A Practical Approach, Second Edition=Ronald D. Ho.pdf

NONCLINICAL JUVENILE TOXICITY TESTING 311Total Counts27502500225020001750150012501000750Male500 Female250023 41 63 79 95 111 127 148Postnatal Day of Locomotor Activity AssessmentFigure 8.20Locomotor activity development of the beagle dog. Mean number of total counts for litters by sexat each day of locomotor activity assessment (n = 7 to 8 litters per time point). Data were collectedat WIL Research Laboratories, LLC.conducted for the pre- and postnatal development studies, 131 although these assessments are generallyconducted in a longitudinal fashion as well.The first three time points listed above for rats examine the ontogeny of habituation, thedevelopment of motor activity coordination, and the presence or absence of the characteristic patternof early rodent activity. 150–151 In more traditional reproduction and developmental neurotoxicitystudies, the assessment at approximately PND 60 examines potential latent alterations in motoractivity and the persistence of changes observed prior to weaning. Other ages may be substitutedor added as appropriate for the age at which dose administration occurs and to assess potentialrecovery from or latency of motor activity decrements after juvenile exposure.The use of different species, such as the dog, will require adjustments in the timing for evaluatingchanges in the ontogenic profile of activity. Figure 8.20 illustrates the development of locomotoractivity in beagle puppies over a period of approximately 18 weeks. 124 If no data are availableregarding the ontogeny of motor activity in the species selected for the juvenile study and if it isconsidered necessary to understand the potential effects of the test article on this profile, somespecies characterization will be required prior to study initiation or else selection of a differentanimal model should be considered. Many nonrodent species have substantially longer periods ofmotor development than those of rodents (refer to Figure 8.20 for ontogeny of motor function inthe dog), requiring longer study durations to assess changes in the ontogeny of motor activity. 115When evaluating locomotor activity, the pattern of habituation should be examined within thecontrol group at each age of assessment. In the rat on PND 13, there should be very little changein total activity across each test interval. A test interval is defined in this text as a period duringwhich activity counts are collected and then presented. A test interval is typically between 10 and15 min and is determined through validation of the equipment. Between PND 17 and 21, a graphof cross-interval activity should begin to show a near-hyperbolic shape. The first test interval shouldcontain the most movement, with each subsequent interval showing an approximately 30 to 50%decrease in movement (when the total activity session is divided into four 15-min intervals) untilthe final test interval, when very little change should occur. In testing paradigms in which six ornine intervals (usually 10 min each) are used for data analysis, the magnitude of interintervaldecreases will likely differ from that described above. Interval data from motor activity sessionsat adulthood should demonstrate a well-defined habituation curve. There should be no consistentsex-related differences among young animals, although gender-specific differences may developwith age.© 2006 by Taylor & Francis Group, LLC