Comparative organ system development: introduction.

Abstract

It is well known that development continues postna-tally in both humans and animals. There has also beenrecent concern in the scientific and regulatory arenas thatimproved safety assessments for pediatric populationsare needed. The need for the evaluation of potentialtoxicity in immature animals has been raised (WHO,1986; Guzelian et al., 1992; EPA, 1999). Regulatoryrequirements for hazard and risk assessment specific tothe immature individual have received a lot moreattention within the past several years (Kimmel andMakris, 2001). For pesticides, regulatory attention hasincluded the 1996 Food Quality Protection Act (FQPA),an amendment to the Federal Insecticide, Fungicide, andRodenticide Act (FIFRA) and the Federal Food, Drug,and Cosmetic Act (FFDCA), which specifically mandatesa focus on children’s health risks from pesticideexposure. For pharmaceuticals, the FDA Center for DrugEvaluation and Research (CDER) developed regulationsrequiring the assessment for use in pediatric patients(FDA, 1998a,b), including functional evaluations depend-ing on the intended use, pharmacologic activity of thedrug, and expected target organ or system. In order tocomply with the FDA’s and EPA’s regulations, studies injuvenile animals are being initiated. However, as theincrease in studies in young animals continues, it hasbecome clear that there are many challenges to thedesign, conduct, and interpretation of these new data.The Developmental and Reproductive ToxicologyTechnical Committee of the ILSI Health and Environ-mental Sciences Institute (HESI) has undertaken a projectto address the need for developing information oncomparative postnatal development in animal modelsand humans. Overall, the project is focused around 4objectives. First, a focused review of current knowledgeof comparative postnatal development (functional and/or physiological) identifying stage marks for organsystem development and key physiologic developmentallandmarks was undertaken. This information wasdeemed a critical component in the design and conductof studies in young animals. Second, a review of theclinical experience for pediatric toxicity was undertaken.The intent was to evaluate the differences in sensitivitybetween children and adults, reviewing relevant casestudies focusing on the key endpoints of significance andtheir relationships to endpoints used in animal models.The third objective is to define the decision process(es)to determine when juvenile animal studies are needed toprovide safety assessments; and the fourth objective is topropose effective study designs and testing strategies.The following series of mini-reviews on the malereproductive system, the female reproductive system, thelung, kidney, and bone, is the result of efforts to addressthe first objective. Additional reviews on the heart,central nervous system, and immune system will followand complete this objective. Activity is ongoing on theadditional objectives and a workshop is being plannedfor summer/fall 2003, to address the overall project andspecifically objectives three and four. The reviews serveas the basis for identifying information to guide animalmodel selection for pediatric safety assessments.