Regulatory Testing for Developmental Neurotoxicology

Li, A.A.; Garman, Robert H.; Sheets, Larry P.; Bowers, Wayne J.; Kaufmann, Wolfgang; KGaA, M.; Auer, Roland N.; Bolon, Brad

doi:10.1016/b978-0-12-801238-3.64227-7

Cited by 2 publications

(5 citation statements)

References 74 publications

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“…In the EPA DNT survey, qualitative neuropathology was never the basis for an LOAEL, suggesting that functional measures were more sensitive, although the question was raised whether enhancements of neuropathology methods could improve the sensitivity of these evaluations. 36 The conduct of neurohistopathology examinations at a single time point at the end of the dosing period, as is the usual practice, is not optimal or sufficient for detecting effects that may occur at any time over an extended dosing period. Given the importance of sacrifice time for adequate neuropathology evaluations, more frequent assessments during the course of treatment in a JAS may be needed.…”

Section: Discussionmentioning

confidence: 99%

CDER Experience With Juvenile Animal Studies for CNS Drugs

2019

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A survey was undertaken to evaluate juvenile animal studies conducted for drug applications reviewed by the Center for Drug Evaluation and Research between 2009 and 2014. Some conclusions about the nonclinical pediatric safety assessment based on studies performed in support of central nervous system–active compounds are presented here. A total of 44 completed studies from 32 New Drug Applications submitted to the Divisions of Psychiatry and Neurology Products were evaluated. Data on animal species and age range used, endpoints evaluated, and outcomes included in labeling were analyzed. Of the drugs evaluated, all but one had studies conducted in rats. In some cases, a second study in a nonrodent species (dog) was also conducted. Indices of growth and development and standard general toxicity parameters were included in all of the studies. Expanded neurohistopathology evaluations, bone mineral density measurements, and reproductive and neurobehavioral functional assessments were also generally carried out. A variety of neurological and neurobehavioral tests were employed. In the majority of rat studies, the potential for long-term cognitive impairment was evaluated using a complex water maze. Juvenile animal studies provided safety information considered relevant to drug use in children and that was included in labeling for 78% of the applications surveyed. The most commonly reported findings in labeling were for neurobehavioral effects, including changes in locomotor activity, auditory startle habituation, and learning and memory. Of the studies described in labeling with neurobehavioral effects, 54% found these effects to be persistent and to provide evidence of developmental neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

CDER Experience With Juvenile Animal Studies for CNS Drugs

2019

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“…Neuropathology evaluation is a primary component of assessing neural development in animal toxicity studies. 48,51,52 Structure-based endpoints are particularly valuable for developmental neuropathology screening due to their reproducibility within and across laboratories. 80 The neuropathology evaluations for DNTS and JAS are similar but not identical.…”

Section: Discussionmentioning

confidence: 99%

“…7,50 Working groups of toxicologic pathologists and toxicologists have created "best practice" recommendations 48,49 for implementing the neuropathology evaluation as well as integrating the neuropathology data with associated neurobehavioral (cognitive, motor, and sensory) data acquired during a DNTS. 51,52 Study procedures for immature (pre-weaning) animals may differ from those of mature animals, so positive control test substances often are included in the DNTS design to ensure that the experimental methods are capable of detecting xenobioticinduced changes in neural structure or function. 53,54 In routine DNTS performed in rats, indirect exposure of developing animals occurs during gestation (by maternal treatment) and after birth (usually by continued maternal treatment leading to lactational exposure of the nursing offspring).…”

Section: Developmental Neurotoxicity Studies For Chemicalsmentioning

confidence: 99%

“…18,48,49 The quantitative analysis is performed in the control and high-dose groups initially, adding other dose groups only if warranted by discovery of altered (usually reduced) dimensions in one or more brain regions in the high-dose animals. 48,52 To limit processing artifacts as a confounding factor when interpreting quantitative measurements, all tissues intended for potential morphometric analysis should be processed to the block stage for all dose groups at the same time. The analysis itself is performed in coded ("blinded") fashion to minimize observer bias.…”

Section: Developmental Neurotoxicity Studies For Chemicalsmentioning

confidence: 99%

“…Accordingly, the quantitative data are deemed acceptable if measurements can be acquired from 6 (of 10) animals/sex/group. 48,52 Conceptually, other methods might be used for the DNTS quantitative analysis to try to increase the number of animals per group from which quantitative measurements may be obtained. One option is to embed multiple brains in one block so that all brains are sectioned at essentially the same level (Figure 2).…”

Section: Developmental Neurotoxicity Studies For Chemicalsmentioning

confidence: 99%

See 2 more Smart Citations

Neuropathology Evaluation in Juvenile Toxicity Studies in Rodents: Comparison of Developmental Neurotoxicity Studies for Chemicals With Juvenile Animal Studies for Pediatric Pharmaceuticals

Bolon

Dostal²,

Garman³

2021

Toxicol Pathol

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The developmental neuropathology examination in juvenile toxicity studies depends on the nature of the product candidate, its intended use, and the exposure scenario (eg, dose, duration, and route). Expectations for sampling, processing, and evaluating neural tissues differ for developmental neurotoxicity studies (DNTS) for chemicals and juvenile animal studies (JAS) for pediatric pharmaceuticals. Juvenile toxicity studies typically include macroscopic observations, brain weights, and light microscopic evaluation of routine hematoxylin and eosin (H&E)-stained sections from major neural tissues (brain, spinal cord, and sciatic nerve) as neuropathology endpoints. The DNTS is a focused evaluation of the nervous system, so the study design incorporates perfusion fixation, plastic embedding of at least one nerve, quantitative analysis of selected brain regions, and sometimes special neurohistological stains. In contrast, the JAS examines multiple systems, so neural tissues undergo conventional tissue processing (eg, immersion fixation, paraffin embedding, H&E staining only). An “expanded neurohistopathology” (or “expanded neuropathology”) approach may be performed for JAS if warranted, typically by light microscopic evaluation of more neural tissues (usually additional sections of brain, ganglia, and/or more nerves) or/and special neurohistological stains, to investigate specific questions (eg, a more detailed exploration of a potential neuroactive effect) or to fulfill regulatory requests.

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Regulatory Testing for Developmental Neurotoxicology

Cited by 2 publications

References 74 publications

CDER Experience With Juvenile Animal Studies for CNS Drugs

CDER Experience With Juvenile Animal Studies for CNS Drugs

Neuropathology Evaluation in Juvenile Toxicity Studies in Rodents: Comparison of Developmental Neurotoxicity Studies for Chemicals With Juvenile Animal Studies for Pediatric Pharmaceuticals

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