, although potential limitations are also described.
ESTHER : Bogdan_2001_Risk.Anal_21_107
PubMedSearch : Bogdan_2001_Risk.Anal_21_107
PubMedID: 11332540

Title : Episodic exposures to chemicals: what relevance to chemical intolerance? - MacPhail_2001_Ann.N.Y.Acad.Sci_933_103
Author(s) : MacPhail RC
Ref : Annals of the New York Academy of Sciences , 933 :103 , 2001
Abstract : Episodic exposures refer to intermittent acute exposures to chemicals that ordinarily have a rapid onset and short duration of effect. There has been a long tradition in preclinical behavioral pharmacology of using episodic-exposure paradigms in order to establish dose-response functions in individual organisms. In these experiments, stable baselines of behavior are first established and then followed by administering varying doses of a drug intermittently, for example, once or twice a week. The power of this approach is well established; the within-subjects design reduces error variance, allows exploration of the entire range of effective doses, and can be used to identify individual differences in drug sensitivity. Of course, the approach is only applicable to reversibly acting compounds, and checks need to be included to insure effects of one dose are not influenced by prior exposure to another dose. We have used baseline approaches to evaluate the effects of pesticides and solvents on the behavior of adult male rats and mice. Moreover, a novel probabilistic dose-tolerance analysis applied to the data suggests substantial individual differences in chemical sensitivity, often spanning orders of magnitude. These results suggest that individual differences in chemical sensitivity may be much greater than previously acknowledged.
ESTHER : MacPhail_2001_Ann.N.Y.Acad.Sci_933_103
PubMedSearch : MacPhail_2001_Ann.N.Y.Acad.Sci_933_103
PubMedID: 12000013

Title : Chlorpyrifos produces selective learning deficits in rats working under a schedule of repeated acquisition and performance - Cohn_1997_J.Pharmacol.Exp.Ther_283_312
Author(s) : Cohn J , MacPhail RC
Ref : Journal of Pharmacology & Experimental Therapeutics , 283 :312 , 1997
Abstract : Chlorpyrifos (CPF) is a cholinesterase-inhibiting organophosphate pesticide used extensively to treat crops and domestic animals. Two experiments determined the effects of acute and repeated CPF exposure on the acquisition and performance of response sequences. Adult male Long-Evans rats (n = 16), maintained at 300 g body weight were trained using food reinforcement under a multiple schedule of repeated acquisition (RA) and performance (P). The RA component required completion of a four-response sequence on three levers (e.g., center, right, left, right) that changed with each session, while the correct sequence in the P component was invariant. In experiment I, rats were orally administered vehicle (corn oil), 12.5, 25, 37.5 and 50 mg/kg CPF. Doses of 37.5 and 50 mg/kg produced greater accuracy decreases in RA than in P, suggesting a selective learning deficit. In experiment II, the rats were divided into two groups (n = 7), and received either vehicle or 12.5 mg/kg CPF, 5 day/wk, for 8 wk. Although 12.5 mg/kg CPF was barely effective when administered acutely, when administered repeatedly it initially decreased accuracy in both RA and P. Tolerance developed to CPF effects on P accuracy but not on RA accuracy. Microanalyses of response patterns indicated the most common type of error was a progression through the sequence as if incorrect responses were actually correct. Radiometric analyses of serum cholinesterase activity showed CPF produced 90% inhibition at 3 hr and 85% inhibition at 24 hr postexposure. These results show that both acute and repeated CPF produced a selective deficit in the learning of response sequences in rats. This selectivity was most clearly expressed through the development of tolerance to the disruptive effects of repeated CPF on the performance but not the learning of response sequences.
ESTHER : Cohn_1997_J.Pharmacol.Exp.Ther_283_312
PubMedSearch : Cohn_1997_J.Pharmacol.Exp.Ther_283_312
PubMedID: 9336338

Title : The impact of dose rate on the neurotoxicity of acrylamide: the interaction of administered dose, target tissue concentrations, tissue damage, and functional effects - Crofton_1996_Toxicol.Appl.Pharmacol_139_163
Author(s) : Crofton KM , Padilla S , Tilson HA , Anthony DC , Raymer JH , MacPhail RC
Ref : Toxicol Appl Pharmacol , 139 :163 , 1996
Abstract : Health agencies are often required to predict the effects of long term low level exposure in humans based on annual data involving short-term high-level exposures. Uncertainties in extrapolation can be, in part, based on potentially different mechanism associated with different exposure scenarios. This study evaluated the adequacy of short-term exposures to acrylamide for predicting neurotoxicity produced by long-term exposures. The neurotoxic effects of acrylamide (ip) were assessed in rats after acute (0-150 mg/kg), 10-day (0-30 mg/kg), 30-day (0-20 mg/kg), and 90-day (0-10 mg/kg) exposures. Behavioral endpoints included motor activity, grip strength, and the acoustic startle response. Histological examination of sciatic nerve and spinal cord was also performed. Internal and target tissue doses were estimated by measurement of the concentration of acrylamide in serum and sciatic nerve. Functional and pathological results demonstrated that the effects of acrylamide depended on the dose rate and that the neurotoxicity of acrylamide was less than that predicted by a strict dose x time relationship. Behavioral endpoints showed both qualitative and quantitative changes as a function of dose rate. Recovery of behavioral function in these studies was independent of the duration of dosing. Because duration of dosing had no impact on the kinetics of acrylamide, these data indicate that the toxicity of acrylamide is not due to an accumulation of acrylamide in the target tissue. The less than strict cumulative toxicity of acrylamide may result from an interaction between administered dose, tissue damage, and repair processes.
ESTHER : Crofton_1996_Toxicol.Appl.Pharmacol_139_163
PubMedSearch : Crofton_1996_Toxicol.Appl.Pharmacol_139_163
PubMedID: 8685900

