Adverse Outcome Pathways for Developmental Toxicity

Abstract

Adverse Outcome Pathways (AOPs) (frameworks for organizing knowledge about the etiology of an adverse phenotypic outcome) for developmental toxicity are still in their infancy yet represent the culmination of literally centuries of thinking and experimentation. Throughout history people have wondered about the origins of birth defects. It was not until the late nineteenth century that experimental teratology demonstrated that development of embryos could be predictably perturbed by noxious agents, and not until the twentieth century did those experiments include mammalian species. In the mid- to late twentieth century scientists began to design experiments in multiple species to understand the etiology of birth defects. Progress was slow due to limitations in both knowledge of developmental biology and technology. These studies typically took place in individual scientists’ laboratories, so lack of collaboration was another impediment. Nevertheless, ideas and experimentation abounded, as in the case of the notorious human teratogen thalidomide, which spurred research producing dozens of hypotheses about mechanisms of teratogenesis and the biology underlying the stark species differences in sensitivity. Developmental biologists began to uncover molecular signaling pathways critical for normal morphogenesis and new approaches to studying them. In the first decade of the twenty-first century, teratologists, developmental biologists, and toxicologists came together first to advocate exploiting new knowledge about evolutionarily conserved signaling pathways to design assays for developmental toxicity done in vitro or in alternative species, and again to advocate for development and application of new approaches including high-throughput batteries of in vitro assays using human materials and robotic instrumentation to speed the accrual of new knowledge. At the same time, rapid advances in computational capabilities spawned in silico models of morphogenesis and powerful cheminformatic approaches. Online databases now provide public access to an ever-expanding volume of data and information, and collaborative tools provide accessible platforms for collective thinking. For AOPs, this includes the AOPwiki (http://aopkb.org/), a public repository for AOPs across the broad field of toxicology that allows for public comments on, and contributions to, AOPs under development. There are at present few AOPs for developmental toxicity in the AOPwiki, but the opportunities are great for this valuable resource. This chapter will briefly recount some historical milestones in teratology and articulate several illustrative examples of research on mechanisms of normal and abnormal development that have served to provide the bricks and mortar from which AOPS for developmental toxicity can be built. AOPs emerging from this knowledge are presented to demonstrate the value of this approach and finally, remaining hurdles to effectively applying the AOP framework to human risk assessments will be discussed.