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Biomedical subjects

V C Moser

Publications and source records attributed to V C Moser.

At least 73 records · Page 4Linked to original sources
PubMed1985

Effects of toluene, halothane and ethanol vapor on fixed-ratio performance in mice.

The behavioral effects of inhalation of the vapors of volatile compounds representative of different chemical groups were studied in mice under conditions where behavior and exposure concentrations could be concurrently monitored. The magnitude and time course of the effects of toluene, halothane and ethanol inhalation on fixed-ratio (FR) responding were compared. The subjects were trained to lever-press under a FR-100 schedule of water reinforcement. Daily operant sessions took place in the exposure chambers, and solvent exposures were conducted once a week. The test exposures lasted for 20 min, and the sessions continued until the subjects resumed baseline rates of responding to give a measure of recovery. All solvents produced concentration-dependent response rate decreases, and only halothane showed any evidence of response rate increases at low concentrations. Halothane quickly produced maximal response rate-decreasing effects and recovery was rapid, while the effects of toluene became progressively greater during the exposure and recovery was prolonged. Ethanol displayed the most rapid onset and recovery of effects. Thus, these solvents produced somewhat similar effects on FR responding but displayed potency and time course differences.

Animals↗
PubMed1985

Yohimbine attenuates the delayed lethality induced in mice by amitraz, a formamidine pesticide.

We have found that a single dose of amitraz, a formamidine pesticide, produces death in mice 2-5 days after dosing. To further examine this phenomenon, adult albino mice of both sexes were treated with either yohimbine (10 mg/kg, i.p.) or deionized water (6 ml/kg, i.p.), immediately before an injection of amitraz (600 mg/kg, i.p.) and twice daily thereafter for 8 days. Male mice treated with water were more susceptible than water-treated females to the lethal effects of amitraz. In addition, yohimbine treatment significantly decreased the number of deaths in both sexes. These data suggest that an alpha 2-adrenergic mechanism is involved in the delayed lethality produced by amitraz.

Animals↗
PubMed1985

Minimal tolerance to the effects of 1,1,1-trichloroethane on fixed-ratio responding in mice.

Most laboratory animal studies of the behavioral or neurophysiological effects of repeated exposures to volatile organic solvents find little evidence for substantial tolerance. This study examined the development of tolerance to the effects of 1,1,1-trichloroethane (1,1,1-TCE) on fixed-ratio responding in four mice. The subjects were exposed to 6000 ppm solvent vapor for 20 min of the daily 45-min operant sessions. Once a week, a series of four concentrations (1000-8000 ppm) were substituted for the daily exposure in order to obtain a cumulative concentration-effect curve. This proved to be a rapid and reliable method with which to ascertain the effects of 1,1,1-TCE over a range of concentrations. During the 15 days of 20-min exposure, the subjects showed a slight but significant increase in both response rates during exposure and in the rate of recovery following exposure. Maximal changes in these measures were evident in the first 7 days, with no further decreased sensitivity over the final 8 days of exposure. The concentration-effect curves determined during and after the daily exposures showed no significant shifts in either direction from the initial curve. Thus, while some alteration in the daily acute effects was noted, this tolerance was not of large magnitude and could not be detected as a change in the concentration-effect curve.

Air Pollutants↗
PubMed1982

Concurrent measurement of solvent vapor concentrations and effects on operant behavior using a dynamic exposure system.

A method is described for exposing mice, lever-pressing on an operant schedule for water reinforcement, to continuously-generated solvent vapors. Concurrent monitoring of chamber concentration and schedule-controlled behavior allows a correlation of the magnitude and time course for behavioral effects with changes in the levels of solvent exposure. Data are presented showing the acute effects of 1,1,1-trichloroethane over the range of 1000-8000 ppm on behavior maintained by a fixed-ratio 100 schedule of water presentation. Concentration-dependent decreases in response rates with a rapid onset and recovery were obtained.

Animals↗
PubMed1981

The effects of acute and repeated toluene exposure on operant behavior in mice.

