Environmental Factor, January 2009, National Institute of Environmental Health Sciences
EPA Leader Reports on Progress in Toxicity Testing
By Eddy Ball
Robert Kavlock, Ph.D., visited NIEHS on May 7 to present a status report on the ToxCast™ program he oversees as the director of the National Center for Computational Toxicology (NCCT) at the U.S. Environmental Protection Agency (EPA). EPA is a partner in the five-year Memorandum of Understanding (MOU) signed in 2008 with NIEHS and the National Human Genome Research Institute to improve the evaluation of health risks posed by chemicals found in the environment.
Members of this MOU are informally known as the Tox21 community - for toxicology in the 21st century. This seminar was sponsored by the National Toxicology Program (NTP) Biomolecular Screening Branch, which is responsible for managing the NTP's High Throughput Screening (HTS) Initiative. (https://ntp.niehs.nih.gov/index.cfm?objectid=06002ADB-F1F6-975E-73B25B4E3F2A41CB) The presentation by "ToxCast: Profiling Bioactivity, Identifying Pathways and Predicting Toxicity," attracted a group of scientists from NIEHS and the NTP, including Linda Birnbaum, Ph.D., director of both organizations.
The goal of ToxCast™ (https://www.epa.gov/ncct/toxcast/) is to develop a high throughput-based program for evaluating the biological targets of environmental chemicals responsible for adverse effects in exposed individuals. EPA needs such a process in order to close the large information gap that exists for thousands of man-made chemicals present in the environment. EPA began planning the ToxCast™ program in fiscal year (FY) 2005, with a "reduce-to-practice" target date of FY 2012.
As he talked about ToxCast™, Kavlock reviewed progress by the NCCT (https://www.epa.gov/ncct/") and the other Tox21 partners toward implementing the vision outlined in a 2007 report (https://www.epa.gov/ncct/) by the National Research Council on a vision and strategy for toxicity testing in the 21st century. Kavlock also said he was encouraged by the growing cooperation that NCCT is enjoying from manufacturers and drug companies - potentially valuable sources of privileged toxicity data.
According to Kavlock, the toxicology community now acknowledges that by itself the classical model for animal studies is inadequate for the task of assessing the toxicity of the growing number of chemicals in the environment. Animal studies are expensive - costing millions of dollars for a single chemical - time consuming and controversial, he explained. The challenge scientists and regulators face involves developing cost-effective HTS assays to assess biochemical pathways triggered by chemicals, their "biological fingerprints" and "toxicity signatures," that can be used in predicting the potential health effects of exposures.
"We don't rely on a single technology," Kavlock noted as he reviewed the range of assays the program is using. As an example, he pointed to five different methods the program uses for checking whether a chemical can act as an estrogen.
ToxCast™ examines how each chemical affects a variety of biological processes and compiles the information into a huge database to complement existing animal data. This data will be combined with information on the chemical's structure and behavior in the human body to help quickly classify chemicals based on their potential for human or environmental harm. Phase One of ToxCast™ has produced data from 320 chemicals, approximately 500 in vitro assays and some 100 in vivo endpoints, Kavlock said. The data analysis challenge for such a massive amount of data is daunting. "It's like the early days of microarrays," he added. "We have lots of data, and we're looking for the best ways to interpret the observations."
Phase Two of the program, set to start later this year, will include a groundbreaking collaboration with Pfizer, Inc. To help validate the approach for predicting human toxicity, Pfizer has agreed to provide EPA with information on drugs that were found to cause toxicity in clinical trials.
While he and his audience were upbeat about the future of ToxCast™ and alternative toxicity testing, Kavlock acknowledged the challenges ahead. "The deluge is coming," he said. "We are really on the tip of the iceberg in terms of looking at the data."