Toxicity Testing in the 21st Century
The Hamner is leading an effort to help chart the future of toxicity testing through the implementation and validation of new quantitative risk assessment methods.
Hamner Co-Hosts First Systems Toxicology Workshop in China (October 15-16, 2014)
TT21C: Toxicity Pathway and Network Biology Program Midyear Report (September 3, 2014)
TT21C: Toxicity Pathway and Network Biology Program Review Final Report (December 9-10, 2013)
Toxicity testing is undergoing a fundamental change as new tools and technologies are brought to bear, integrating modern biology into the process. These changes are spurred by the 2007 NRC report, "Toxicity Testing in the 21st Century (TT21C): A Vision and a Strategy." The vision of this report is that in the near future, advances in toxicity testing would greatly increase human relevance, significantly reduce the cost and time required to conduct chemical safety assessments, and markedly reduce and potentially eliminate high-dose animal testing by utilizing in vitro assays, high throughput methodologies, and new predictive tools.
Dr. Melvin E. Andersen, the Charles E. Hamner, Jr. Distinguished Fellow and director of The Institute for Chemical Safety Sciences (ICSS), discusses some of these new tools and technologies for toxicity testing and how the Hamner seeks to incorporate and improve these technologies through a program that would seek to implement the new paradigm for toxicity testing outlined in the 2007 NRC report:
Podcast: Dr. Melvin Andersen - Tools and Technologies
Download the MP3 - (3 MB) (Right-click, Save As)
Implementing the Vision
The Hamner Institute for Chemical Safety Sciences (ICSS), with a history of risk assessment excellence, is working with commercial, NGO, academic and national and international government partners to accelerate the implementation of the TT21C vision and to ensure emphasis on risk-based chemical management in future toxicity testing paradigms. As part of the ICSS program, in vitro toxicity assays will be extended and refined, and work on key prototype pathways will produce relevant examples for in vitro toxicity pathway assay optimization, provide computational systems biology tools for dose response modeling, and establish pharmacokinetic strategies for in vitro-in vivo and biomonitoring interpretation. Success with prototypes will provide more rapid acceptance of new testing approaches, allow efficient expansion to include other toxicity pathways and clearly demonstrate the applications of test results for risk-based human health assessments.
In addition to developing a framework for broader expansion into other toxicity pathways, the ICSS will create a postdoctoral and visiting scientist training program to educate the next generation of toxicologists in the application and use of these new tools. Successful implementation of this paradigm shift in toxicity testing will require these well-trained practitioners to disseminate the knowledge into their organizations.
First Steps: Estrogen Signaling Pathways
In a first step towards implementing the TT21C vision, The Hamner ICSS is investing in a pilot project with estrogen signaling pathways to create a new paradigm for risk assessment that will be based on in vitro methods that will not require in vivo testing. This research program develops targeted in vitro assays for estrogenic compounds in uterine cells/tissues, refines interpretive bioinformatic tools to map estrogen pathway circuitry in these cells, and creates computational pathway models for the dose-response relationships for pathway perturbations. Our overall goal is to provide ‘validated’ in vitro assays for estrogen pathways in human uterine cells and the necessary dose-response modeling modalities so that dose-response information from the ‘validated’ in vitro assays will be considered sufficient for conducting safety assessments with estrogenic compounds without progressing to toxicity studies in intact animals; thus the concept – “Tier 1 and Done”. In this usage, Tier 1 implies well-designed, ‘validated’ in vitro assays rather than referring explicitly to the existing Tier 1 studies in US EPA Endocrine Disruptor Screening Program (EDSP). We will achieve our overall objective by pursuing five specific aims over a three-year period.
|Read our full TT21C proposal||Read the full 2007 NRC report|
Andersen ME, Clewell HJ, Carmichael PL, Boekelheide K. Can case study approaches speed implementation of the NRC report: "Toxicity Testing in the 21st Century: A Vision and a Strategy?". ALTEX. 2011;28(3):175-82.
Bhattacharya, S., Zhang, Q., Carmichael, P.C., Boekelheide, K. and Andersen, M.E. Toxicity Testing In the 21st Century: Defining New Risk AssessmentApproaches Based on Perturbation of Intracellular Toxicity Pathways Using the p53 DNA-Damage and Repair Pathway as a Prototype. PLoS One. June 2011, Volume 6, Issue 6, e20887.
Boekelheide K, Andersen ME. A mechanistic redefinition of adverse effects - a key step in the toxicity testing paradigm shift. ALTEX. 2010;27(4):243-52.
For additional information, please contact
Melvin E. Andersen, CIH, Ph.D., DABT, FATS