Adult male CD-1 mice were trained on a differential reinforcement of low rate (DRL) 10-sec schedule for milk presentation during 15-min sessions. After training, an initial concentration-effect curve was determined for acute exposure to toluene (200-6400 ppm). Exposures were carried out in a static exposure chamber for 30 min; operant sessions began immediately after removal from the chamber. Mice were exposed to air under the same conditions on days they were not exposed to toluene. Response rate increases were seen at low concentrations and decreases at higher concentrations (greater than 3200 ppm). The rate of reinforcement decreased in a concentration-dependent manner. Mice were then exposed to 6000 ppm toluene for 30 min daily, 7 days a week for 7 weeks, immediately before each session. During this time the response rate was variable, but reinforcement rate remained consistently low. Following the termination of chronic toluene exposure, a second concentration-effect curve was determined which was not significantly different from the initial curve. There was, however, a nonsignificant tendency towards higher response rates at the rate-increasing concentrations. Thus after repeated exposures no tolerance to toluene was seen under these test conditions.

Animals↗
PubMedDate not supplied

Potential developmental toxicity of anatoxin-a, a cyanobacterial toxin.

Some 2000 species of cyanobacteria (blue-green algae) occur globally in aquatic habitats. They are able to survive under a wide range of environmental conditions and some produce potent toxins. Toxin production is correlated with periods of rapid growth (blooms) and 25%-70% of blooms may be toxic. Anatoxin-a is an alkaloid neurotoxin that acts as a potent neuro-muscular blocking agent at the nicotinic receptor. Acute toxicity, following consumption of contaminated water, is characterized by rapid onset of paralysis, tremors, convulsions and death. Human exposures may occur from recreational water activities and dietary supplements, but are primarily through drinking water. The current studies were conducted to examine the effect of in utero exposure on postnatal viability, growth and neurodevelopment, to evaluate the potential of in vitro embryotoxicity, and to explore the synergistic relationship between anatoxin-a and the algal toxin microcystin-LR by the oral route. The results of preliminary studies on amphibian toxicity are also reported. Time-pregnant mice received 125 or 200 microg kg(-1) anatoxin-a by intraperitoneal injection on gestation days (GD) 8-12 or 13-17. Pup viability and weight were monitored over a 6-day period. Maternal toxicity (decreased motor activity) was observed at 200 microg kg(-1) in both treatment periods. There were no significant treatment-related effects on pup viability or weight on postnatal day (PND) 1 or 6. The GD 13-17 pups were evaluated on PND 6, 12 and 20 for standard markers of neurodevelopmental maturation (righting reflex, negative geotaxis and hanging grip time). No significant postnatal neurotoxicity was observed. In vitro developmental toxicity was evaluated in GD 8 mouse embryos exposed to 0.1-25 microm anatoxin-a for 26-28 h. Perturbations in mouse yolk sac vasculature were noted from the 1.0 microm concentration in the absence of significant embryonic dysmorphology. Potential algal toxin synergism was tested in mice receiving either 0, 500 or 1,000 microg kg(-1) microcystin-LR by gavage and approximately 50 min later receiving either 0, 500, 1,000 or 2,500 microg kg(-1) anatoxin-a by the same route. No deaths occurred at any dose and no definitive signs of intoxication were observed. Stages 17 and 25 toad embryos (Bufo arenarum) were exposed to 0.03-30.0 mg l(-1) of anatoxin-a for 10 days. Adverse effects included a dose-dependent transient narcosis, edema and loss of equilibrium. Most notable was the occurrence of 100% mortality at the high dose in both groups 6-13 days post-exposure. The observed delay between initial exposure and death is highly unusual for anatoxin-a.

Animals↗
PubMedDate not supplied

Neurobehavioral effect of triadimefon, a triazole fungicide, in male and female rats.

