Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group IV report: triggers for developmental neurotoxicity testing.

A Work Group was formed to evaluate the criteria considered important in determining when to require developmental neurotoxicity testing in animal studies (i.e., triggers for testing). The primary objective of the Work Group was to determine whether there is sufficient scientific evidence to support the triggers identified by the Environmental Protection Agency and determine whether there is sufficient evidence to use structure activity relationships (SAR) to trigger automatic testing of certain classes of chemicals. A weight of evidence (WOE) approach was recommended by the Work Group in order to assist in determining which agents should undergo developmental neurotoxicity testing and to what level of testing. Evaluation of biological effects, length and duration of exposure, and quality and quantity of data available on an agent should be used in the WOE approach. Agents that are teratogenic to the central nervous system (CNS) were considered of highest priority for developmental neurotoxicity testing, especially if there is the potential for a high degree of exposure. Neuropathic and neuroactive compounds, chemicals with hormone-like activity, and developmental toxicants (with effects other than structural abnormalities of the CNS) were also considered likely candidates for such testing. Although reluctant to recommend testing based solely on SAR or chemical class, the Work Group recognized the importance of considering SAR along with other toxicity data, pharmacokinetic data and potential human exposure in making final requirements or recommendations for further testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of neonatal and adult 6-hydroxydopamine treatment on random-interval behavior.

Rats were given intraventricular injections of 6-hydroxydopamine (6-HDA) or saline-ascorbate vehicle as neonates (3-days old) and as adults (49 and 51 days old). At 73 days of age, they were trained on a random interval 90-sec schedule of water reinforcement. The rats treated with 6-HDA as adults stabilized at response rates approximately twice those of vehicle-treated rats, while rats treated with 6-HDA as neonates showed response rates which were not significantly different from vehicle-treated rats; Both L-Dopa and apomorphine decreased response rates at all doses tested. There were no differences among the groups with respect to the effect of these drugs. Adult-treated rats showed greater response rate decreases following peripheral decarboxylase inhibition with Ro 4-4602. Catecholamine analyses revealed the rats treated with 6-HDA as neonates had greater depletions in the striatum and the remainder of telencephalon than adult-treated rats but an increase in brainstem norepinephrine. These findings suggest that age of treatment is an important determinant of the biochemical and behavioral effects of treatment with 6-HDA.

DRL performance in 6-hydroxydopamine-treated rats.

Adult rats were given intraventricular injections of 6-hydroxydopamine (6-HDA) or saline-ascorbate vehicle prior to exposure to a differential-reinforcement-of-low-rate (DRL) 18-sec schedule of water reinforcement. The 6-HDA treatment did not alter the acquisition or maintenance of DRL performance despite large depletions of dopamine and norepinephrine in brain. The 6-HDA treatment completely blocked the response rate-increasing effects of amphetamine but did not alter the rate-decreasing effects of amphetamine on DRL performance. These findings suggest that 6-HDA-treated rats are able to responsd to the contingencies necessary to maintain reinforcement on a DRL schedule.

Effects of caffeine on DRL performance in the mouse.

Mice were trained to stable and efficient DRL 18 sec performance utilizing a nose-poke as the operant. Caffeine, at doses less than 48 mg/kg, increased both response bursts (IRTs less than 3 sec) and longer IRTs, and shifted the IRT distribution towards shorter, nonreinforced IRTs. Auditory feedback for responses decreased the number of bursts emitted and produced performance more resistant to drug effects. These results are similar to those previously reported for caffeine on DRL in the rat, and for amphetamine on DRL in a variety of species.

Technique for assessing visual discrimination learning in mice.

An automated technique for the study of visual discrimination learning in mice has been developed. The technique utilizes a nose-poke as the operant response. The nose-poke response requires no shaping, has a relatively high operant level and can be used to measure preacquisition exploratory behavior. CD-1 mice acquired a simultaneous brightness discrimination readily but a successive brightness discrimination proved more difficult. A 20 sec intertrial interval was optimal for acquisition of the simultaneous discrimination. Reversal learning was slow. This procedure should prove useful in the study of the effects of pharmacologic and toxic agents on learning and performance in both weanlings and adult mice.

Effects of carbon disulfide and FLA-63 on operant behavior in pigeons.

Carbon disulfide (CS2) and FLA-63 [bis(4-methyl-1-homopiperazinylthiocarbonyl)disulfide] were studied in pigeons working on a differential-reinforcement-of low-rates or a multiple fixed-interval fixed-ratio schedule of food reinforcement. Response rate on both schedules decreased after 8-hour exposures to CS2 (2 mg/1) of administration of FLA-63 (40 and 80 mg/kg). The effects of two successive 8-hour exposures to CS2 were cumulative and ten successive 4-hour exposures produced changes in differential-reinforcement-of-low-rates performance resembling those following acute exposure. Fixed-interval performance was disrupted by exposures to CS2 and doses of FLA-63 that left fixed-ratio performance intact.

Studies in the behavioral toxicology of environmental contaminants.

Behavioral toxicology represents a relatively new research area in the West, and a new source of information pertinent to standard setting. Despite this abbreviated history, however, it can call on a rather advanced technology, largely provided by the rapid and extensive development of behavioral pharmacology during the past two decades. As exemplified by the U.S. contribution to the joint study of carbon disulfide, the approach derived from this background relies on the acquisition of dose--effect data with a preparation yielding stable baseline performance. The first study in this collaborative series employed pigeons trained to peck a response device consisting of a transilluminnated plastic disk. Various relationships between this response and the occasions on which it led to the delivery of food were explored in order to ascertain which behavioral variables were most sensitive to acute exposures. In addition, a central nervous system drug, whose neurochemical mode of action is believed to parallel that of carbon disulfide, was tested in the same preparations. Further research on these questions is being continued with monkeys.