Current Topics in Postnatal Behavioral Testing

Abstract

The study of developmental neurotoxicity (DNT) continues to be an important component of safety evaluation of candidate therapeutic agents and of industrial and environmental chemicals. Developmental neurotoxicity is considered to be an adverse change in the central and/or peripheral nervous system during development of an organism and has been primarily evaluated by studying functional outcomes, such as changes in behavior, neuropathology, neurochemistry, and/or neurophysiology. Neurobehavioral evaluations are a component of a wide range of toxicology studies in laboratory animal models, whereas neurochemistry and neurophysiology are less commonly employed. Although the primary focus of this article is on neurobehavioral evaluation in pre- and postnatal development and juvenile toxicology studies used in pharmaceutical development, concepts may also apply to adult nonclinical safety studies and Environmental Protection Agency/chemical assessments. This article summarizes the proceedings of a symposium held during the 2015 American College of Toxicology annual meeting and includes a discussion of the current status of DNT testing as well as potential issues and recommendations. Topics include the regulatory context for DNT testing; study design and interpretation; behavioral test selection, including a comparison of core learning and memory systems; age of testing; repeated testing of the same animals; use of alternative animal models; impact of findings; and extrapolation of animal results to humans. Integration of the regulatory experience and scientific concepts presented during this symposium, as well as from subsequent discussion and input, provides a synopsis of the current state of DNT testing in safety assessment, as well as a potential roadmap for future advancement.

CDER Experience With Juvenile Animal Studies for CNS Drugs

“…This was primarily seen in rat studies that assessed navigational learning and memory using either labyrinthine (Cincinnati and Biel) or open-field (Morris) water mazes, tests that have been recommended for regulatory use based on characteristics such as sensitivity, construct/theoretical validity, practicality, and interpretational/predictive value. 12,33 Cognitive impairment is among the most common neurotoxic effects associated with developmental exposure to environmental agents and drugs in epidemiological studies. 34 However, the clinical detection of cognitive deficits resulting from developmental exposures is fraught with difficulties; for example, clinical evaluation of the developmental effects of pediatric drug exposure may be confounded by an underlying neurological disorder.…”

“…28 Appropriate neurobehavioral endpoints appear well suited for the detection of DNT in juvenile animal studies, and our findings generally support recent recommendations regarding regulatory neurobehavioral testing. 12,16,26 The innate sensitivity and prolonged postnatal development of the CNS make it particularly susceptible to environmental influences during childhood, so a thorough evaluaton of possible long-term effects of drug exposure on brain development is essential for an adequate pediatric safety assessment. 29 And, since many potent neurotoxic agents produce no detectable morphological changes, functional measures may provide the only evidence of DNT.…”

“…For DNT evaluations, well-established methods should be used to monitor important central nervous system (CNS) functions, including assessments of reflex ontogeny, sensorimotor function, locomotor activity, reactivity, and learning and memory. 12 Experience gained with juvenile animal studies may make it possible to draw some valuable conclusions about which endpoints and methods are best suited for identifying postnatal developmental toxicity or other age-related risk. With this in mind, we have surveyed the juvenile animal studies conducted for drug applications reviewed in the Divisions of Psychiatry and Neurology Products between 2009 and 2014.…”

Evaluation of Juvenile Animal Studies for Pediatric CNS-Targeted Compounds: A Regulatory Perspective

“…Behavioral examinations in the rat studies, which were usually assessed a few weeks after start of treatment (sometimes just before daily dosing), generally consisted of: Open field observation/functional observatory battery (FOB), or modified Irwin Auditory (or acoustic) startle reflex testing Learning and memory testing: Water maze tests were used for these purposes. 9 These tests were conducted at ages >PND 50, usually once during treatment, and once during off-treatment. Morris 10 or Cincinnati 11 water maze tests were most commonly used (Tou1, Adhd1, Adhd2, Epi1, Epi5, Epi6, Schi2, Schi2, Dep1, and Dep2), while in 2 cases (Nar1, Schi3), the type of water maze was not specified.…”