Triadimefon is a widely used systemic fungicide, yet there is little published information on its effects in mammals. This study describes the effects of triadimefon in male and female rats using a functional observational battery (FOB), motor activity (measured in a figure-eight maze), and operant performance (responding under a fixed-interval 3-min schedule). For the FOB, Long-Evans hooded rats were tested immediately before dosing and 0.5, 4, 24, and 48 hr after IP dosing with either vehicle, 30, 100, or 300 mg/kg triadimefon. Prominent effects of triadimefon (100 and 300 mg/kg) included increased arousal, stereotypies involving repetitive sniffing, head bobbing, and pacing, and self-mutilation. Dose-related handling-induced convulsions, changes in reflexes and sensory reactivity, hypothermia, and body weight loss were also significant findings. Doses of 30, 75 and 150 mg/kg triadimefon increased figure-eight maze activity whereas 300 mg/kg decreased activity. Habituation of activity during the session as well as the spatial distribution within the maze were also affected by triadimefon. Overall rates of responding maintained by fixed-interval milk reinforcement were increased at 30 and 56 mg/kg, and decreased at 100 and 200 mg/kg. Responding within the 3-min fixed-interval was also affected, with low rates normally occurring early in the interval markedly increased. These effects on operant performance were similar to those seen following d-amphetamine, and were attenuated by pretreatment with chlorpromazine (0.5 mg/kg). On many measures, female rats appeared to be somewhat more sensitive than males. Recovery was evident in some measures the day after dosing, but the effects of high doses (greater than or equal to 100 mg/kg) were typically prolonged (several days). Thus triadimefon produced a unique neurotoxic syndrome which is similar in many aspects to that produced by CNS stimulants.

Animals↗
PubMedDate not supplied

Approaches for assessing the validity of a functional observational battery.

As neurobehavioral assessments during the preliminary stages of chemical testing are more widely undertaken, it is critical that the screening procedures utilized be valid indicators of neurobehavioral function and that they be sensitive, specific, and reliable. Efforts in this laboratory have been directed towards assessing these features in the use of a functional observational battery (FOB). For the purpose of assessing validity, we have examined FOB data which addresses the issues of criterion, predictive, concurrent, and construct validities. The FOB appears to be valid for detecting chemical-induced neurological dysfunction in rats, i.e., shows a good degree of criterion validity. Furthermore, in many instances the effects observed with the FOB may be predictive of symptomatology in humans. When comparisons can be made between effects detected with the FOB and other methods of measuring neurotoxicity (e.g., neuropathology), concurrent validity can also be established. To assess construct validity, effects of neurotoxicants can be classified into functional domains which are described by various measures in the FOB. Approaches for assessing the validity of the test method thus include answering specific research questions directed at assessing criterion, predictive, concurrent, and construct validity. Available data indicate that, in these aspects, the FOB is a valid screening method for the detection of neurotoxicity.

Animals↗
PubMedDate not supplied

Interlaboratory comparison of motor activity experiments: implications for neurotoxicological assessments.

Motor activity is an important functional measure used in neurotoxicology. The effects of chemicals on motor activity, however, may depend on variables such as type of measurement apparatus, physical and environmental testing conditions, and many other experimental protocol and organismic variables. Due to the increasing use of motor activity in neurotoxicology, a major question concerns the potential for differences in experimental findings due to variations in sensitivity and reliability between different laboratories and devices used to measure motor activity. This study examined historical data from a number of laboratories that employed different devices and experimental protocols to measure motor activity. Four aspects of the motor activity data were compared: 1) within-laboratory control variability across time; 2) within-laboratory replicability of control data; 3) between-laboratory variability in the effects of chemicals; and 4) between-laboratory comparison of the control rates of habituation. The analyses indicated that there was a relatively restricted range of within-laboratory variability and reliability in control values, and that these ranges were comparable across laboratories. Similar profiles of habituation were also seen across the different laboratories. Moreover, in virtually every case, all laboratories were capable of detecting qualitatively similar changes in motor activity following acute exposure to a variety of chemicals. These data indicate a high degree of comparability in the data generated by the different devices and experimental protocols.

