Transforming Environmental Health ProtectionFrancis S. Collins1,*,†, George M. Gray2,*, and John R. Bucher3,*1Director, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda,MD 208922Assistant Administrator for the Office of Research and Development, U.S. Environmental Protection Agency,Washington, DC 204603Associate Director, U.S. National Toxicology Program, National Institute of Environmental Health Sciences(NIEHS), Research Triangle Park, NC 27709, USA.In 2005, the U.S. Environmental Protection Agency (EPA), with support from the U.S. NationalToxicology Program (NTP), funded a project at the National Research Council (NRC) todevelop a long-range vision for toxicity testing and a strategic plan for implementing thatvision. Both agencies wanted future toxicity testing and assessment paradigms to meet evolvingregulatory needs. Challenges include the large numbers of substances that need to be testedand how to incorporate recent advances in molecular toxicology, computational sciences, andinformation technology; to rely increasingly on human as opposed to animal data; and to offerincreased efficiency in design and costs (1–5). In response, the NRC Committee on ToxicityTesting and Assessment of Environmental Agents produced two reports that reviewed currenttoxicity testing, identified key issues, and developed a vision and implementation strategy tocreate a major shift in the assessment of chemical hazard and risk (6,7). Although the NRCreports have laid out a solid theoretical rationale, comprehensive and rigorously gathered data(and comparisons with historical animal data) will determine whether the hypothesizedimprovements will be realized in practice. For this purpose, NTP, EPA, and the NationalInstitutes of Health Chemical Genomics Center (NCGC) (organizations with expertise inexperimental toxicology, computational toxicology, and high-throughput technologies,respectively) have established a collaborative research program.EPA, NCGC, and NTP Joint ActivitiesIn 2004, the NTP released its vision and roadmap for the 21st century (1), which establishedinitiatives to integrate high-throughput screening (HTS) and other automated screening assaysinto its testing program. In 2005, the EPA established the National Center for ComputationalToxicology (NCCT). Through these initiatives, NTP and EPA, with the NCGC, are promotingthe evolution of toxicology from a predominantly observational science at the level of disease-specific models in vivo to a predominantly predictive science focused on broad inclusion oftarget-specific, mechanism-based, biological observations in vitro (1,4) (see figure, below).Toxicity pathwaysIn vitro and in vivo tools are being used to identify cellular responses after chemical exposureexpected to result in adverse health effects (7). HTS methods are a primary means of discovery†Author for correspondence. E-mail: E-mail: [email protected].*The views expressed here are those of the individual authors and do not necessarily reflect the views and policies of their respectiveagencies.We propose a shift from primarily in vivo animal studies to in vitro assays, in vivo assays with lower organisms, and computationalmodeling for toxicity assessments.NIH Public AccessAuthor ManuscriptScience. Author manuscript; available in PMC 2009 May 8.Published in final edited form as:Science. 2008 February 15; 319(5865): 906–907. doi:10.1126/science.1154619.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscriptfor drug development, and screening of >100,000 compounds per day is routine (8). However,drug-discovery HTS methods traditionally test compounds at one concentration, usuallybetween 2 and 10 µM, and tolerate high false-negative rates. In contrast, in the EPA, NCGC,and NTP combined effort, all compounds are tested at as many as 15 concentrations, generallyranging from ∼5 nM to ∼100 µM, to generate a concentration-response curve (9). Thisapproach is highly reproducible, produces significantly lower false-positive and false-negativerates than the traditional HTS methods (9), and facilitates multiassay comparisons. Finally, aninformatics platform has been built to compare results among HTS screens; this is beingexpanded to allow comparisons with historical toxicologic NTP and EPA data(http://ncgc.nih.gov/pub/openhts). HTS data collected by EPA and NTP, as well as by theNCGC and other Molecular Libraries Initiative centers (http://mli.nih.gov/), are being madepublicly available through Webbased databases [e.g., PubChem(http://pubchem.ncbi.nlm.nih.gov)]. In addition, efforts are under way to link HTS data tohistorical toxicological test results, including creating relational databases with controlledontologies, annotation of the chemical entity, and public availability of information at thechemical and biological level needed to interpret the HTS data. EPA’s DSSTox (DistributedStructure Searchable Toxicity) effort is one example of a quality-controlled, structure-searchable database of chemicals that is linked to physicochemical and toxicological data(www.epa.gov/ncct/dsstox/).At present, more than 2800 NTP and EPA compounds are under study at the NCGC in over50 biochemical- and cell-based assays. Results from the first study, in which 1408 NTPcompounds were tested for their ability to induce cytotoxicity in 13 rodent and human celltypes, have been published (10). Some compounds were cytotoxic across all cell types andspecies, whereas others were more selective. This work demonstrates that titration-based HTScan produce high-quality in vitro toxicity data on thousands of compounds simultaneously andillustrates the complexities of selecting the most appropriate cell types and assay end points.Additional compounds, end points, and assay variables will need to be evaluated to generatea data set sufficiently robust for predicting a given in vivo toxic response.In 2007, the EPA launched ToxCast (www.epa.gov/ncct/toxcast) to evaluate HTS assays astools for prioritizing compounds for traditional toxicity testing (5). In its first phase, ToxCastis profiling over 300 wellcharacterized toxicants (primarily pesticides) across more than 400end points. These end points include biochemical assays of protein function, cell-basedtranscriptional reporter assays, multicell interaction assays, transcriptomics on primary cellcultures, and developmental assays in zebrafish embryos. Almost all of the compounds beingexamined in
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