Title : Determination of acrylamide in rat serum and sciatic nerve by gas chromatography-electron-capture detection - Raymer_1993_J.Chromatogr_619_223
Author(s) : Raymer JH , Sparacino CM , Velez GR , Padilla S , MacPhail RC , Crofton KM
Ref : Journal of Chromatography , 619 :223 , 1993
Abstract : A modified method for the derivatization and determination of acrylamide as 2-bromopropenamide by gas chromatography-electron-capture detection was developed and applied to serum and sciatic nerve from rats. The method was accurate and precise over the calibration range 2.24-7.47 micrograms/ml in serum diluted 1:125 and 4-122 micrograms/g in sciatic nerve homogenate (5 mg/ml). limits of detection were estimated to be 1200 ng/ml in undiluted serum and 3 micrograms/g in intact sciatic nerve. The use of less dilute samples to allow for lower limits of detection appears feasible. The time-course of acrylamide in serum and sciatic nerve was studied after acute dosing and indicated elimination half-lives of 1.8 and 2.0 h for serum and sciatic nerve, respectively. A dose-effect relationship was established for each matrix after acute dosing and the measured acrylamide concentrations in serum (microgram/ml) were approximately the same as in sciatic nerve (microgram/g).
ESTHER : Raymer_1993_J.Chromatogr_619_223
PubMedSearch : Raymer_1993_J.Chromatogr_619_223
PubMedID: 8263094

Title : Strain comparisons of DFP neurotoxicity in rats - Gordon_1993_J.Toxicol.Env.Health_38_257
Author(s) : Gordon CJ , MacPhail RC
Ref : Journal of Toxicology & Environmental Health , 38 :257 , 1993
Abstract : The purpose of this study was to assess intraspecies differences in behavioral and autonomic function in three strains of rat following administration of diisopropyl fluorophosphate (DFP), an irreversible inhibitor of acetylcholinesterase activity. Male rats of the Long-Evans (LE), Fischer 344 (F344), and Sprague-Dawley (SD) strains wer administered DFP at doses of 0-1.5 mg/kg (sc). The animals were placed 60 min later into one of two motor activity chambers and tested for 30 min. Motor activity was measured using either a Doppler-based system or a commercial photocell device. Following measurement of motor activity in the Doppler system, body temperature (Tb) was measured and blood was then withdrawn by cardiac puncture and analyzed for serum cholinesterase activity (ChE). The remaining rats were retested 1 d after DFP administration in the photocell device. The results showed a significant influence of strain on the effects of DFP. Motor activity of LE rats was reduced by DFP at doses of 1.0 and 1.5 mg/kg, whereas the activity of F344 rats was reduced only at 1.5 mg/kg. The relative sensitivity of SD rats depended on the device used to measure motor activity. The SD rats resembled F344 rats in their response to DFP when motor activity was measured in the photocell device, and LE rats when motor activity was measured in the Doppler system. The Tb of F344 rats was unaffected by DFP, while the LE and SD rats became hypothermic at 1.5 mg/kg. The DFP-induced inhibition of serum ChE activity was significantly less in F344 rats. All three strains retested the day after DFP still showed significant decreases in motor activity. Overall, it appears that the F344 strain is relatively resistant to the behavioral and autonomic effects of DFP. This intraspecies variability should be considered in selecting appropriate experimental models for assessing the neurotoxicological hazards of cholinesterase-inhibiting pesticides.
ESTHER : Gordon_1993_J.Toxicol.Env.Health_38_257
PubMedSearch : Gordon_1993_J.Toxicol.Env.Health_38_257
PubMedID: 8450557

Title : Cholinergic involvement in the action of formetanate on operant behavior in rats - Moser_1987_Pharmacol.Biochem.Behav_26_119
Author(s) : Moser VC , MacPhail RC
Ref : Pharmacol Biochem Behav , 26 :119 , 1987
Abstract : Formetanate (FMT) is a formamidine acaricide/insecticide with a carbamate moiety in its molecular structure. FMT-induced lethality is reportedly due to inhibition of acetylcholinesterase. Here we report evidence of the neurochemical basis for the sublethal, behavioral effects of FMT in rats. In this experiment, 0.5 mg/kg of FMT (5 min before the 55-min test session) produced a pronounced suppression of response rates in rats trained to lever-press under a multiple fixed-interval 1-min fixed-interval 5-min schedule of milk reinforcement. Injections of scopolamine (0.1 mg/kg) and methylscopolamine (0.1 mg/kg) 15 min before FMT blocked the response rate suppression, whereas pretreatment with either mecamylamine (2 mg/kg) or hexamethonium (2 mg/kg) did not. These data suggest that FMT acts as an indirect agonist on central and peripheral muscarinic receptors, by inhibiting acetylcholinesterase, to produce changes in schedule-controlled responding.
ESTHER : Moser_1987_Pharmacol.Biochem.Behav_26_119
PubMedSearch : Moser_1987_Pharmacol.Biochem.Behav_26_119
PubMedID: 3562483