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

Comparisons of the acute effects of cholinesterase inhibitors using a neurobehavioral screening battery in rats.

The clinical signs of intoxication produced by cholinesterase inhibitors, many of which are used as pesticides, are considered important information for regulatory purposes. We conducted acute studies of cholinesterase inhibitors to compare their effects as determined by a functional observational battery (FOB) and motor activity. The acute effects of two carbamates (carbaryl, aldicarb) and five organophosphates (OP) (chlorpyrifos, diazinon, parathion, fenthion, and diisopropyl fluorophosphate, or DFP) were evaluated on the day of dosing at the time of peak effect, at 1 and 3 days, and 1 week after dosing (oral gavage, in corn oil). A high dose was selected that produced clear cholinergic signs, and lower doses were chosen to produce a range of effects. Generally all cholinesterase inhibitors produced autonomic signs of cholinergic overstimulation (salivation, lacrimation, and miosis), hypothermia, mild tremors and mouth-smacking (chewing motions), lowered motor activity, decreased tail-pinch response, and altered neuromuscular function (gait changes and increased foot splay). The measures generally found to be most sensitive on the day of dosing were body temperature, motor activity, gait, and the presence of mouth-smacking and fine tremors. However, no single measure was the most sensitive across all compounds; for example, the lowest dose of fenthion decreased motor activity by 86% but did not alter the tail-pinch response, whereas the lowest dose of parathion did not lower activity but did decrease the tail-pinch response. For some measures, differences in the slopes of the dose-response curves were evident. Many effects were still observed at 24 h, but recovery was apparent for all compounds. Interestingly, residual effects at 72 h were obtained with the carbamates (carbaryl, aldicarb) as well as with the Op fenthion, but not with the other compounds. Thus, the overall clinical picture of toxicity was similar for these cholinesterase inhibitors, but compound-specific differences emerged in terms of the individual measures, dose-response, and time course.

Aldicarb↗
PubMedDate not supplied

Rapid neurobehavioral analysis of Pfiesteria piscicida effects in juvenile and adult rats.

The estuarine dinoflagellate Pfiesteria piscicida is known to kill fish and has been associated with neurocognitive deficits in humans. We have developed a rat model to demonstrate that exposure to Pfiesteria causes significant learning impairments. This has been repeatedly seen as a choice accuracy impairment during radial-arm maze learning. Pfiesteria-induced effects were also seen in a locomotor activity test in the figure-8 apparatus. The current studies used the short-term radial-arm maze acquisition, the figure-8 activity test, and the functional observational battery (FOB) to assess Pfiesteria-induced neurobehavioral effects in adult and juvenile rats. In study 1, the neurobehavioral potency of three different Pfiesteria cultures (Pf 113, Pf 728, and Pf Vandermere) was assessed. Ninety-six (12 per group) adult female Sprague-Dawley rats were injected subcutaneously with a single dose of Pfiesteria taken from aquarium-cultured Pfiesteria (35,600 or 106,800 Pfiesteria cells per kilogram of rat body weight). One control group (N = 12) was injected with saline and one (N = 12) with aquarium water not containing Pfiesteria. All three of the Pfiesteria samples (p < 0.05) impaired choice accuracy over the first six sessions of training. At the time of the radial-arm maze choice accuracy impairment, no overt Pfiesteria-related effects were seen using an FOB, indicating that the Pfiesteria-induced choice accuracy deficit was not due to generalized debilitation. In the figure-8 apparatus, Pfiesteria treatment caused a significant decrease in mean locomotor activity. In study 2, the neurobehavioral effects of the Pf 728 sample type were assessed in juvenile rats. Twenty-four day-old male and female rats were injected with 35,600 or 106,800 Pf-728 Pfiesteria cells per kilogram of rat body weight. As with adult females, the juvenile rats showed a significant impairment in radial-arm maze choice accuracy. No changes in locomotor activity or the FOB were detected in the juvenile rats. Furthermore, there were no differences between male and female rats in the Pfiesteria-induced choice accuracy impairment. Pfiesteria effects on choice accuracy in the radial-arm maze in rats constitute a critical component of the model of Pfiesteria toxicity, because the hallmark of Pfiesteria toxicity in humans is cognitive dysfunction. Our finding that analysis of the first six sessions of radial-arm maze testing is sufficient for determining the effect means that this test will be useful as a rapid screen for identifying the critical neurotoxin(s) of Pfiesteria in future studies.

