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About the Authors:
Xiugong Gao
* E-mail: [email protected]
Affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland, United States of America
Jeffrey J. Yourick
Affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland, United States of America
Robert L. Sprando
Affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland, United States of America
Introduction
Toxicity testing has traditionally relied on animal models which are costly, time consuming and low throughput. Moreover, it often causes pain and stress to, and frequently involves the sacrifice of, large numbers of laboratory animals. This is especially true for reproductive and developmental toxicity testing [1]. With the EU chemicals regulation protocol REACH [2] in force, it has been estimated that over 70–80% of all animals used for safety testing would be used for examining reproductive and developmental toxicity [3], [4]. Under such circumstances, the Tox21 program [5] partnered by several US Federal agencies calls for transforming toxicology testing from traditional in vivo tests to less expensive and higher throughput in vitro methods to prioritize compounds for further study, identify mechanisms of action and ultimately develop predictive models for adverse health effects in humans. In support of the program, the US FDA is developing alternative models for safety assessment of foods, dietary supplements and cosmetics.
Over the last three decades, multiple alternative in vitro or nonmammalian in vivo models for developmental toxicity screening has been developed. Examples of in vivo nonmammalian models include invertebrates such as the nematode (Caenorhabditis elegans) and fruit fly (Drosophila melanogaster), and vertebrates such as the frog (Xenopus laevis) and zebrafish (Danio rerio) [6]. Alternative in vitro test systems utilize organ-, embryo-, or cell-cultures and include the limb bud micromass (MM) [7], the rat postimplantation whole embryo culture (WEC) [8], and the mouse embryonic stem cell test (EST) [9].
Embryonic stem cells (ESCs) have gained considerable interest for their use in developmental toxicity testing due to their fundamental attributes of unlimited...