New Paradigm in Toxicity Testing: Integrated Discrete Multiple Organ Co-cultures (IdMOC) for the Evaluation of Xenobiotic Toxicity

Concerns regarding the toxicity of environmental chemicals, consumer products, food additives, pharmaceuticals, and biologics have prompted several US legislative and regulatory initiatives. In 1998, the U.S. Environmental Protection Agency (EPA) initiated the High Production Volume (HPV) program1 to provide health and environmental data for chemicals that are manufactured or imported in the United States in quantities greater than 1 million pounds annually. This represented 95% of US chemical production and use by volume at the time. The extended HPV program2 was announced in 2005 to address newer HPV chemicals (574) and broaden the scope of the program to include use and exposure information of all HPV chemicals. The European Union passed the REACH law (Registration, Evaluation, Authorization and restriction of Chemicals), which aimed to regulate all chemicals produced in quantities greater than one ton/year. Such initiatives were directed at making industry responsible for assessing and managing the risks posed by chemicals, as well as to provide appropriate safety information to all its users. Furthermore, such legislation has allowed authorities to take appropriate action and ban highly toxic substances (Knight, 2008; Cohen, 2011; Schoeters, 2010). In 1998, the EPA announced the Endocrine Disrupting Chemicals program3 to test dietary and environmental chemicals that could potentially disrupt the hormonal milieu of humans and wildlife. In 2009, the EPA proposed a set of 73 chemicals for initial screening, followed by another set in 2010 consisting of 134 chemicals (Borgert, et al., 2011). In addition to the unprecedented demands of REACH and the EPA, the National Toxicology Program (NTP), based at the National Institutes of Health and Environmental Sciences (NIEHS), has actively solicited nominations from the public and scientific community for toxicological evaluation of chemicals4. Such nominations are reviewed based on supporting information and priorities of the agency and, when considered appropriate, are evaluated at the laboratories of the NIEHS. The U.S. Food and Drug Administration (FDA) has routinely regulated pharmaceuticals, biologics (vaccines, blood products), devices, food additives, veterinary products, and cosmetics for safety. Thus, there is a clear need for increased testing and early screening of thousands of compounds to eliminate dangerous substances and develop safe products with marketable potential. New Paradigm in Toxicity Testing: Integrated Discrete Multiple Organ Co-cultures (IdMOC) for the Evaluation of Xenobiotic Toxicity