Aging↗
PubMedDate not supplied

Dose-response and time-course of neurobehavioral changes following oral chlorpyrifos in rats of different ages.

Young rats have been shown in several laboratories to be more sensitive to the neurotoxic effects of acute exposure to chlorpyrifos. To examine the neurobehavioral effects of chlorpyrifos as a function of age and dose, we conducted dose-response and time-course assessments in rats of three different ages (postnatal day, or PND, 17, 27, and adults). Doses were selected to span the effective dose range in each age group: PND17 - 4, 10, 20 mg/kg; PND27 - 10, 25, 50 mg/kg; adult - 10, 50, 100 mg/kg. Rats were tested at the time of peak effect on the day of dosing, and again at 1 and 3 days, and at 1 and 2 weeks after a single oral dose. There were age- and sex-related differences in the recovery of these behavioral effects; the adult males recovered from the behavioral effects more quickly than the other age groups, and the adult females showed the slowest recovery (up to at least 3 days). Although these doses had been shown previously to produce a similar degree of cholinesterase inhibition, the neurobehavioral alterations fell into the following three patterns of effect as a function of age. (1) Some endpoints (e.g., gait abnormalities, tremor) showed a dose-response curve that was shifted to the right in the older animals. Calculated ED50 values indicated that the PND17 rats were three- to five-fold more sensitive than the adults. (2) Some measures showed less effect in the youngest rats; for example, maximal motor activity decreases were half as great as with adults. (3) A few effects that were typically observed in adults, e.g., salivation, were not seen at all in the PND17 rats. Thus, differential responses on these neurobehavioral endpoints were observed as a function of age. These data suggest that, for some endpoints, young rats are more sensitive to a range of chlorpyrifos doses; however, the magnitude of age-related differences depends on the specific endpoint and time of assessment, as well as age and sex of the test subject.

Administration, Oral↗
PubMedDate not supplied

Comparing cognitive and screening tests for neurotoxicity. Effects of acute chlorpyrifos on visual signal detection and a neurobehavioral test battery in rats.

It is often assumed that cognitive function is more sensitive to neurotoxic chemicals than are the unconditioned behaviors employed in neurobehavioral screens; however, direct comparisons of the sensitivity of these test methods are lacking. The present studies were conducted to compare the effects of the widely used cholinesterase-inhibiting insecticide, chlorpyrifos (O,O'-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), on a visual signal detection task (SDT) with its effects on a neurobehavioral test battery. Adult male Long-Evans rats were trained to perform the SDT, dosed with CPF, and then assessed with both test instruments. Oral CPF (50 mg/kg) impaired signal detection for 8 days, and subcutaneous CPF (250 mg/kg) did so for 4 weeks. CPF (30 and 50 mg/kg po and 250 mg/kg sc) also lowered activity in the test battery for up to 18 days. Thus, CPF impaired attention and altered behavior in the test battery in the same dose ranges under two very different dosing scenarios.

Acetylcholinesterase↗
PubMedDate not supplied

Pfiesteria toxin and learning performance.

