Review Article Postnatal Growth and Morphological Development of the Brain: A Species Comparison Rebecca E. Watson, 1 John M. DeSesso, 1 Mark E. Hurtt, 2 and Gregg D. Cappon 2Ã 1 Mitretek Systems, Falls Church, Virginia 2 Pfizer Global Research and Development, Groton, Connecticut The objective of this report is to summarize the available literature regarding the postnatal growth and morphological development of the brain and compare the timelines for these events between humans and experimental species. While not the primary focus of this report, in acknowledgement of the evident role of maturation of neurotransmitter systems in development, a brief description of the comparative development of the NMDA receptor is included. To illustrate the challenges faced in estimating developmental toxicity potential in humans, the importance of postnatal experience in CNS development is also briefly reviewed. This review is part of the initial phase of a project undertaken by the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) to bring together information on a selected number of organ systems and compare their postnatal development across several species (Hurtt and Sandler: Birth Defects Res Part B 68:307–308, 2003). Birth Defects Res (Part B) 77:471–484, 2006. r 2006 Wiley-Liss, Inc. INTRODUCTION An improved understanding of brain development in the human could shed light upon the etiology of certain neurological disorders, and help determine when it is safe and unsafe to administer central nervous system (CNS)-altering drugs to pregnant/lactating women and young children. Currently, the cause of many develop- mental neurological disorders is difficult to ascertain, often because symptoms are not easily or immediately observable and/or do not manifest themselves until well after irreparable neurological damage has been done. Even if symptoms are observed, retrospectively identify- ing a causative factor can pose significant challenges. Fetal alcohol syndrome, a disorder characterized by a pattern of observable physical changes, has been recog- nized only relatively recently. This is surprising when one considers that millions of children over many centuries must have exhibited this syndrome (Jones, 2003). Additionally, if an agent were to affect learning or IQ, it would be difficult to detect the impact because there is no way of knowing what one’s IQ or learning patterns would have been had the damage not occurred. Children are not the equivalent of low-weight adults and there are considerable dangers with treating them as such. Brain damage of all forms including frank mental retardation to milder learning disabilities occurs in 10– 20% of all births and many of these disabilities persist in adulthood (Lipkin, 1991; Ito, 2004). The mature CNS is not a common target for toxicants. But some toxicants, such as lithium and inorganic mercury, have more pronounced adverse effects or act only on processes occurring during development (Rodier, 1994a). In light of the fact that young children and pregnant/lactating women may be given drugs that are intended to affect the central nervous system, including antiepileptics, antidepressants, and anesthetics, it is important to understand if and how developing neurological pro- cesses might be adversely impacted. In order to more thoroughly understand potential toxicity to the develop- ing nervous system, it is desirable to have experimental animal models that, to the extent possible, are represen- tative of the human. Thus, there is a need to examine measures of comparative neurological development in a variety of experimental species. The human and other higher old world primates are unique in that they have an extended childhood characterized by long periods of neurological develop- ment. Unfortunately, there is no simple mathematical relationship relating animal and human development, which complicates the extrapolation from an experi- mental animal to the human. It is commonly (and erroneously) said that 1 ‘‘dog year’’ is equivalent to 7 ‘‘human years,’’ but a one-year-old dog certainly more closely resembles an adult canine than a 7-year-old child resembles an adult human. The use of animal models to help understand central nervous system development in the human is further complicated by the fact that there are few robust parallel relationships between certain Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/bdrb.20090 *Correspondence to: Dr. Gregg D. Cappon, Pfizer Global Research & Development, Safety Sciences, Eastern Point Road, Groton, CT 06340. E-mail: gregg.d.cappon@pfizer.com Received 1 August 2006; Accepted 8 August 2006 Birth Defects Research (Part B) 77:471–484 (2006) & 2006 Wiley-Liss, Inc.