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A newer locomotor activity system for rodents is described. The system consists of a black, ventilated test chamber, internally lighted with a ceiling mounted video camera. The camera's image is transmitted to a contrast-sensitive tracker which maps the point of highest contrast and relays the digitalized coordinates to a PC. Dedicated software stores the information and simultaneously displays a map of the tracked subject. To illustrate the system's utility, results from an experiment are presented using an established behavioral teratogen, phenytoin. Pregnant Sprague-Dawley CD rats were exposed to 0 or 200 mg/kg of phenytoin by gavage on embryonic days 7-18 and the offspring tested in the videotracker activity monitoring device. Phenytoin is known to induce hyperactivity and circling behavior in the offspring. The system revealed that phenytoin-exposed offspring that exhibit neurological impairment were hyperactive compared to controls and the effect was predominantly seen in females. These animals exhibited more section transitions and more central and peripheral activity. When peripheral activity was subdivided into that occurring along corners versus sides, it was found that corner activity represented only a small component of the group differences whereas the side component represented most of the effect. Moreover, phenytoin offspring exhibiting the circling defect were found to display a qualitatively different pattern than noncirclers or controls. Videotracking represents a different approach to the analysis of locomotor activity patterns in experimental animals compared to older methods. Two advantages of this method are higher spatial resolution and not having to pre-specify data capture intervals. Other features are detailed regional movement information and qualitative mapping of ambulatory patterns.

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)

Regulatory guidelines have produced a need to develop behavioral screening techniques to accompany teratology and reproduction testing. In the repeated use of a provisional test battery, we have found that conclusions about the behavioral teratogenic potential of test compounds are most likely to be revealed using tests having intermediate levels of variability. The results obtained from examining animals exposed developmentally to brominated vegetable oil (BVO as 2.0, 1.0, 0.5, or 0.25 percent of the diet) and comparisons of the tests' coefficients of variation, offer an empirical example of this concept. Preweaning tests of locomotion and reflex development demonstrated numerous instances of developmental delay in the BVO-treated subjects, but postweaning tests revealed few abnormalities. Behavioral testing revealed functional deficits from BVO administration at doses lower than those which have adverse effects on reproduction. Examination of the tests' variability by using coefficients of variation as a comparative index, disclosed that the postweaning test variability was almost twice that of the preweaning tests. Thus, the lack of effects of BVO on most of the postweaning tests should not be conclusively interpreted as indicative of recovery of function, because this pattern is equally likely to have resulted from the lower sensitivity of these tests. An acceptable standard for future behavioral teratology screening requires a close examination of test variability, as it appears to be an important element in the sensitivity and, hence, the interpretation of such procedures.

The permanence of developmental abnormalities from prenatal methylmercuric chloride (MMC) was examined in the offspring of Sprague-Dawley rats exposed on Days 6-15 of gestation to 0.00, 0.25, 1.25, 2.50, or 5.0 mg/kg MMC. The effects of MMC on reproduction and early physical development were examined together with tests of negative geotaxis, righting, pivoting, swimming, locomotor activity in an open field, and startle responses to either tactile or acoustic stimuli. No live offspring were produced by females treated with 5.0 mg/kg MMC. Offspring from the 2.50 mg/kg dose group displayed impaired performance on almost all pre-weaning measures and continuing abnormalities on longitudinal tests of locomotor activity in an open field and startle response performance.

Coffee and caffeine solutions were administered as the sole source of fluid to male and female Sprague-Dawley rats (F0) beginning 60 days before breeding and continuing until the litters (F1) from these animals were weaned. Treatments were administered as 100% brewed coffee (COF-100), and a 25% dilution of coffee (COF-25), together with solutions of caffeine in water that paralleled the caffeine content of the coffee groups, 0.056% caffeine (CAF-100) and 0.014% (CAF-25). Controls received measured amounts of plain water (CNL) and another group received vitamin A (40,000 IU/kg) on Days 7-20 of gestation (positive control treatment). During pregnancy all groups receiving COF and CAF consumed significantly more fluid than CNLs. Offspring from the COF-100 and CAF-100 dams were significantly lower in weight than CNLs. No abnormalities of reproductive performance were observed. Of 10 preweaning tests, COF-100 and CAF-100 litters displayed delayed incisor eruption, delayed swimming development, and altered activity. On 7 postweaning measures, these groups showed decreased running wheel activity and increased open-field ambulation and/or defecation. The CAF-25 group, by contrast, showed an increase in running wheel activity. Vitamin A (Vit-A) offspring showed multiple effects, including delayed incisor eruption, increased pre- and postweaning open-field activity, and reduced running wheel activity. COF and CAF produced effects on tests for psychoteratogenesis that appear consistent with the morphological consequences (delayed development) known to be associated with pre- and neonatal administration of caffeine, alone or in coffee, at high doses. The data indicate that most of the behavioral effects observed from caffeine exposure were consistent with the expected effects of concurrent administration of this agent, while the postweaning exposure effects suggest a longer-term change in activity. No effects of caffeine were found, however, on measures of learning, memory, or motoric functioning.

Pregnant Sprague-Dawley rats received 25 mg/kg of prochlorperazine, 20 mg/kg of fenfluramine, 75 mg/kg of propoxyphene or 200 mg/kg of diazepam daily between the 7th and 20th days of gestation. Vehicle control groups and a positive control group (vitamin A 40,000 IU/kg/day) were similarly prepared. Observations of reproductive performance were made and the offspring examined in a battery of neurobehavioral tests. Fenfluramine and prochlorperazine produced abnormalities in both the reproductive measures and neurobehavioral testing. Propoxyphene produced developmental delays and other signs of "pure" behavioral teratogenesis in that these effects were not anticipated in any of the observations of reproductive performance. Diazepam appeared to have the mildest effect on all the measurements taken. The test methods used in this study appear to be a reasonable initial approach to the development of neurobehavioral screening procedures which are comprehensive, sensitive, and usable.