Pfiesteria piscicida is an estuarine dinoflagellate involved with fish kills along the east coast of the United States. We previously documented a radial-arm maze learning deficit in rats exposed to Pfiesteria that may be related to cognitive deficits seen in humans after accidental Pfiesteria exposure. The current study elucidated important behavioral parameters of this deficit. There were six dose groups. Forty (10/group) adult female Sprague-Dawley rats were injected (s.c.) with a single dose of Pfiesteria taken from aquarium-cultured Pfiesteria (35,600, 106,800, or 320,400 Pfiesteria cells/kg of rat body weight or a cell-free filtrate of the 106,800 cells/kg dose). One control group (N = 10) was injected with saline and one (N = 10) with aquarium water not containing Pfiesteria. Half of the rats in each group were tested on an 8-arm radial maze in a standard test room, and the other half were tested on the radial maze in a sound-attenuating chamber. In the standard maze room, there was a significant effect of Pfiesteria (p < 0.05) impairing choice accuracy improvement over the first six sessions of training among rats administered 106,800, 320,400, and the 106,800 cells/kg filtered sample. In contrast, there was no indication of an effect of Pfiesteria when the rats were tested on the same configuration radial maze in the sound-attenuating chamber. After 18 sessions of training in one room, the rats were switched for six sessions of testing in the other room and finally were switched back to their original room for three sessions. There was a significant Pfiesteria-induced deficit when the rats were tested in the standard test room but not when they were tested in the sound-attenuating chamber. When the Pfiesteria-exposed rats were initially switched from the sound-attenuating chamber to the standard test room they performed significantly worse than controls, whereas Pfiesteria-treated rats switched from the standard test room to the sound-attenuating chamber did not perform differently from controls. These results suggest that the Pfiesteria-induced learning impairment may result from the negative impact of distracting stimuli. At the time of the learning impairment, no overt Pfiesteria-related effects were seen using a functional observational battery and no overall response latency effects were seen, indicating that the Pfiesteria-induced choice accuracy deficit was not due to generalized debilitation. In the initial use of the figure-8 maze in this line of research, the rats in the same Pfiesteria treatment groups that showed significant deficits in the radial-arm maze showed greater declines in activity rates in a 1-h figure-8 locomotor activity test. Both the 106,800 and 320,400 Pfiesteria cells/kg groups showed significantly greater linear trends of activity decline relative to tank water-treated controls. This reflected an initial slight hyperactivity in the Pfiesteria-treated animals followed by a decrease to control levels. Pfiesteria effects in the figure-8 maze and in early radial-arm maze training may be useful in a rapid screen for identifying the critical toxin(s) of Pfiesteria in future studies.

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↗
PubMedDate not supplied

Comparison of the role of esterases in the differential age-related sensitivity to chlorpyrifos and methamidophos.

More than 30 years ago, scientists recognized that, at a given dosage, the young rat was more sensitive than the adult to the toxicity of many organophosphorus, anticholinesterase pesticides. This observation went basically unexamined until recently. Renewed interest has emerged in scrutinizing this age-related sensitivity to pesticides, especially in light of the many new pesticides which are currently marketed. Our laboratory has been involved in comparing the age-related sensitivity of young and adult rats to chlorpyrifos [Dursban, Lorsban; O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate] and methamidophos (Monitor; O,S-dimethyl phosphoamidothioate). Using chlorpyrifos, there is marked age-related sensitivity: direct oral dosing of the preweanling rat (postnatal day 17; PND17) with chlorpyrifos causes a toxic response (defined either behaviorally or biochemically) at a approximately 5-fold lower dosage than in adults (oral, maximum tolerated dose for the PND17 is 20 mg/kg versus 100 mg/kg for the adult). Other studies have indicated that the rat detoxifies chlorpyrifos and its oxon by binding to carboxylesterases and hydrolysis by A-esterases. The young rat is deficient in both these detoxification enzymes, which may explain the increased sensitivity of the young to chlorpyrifos toxicity. The age-related pattern for methamidophos is distinctly different: the oral, maximum tolerated dose is the same (8 mg/kg) whether the animal is 17 days old or an adult. We present data which indicate that methamidophos is not detoxified appreciably either in vivo or in vitro by A-esterases or carboxylesterases. Therefore, we submit the following hypothesis: organophosphorus pesticides, like chlorpyrifos, which are detoxified via A-esterases or carboxylesterases are more likely to exhibit age-related differences in sensitivity than pesticides which are not detoxified via these routes.

Acetylcholinesterase↗