Bone development in laboratory mammals used in developmental toxicity studies

Abstract

Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been established, and modification of the evaluation using imaging technologies is under development. The embryology of the rodent, rabbit, and primate skeleton has been characterized in detail and summarized herein. The rich literature on variations and malformations in skeletal development that can occur in the offspring of normal animals and animals exposed to test articles in toxicology studies is reviewed. These perturbations of skeletal development include ossification delays, alterations in number, shape, and size of ossification centers, and alterations in numbers of ribs and vertebrae. Because the skeleton is undergoing developmental changes at the time fetuses are evaluated in most study designs, transient delays in development can produce apparent findings of abnormal skeletal structure. The determination of whether a finding represents a permanent change in embryo development with adverse consequences for the organism is important in study interpretation. Knowledge of embryological processes and schedules can assist in interpretation of skeletal findings. K E Y W O R D Sembryology, developmental toxicity testing, embryofetal toxicology testing, ossification, skeletal development, supernumerary ribs, wavy ribs | DEFINITION OF THE PROBLEMDevelopmental toxicity testing includes assessment of the near-term fetal skeleton in laboratory animals, particularly rats, mice, and rabbits. Alterations associated with treatment usually are categorized as malformations or variations, defined in section 2, below. The distinction between variations and malformations is not always clear, and different laboratories may produce different assessments. The biological importance of variations may also be unclear. We will review the published data on these skeletal findings with emphasis on the biological significance of the skeletal changes that have been the most variably interpreted.We are not the first authors to undertake an assessment of developmental changes in the skeleton. Among the helpful reviews in the literature are those by Kimmel and Wilson (1973), Chernoff and Rogers (2004), Tyl, Chernoff, and Rogers (2007), Daston and Seed (2007), Carney and Kimmel (2007), Beyer et al. (2011), Kimmel, Garry, andDeSesso (2014), and Hofmann, Buesen, Schneider, and van Ravenzwaay (2016). | REGULATORY REQUIREMENTS | TechniquesMost pharmaceutical and many non-pharmaceutical chemicals are evaluated for developmental toxicity in experimental animals prior to marketing approval. The requirements for pharmaceutical chemicals have been harmonized for use in Europe, the US, and Japan (ICH, 2005(ICH, , 2017 wileyonlinelibrary.com/journal/bdr2 1157 examination of preferably all fetuses is part of the developmental toxicity evaluation; however, the method of skeletal examination is not specified. The newer techniques of microcomputerized tomography and magnetic resonance imaging ...

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