Citation:

Rogers, J. Fifty Years of Predictive Testing for Human Developmental Toxicity: From Thalidomide to Virtual Embryos. Chinese Society of Toxicology, Nanjing, Nanjing, CHINA, July 09 - 14, 2017.

Impact/Purpose:

The thalidomide tragedy of the early 1960s led to the three “Segment” tests promulgated by the United States Food and Drug Administration in 1966. The Segment II study involves exposing pregnant rodents or rabbits during organogenesis and examining fetuses prior to parturition. Endpoints include maternal viability, weight gain and food intake during pregnancy, clinical signs of maternal toxicity, fetal viability and weight, and fetal external, internal and skeletal malformations and variations. This study design has stood the test of time, adopted by regulatory agencies around the world and harmonized by the International Conference on Harmonization (ICH). Over the years, modifications and flexibilities have been incorporated, including extending dosing beyond major organogenesis. The Segment III Test, Developmental Neurotoxicity Test and Developmental Immunotoxicity tests assess functional endpoints postnatally. These whole animal tests are costly and time-consuming, and there are currently far more potentially toxic chemicals in the environment than can possibly be tested in rodents and rabbits. Thus, over the decades there have been many alternative ideas and systems proposed for developmental toxicity testing, including embryos of alternative species (e.g., Daphnia, Hydra, C. elegans, frog, chick, zebrafish), in vitro culture of rodent cells, tissues or whole embryos, and human pluripotent stem cells (PSCs). Batteries of high-throughput screening assays in the U.S. Environmental Protection Agency’s ToxCast and the federal Tox21 consortium programs address multiple targets relevant to developmental toxicity and are being developed to prioritize chemicals for testing, to predict toxicity, and to aid in discovery of adverse outcome pathways. These programs take advantage of emerging capabilities in molecular biology, robotics, bioinformatics, cheminformatics and computational modeling to rapidly test hundreds to thousands of chemicals and develop algorithms to predict toxicity. “Organ-on-a-Chip” micro-physiological systems are being designed to recapitulate facets of development using PSCs and other cells in synthetic media under controlled conditions, and “virtual embryo” approaches use cell behavior-based in silico programs to model normal and predict abnormal development. After decades of incremental advances in developmental toxicology, recent progress has rapidly brought us to the dawn of a new paradigm for predictive toxicity testing

Description:

The thalidomide tragedy of the early 1960s led to the three “Segment” tests promulgated by the United States Food and Drug Administration in 1966. The Segment II study involves exposing pregnant rodents or rabbits during organogenesis and examining fetuses prior to parturition. Endpoints include maternal viability, weight gain and food intake during pregnancy, clinical signs of maternal toxicity, fetal viability and weight, and fetal external, internal and skeletal malformations and variations. This study design has stood the test of time, adopted by regulatory agencies around the world and harmonized by the International Conference on Harmonization (ICH). Over the years, modifications and flexibilities have been incorporated, including extending dosing beyond major organogenesis. The Segment III Test, Developmental Neurotoxicity Test and Developmental Immunotoxicity tests assess functional endpoints postnatally. These whole animal tests are costly and time-consuming, and there are currently far more potentially toxic chemicals in the environment than can possibly be tested in rodents and rabbits. Thus, over the decades there have been many alternative ideas and systems proposed for developmental toxicity testing, including embryos of alternative species (e.g., Daphnia, Hydra, C. elegans, frog, chick, zebrafish), in vitro culture of rodent cells, tissues or whole embryos, and human pluripotent stem cells (PSCs). Batteries of high-throughput screening assays in the U.S. Environmental Protection Agency’s ToxCast and the federal Tox21 consortium programs address multiple targets relevant to developmental toxicity and are being developed to prioritize chemicals for testing, to predict toxicity, and to aid in discovery of adverse outcome pathways. These programs take advantage of emerging capabilities in molecular biology, robotics, bioinformatics, cheminformatics and computational modeling to rapidly test hundreds to thousands of chemicals and develop algorithms to predict toxicity. “Organ-on-a-Chip” micro-physiological systems are being designed to recapitulate facets of development using PSCs and other cells in synthetic media under controlled conditions, and “virtual embryo” approaches use cell behavior-based in silico programs to model normal and predict abnormal development. After decades of incremental advances in developmental toxicology, recent progress has rapidly brought us to the dawn of a new paradigm for predictive toxicity testing.

Record Details: