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TOXCAST, A TOOL FOR CATEGORIZATION AND PRIORITIZATION OF CHEMICAL HAZARD BASED ON MULTI-DIMENSIONAL INFORMATION DOMAINS
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Impact/Purpose:
Modern computational chemistry and molecular biology tools bring enabling technologies forward that can provide information about the physical and biological properties of large numbers of chemicals. The essence of the proposal is to conduct a demonstration project based upon a rich toxicological database (e.g., registered pesticides, or the chemicals tested in the NTP bioassay program), select a fairly large number (50-100 or more chemicals) representative of a number of differing structural classes and phenotypic outcomes (e.g., carcinogens, reproductive toxicants, neurotoxicants), and evaluate them across a broad spectrum of information domains that modern technology has provided (i.e., physical-chemical properties, predicted biological activities based on existing structure-activity models, biochemical properties based on high throughput screening assays, cell based organotypic assays, and genomic analysis of cells or organisms). These domains represent increasing biological relevance, as well as increasing resource requirements. The ultimate goal of the project would be to mine the resulting data for association between and among the various domains and the known toxicological properties of the base set of chemicals in order to provide a structured strategy to identify potential toxicity pathways, and to prioritize chemicals them for subsequent testing based on that information. The underlying hypothesis is that whether is concerned with the off target effects of drugs, as desired to be understood by the pharmaceutical industry, or toxicity in case of environmental agents of interest to the EPA, the response is driven by interactions with biomolecular targets of one form or another. One needs only to identify those receptors of concern and identify tools for assessing the likelihood of interaction with the chemicals of concern. In moving from the drug development arena (which can be compared to working along one or just a few vectors) to the environmental toxicology arena (which can be likened to working on a matrix instead of a vector), one needs to shift from a specific screening target to a more global agenda, and it becomes necessary to vastly expand the number of potential biomolecular targets, be these obtained from in silico assays, biochemical assays, cell based in vitro assays, surrogate animal models, or short term studies in traditional species. Hence, a wider net of endpoints and information sources will be applied, at least initially, as the concept transgresses from a concept to a reality.
Description:
Across several EPA Program Offices (e.g., OPPTS, OW, OAR), there is a clear need to develop strategies and methods to screen large numbers of chemicals for potential toxicity, and to use the resulting information to prioritize the use of testing resources towards those entities and endpoints that present the greatest likelihood of risk to human health and the environment. This need could be addressed using the experience of the pharmaceutical industry in the use of advanced modern molecular biology and computational chemistry tools for the development of new drugs, with appropriate adjustment to the needs and desires of environmental toxicology. A conceptual approach named ToxCast has been developed to address the needs of EPA Program Offices in the area of prioritization and screening.
Record Details:
Record Type: PROJECTRelated Records:
EPA CHEMICAL PRIORITIZATION COMMUNITY OF PRACTICE.Relationship Reason: EPA CHEMICAL PRIORITIZATION COMMUNITY OF PRACTICE.156233DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Real-Time Growth Kinetics Measuring Hormone Mimicry for ToxCast Chemicals in T‑47D Human Ductal Carcinoma Cells
Relationship Reason: Real-Time Growth Kinetics Measuring Hormone Mimicry for ToxCast Chemicals in T‑47D Human Ductal Carcinoma Cells 259230DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
A Computational Model Predicting Disruption of Blood Vessel Development
Relationship Reason: A Computational Model Predicting Disruption of Blood Vessel Development259229DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Using in Vitro High Throughput Screening Assays to Identify Potential Endocrine-Disrupting Chemicals
Relationship Reason: Using in Vitro High Throughput Screening Assays to Identify Potential Endocrine-Disrupting Chemicals246835DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Incorporating Biological, Chemical and Toxicological Knowledge into Predictive Models of Toxicity: Letter to the Editor
Relationship Reason: Incorporating Biological, Chemical and Toxicological Knowledge into Predictive Models of Toxicity: Letter to the Editor246591DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Response to “Accurate Risk-Based Chemical Screening Relies on Robust Exposure Estimates”
Relationship Reason: Response to “Accurate Risk-Based Chemical Screening Relies on Robust Exposure Estimates”243792DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Economic benefits of using adaptive predictive models of reproductive toxicity in the context of a tiered testing program
Relationship Reason: Economic benefits of using adaptive predictive models of reproductive toxicity in the context of a tiered testing program 240907DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Zebrafish Developmental Screening of the ToxCast™ Phase I Chemical Library
Relationship Reason: Zebrafish Developmental Screening of the ToxCast™ Phase I Chemical Library 240745DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
AN INTELLIGENT REPRODUCTIVE AND DEVELOPMENTAL TESTING PARADIGM FOR THE 21ST CENTURY
Relationship Reason: AN INTELLIGENT REPRODUCTIVE AND DEVELOPMENTAL TESTING PARADIGM FOR THE 21ST CENTURY240663DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
HIGH THROUGHPUT ASSESSMENTS OF CONVENTIONAL AND ALTERNATIVE COMPOUNDS
Relationship Reason: HIGH THROUGHPUT ASSESSMENTS OF CONVENTIONAL AND ALTERNATIVE COMPOUNDS240004DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Integration of Dosimetry, Exposure and High-Throughput Screening Data in Chemical Toxicity Assessment
Relationship Reason: Integration of Dosimetry, Exposure and High-Throughput Screening Data in Chemical Toxicity Assessment238882DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Inducible 70 kDa Heat Shock Proteins Protect Embryos from Teratogen-Induced Exencephaly: Analysis using Hspa1a/a1b Knockout Mice
Relationship Reason: Inducible 70 kDa Heat Shock Proteins Protect Embryos from Teratogen-Induced Exencephaly: Analysis using Hspa1a/a1b Knockout Mice209853DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
A Call for Nominations of Quantitative High-Throughput Screening Assays from Relevant Human Toxicity Pathways
Relationship Reason: A Call for Nominations of Quantitative High-Throughput Screening Assays from Relevant Human Toxicity Pathways205382DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
The US EPAs ToxCast Program for the Prioritization and Prediction of Environmental Chemical Toxicity
Relationship Reason: The US EPAs ToxCast Program for the Prioritization and Prediction of Environmental Chemical Toxicity205381DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Use of Primary Human Cell Systems for Creating Predictive Toxicology Profiles
Relationship Reason: Use of Primary Human Cell Systems for Creating Predictive Toxicology Profiles205380DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Profiling Chemicals Based on Chronic Toxicity Results from the U.S. EPA ToxRef Database
Relationship Reason: Profiling Chemicals Based on Chronic Toxicity Results from the U.S. EPA ToxRef Database 205153DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPA’s ToxCast Program for Predicting Toxicity and Prioritizing Chemicals for Further Screening and Testing
Relationship Reason: EPA’s ToxCast Program for Predicting Toxicity and Prioritizing Chemicals for Further Screening and Testing205087DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Modeling Biotransformation Using In Vitro Data on Parent-Metabolite Pairs within the ToxCast Phase I Chemical Set
Relationship Reason: Modeling Biotransformation Using In Vitro Data on Parent-Metabolite Pairs within the ToxCast Phase I Chemical Set203510DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
An Integrated In Vitro and Computational Approach to Define the Exposure-Dose-Toxicity Relationships In High-Throughput Screens
Relationship Reason: An Integrated In Vitro and Computational Approach to Define the Exposure-Dose-Toxicity Relationships In High-Throughput Screens203509DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Novel Informatic Approaches to Analyze Gene Expression Data with the ToxCast 320 Chemical Library in Cultures of Primary Human Hepatocytes
Relationship Reason: Novel Informatic Approaches to Analyze Gene Expression Data with the ToxCast 320 Chemical Library in Cultures of Primary Human Hepatocytes203469DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
High Throughput Genotoxicity Profiling of the US EPA ToxCast Chemical Library
Relationship Reason: High Throughput Genotoxicity Profiling of the US EPA ToxCast Chemical Library203466DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Cheminformatics Analysis of EPA ToxCast Chemical Libraries to Identify Domains of Applicability for Predictive Toxicity Models and Prioritize Compounds for Toxicity Testing
Relationship Reason: Cheminformatics Analysis of EPA ToxCast Chemical Libraries to Identify Domains of Applicability for Predictive Toxicity Models and Prioritize Compounds for Toxicity Testing203465DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Developing Predictive Toxicity Signatures Using In Vitro Data from the EPA ToxCast Program
Relationship Reason: Developing Predictive Toxicity Signatures Using In Vitro Data from the EPA ToxCast Program203464DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Pathway-Based Concentration Response Profiles from Toxicogenomics Data
Relationship Reason: Pathway-Based Concentration Response Profiles from Toxicogenomics Data203461DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
The ToxCast Pathway Database for Identifying Toxicity Signatures and Potential Modes of Action from Chemical Screening Data
Relationship Reason: The ToxCast Pathway Database for Identifying Toxicity Signatures and Potential Modes of Action from Chemical Screening Data203455DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Evaluation of the ToxCast Suite of Cellular and Molecular Assays for Prediction of In Vivo Toxicity
Relationship Reason: Evaluation of the ToxCast Suite of Cellular and Molecular Assays for Prediction of In Vivo Toxicity203452DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
In Vitro Models of Human Toxicity Pathways
Relationship Reason: In Vitro Models of Human Toxicity Pathways203451DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Modulation of Xenobiotic Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes by ToxCast Chemicals
Relationship Reason: Modulation of Xenobiotic Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes by ToxCast Chemicals203433DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Biological Profiling of Endocrine Related Effects of Chemicals in ToxCast
Relationship Reason: Biological Profiling of Endocrine Related Effects of Chemicals in ToxCast203432DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Classification of Chemicals Based On Structured Toxicity Information
Relationship Reason: Classification of Chemicals Based On Structured Toxicity Information198215DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Overview of ToxCast™
Relationship Reason: Overview of ToxCast™ 198212DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
An Update on ToxCast™
Relationship Reason: An Update on ToxCast™198211DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ToxCast: One Step in the NRC Vision of 21st Century Toxicology (S)
Relationship Reason: ToxCast: One Step in the NRC Vision of 21st Century Toxicology (S)198210DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ToxCast: One Step in the NRC Vision of 21st Century Toxicology (T)
Relationship Reason: ToxCast: One Step in the NRC Vision of 21st Century Toxicology (T)198208DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ToxCast: One Step in the NRC Vision of 21st Century Toxicology
Relationship Reason: ToxCast: One Step in the NRC Vision of 21st Century Toxicology198207DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPAs ToxCast Research Program: Developing Predictive Bioactivity Signatures for Chemicals
Relationship Reason: EPAs ToxCast Research Program: Developing Predictive Bioactivity Signatures for Chemicals198206DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ToxCast: EPAs Contribution to the Tox21 Consortium
Relationship Reason: ToxCast: EPAs Contribution to the Tox21 Consortium198205DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (S)
Relationship Reason: ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (S)198144DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPA's ToxCast Program for Predicting Toxicity and Prioritizing Chemical Testing
Relationship Reason: EPA's ToxCast Program for Predicting Toxicity and Prioritizing Chemical Testing198128DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPA Analysis for MAQC Toxicogenomics Datasets
Relationship Reason: EPA Analysis for MAQC Toxicogenomics Datasets198125DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
The Analysis of Genomic Dose-Response Data in the EPA ToxCast™ Program
Relationship Reason: The Analysis of Genomic Dose-Response Data in the EPA ToxCast™ Program198123DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Classification and Dose-Response Characterization of Environmental Chemicals Based On Structured Toxicity Information From ToxRefDB
Relationship Reason: Classification and Dose-Response Characterization of Environmental Chemicals Based On Structured Toxicity Information From ToxRefDB198090DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
An Introduction to ToxCast™
Relationship Reason: An Introduction to ToxCast™ 198087DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Predictive Modeling of Apical Toxicity Endpoints Using Data From ToxCast
Relationship Reason: Predictive Modeling of Apical Toxicity Endpoints Using Data From ToxCast197992DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ACToR - Aggregated Computational Toxicology Resource
Relationship Reason: ACToR - Aggregated Computational Toxicology Resource197984DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
The EPA ToxCast Program: Developing Predictive Bioactivity Signatures for Chemicals
Relationship Reason: The EPA ToxCast Program: Developing Predictive Bioactivity Signatures for Chemicals197965DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPAs ToxCast Program for Predicting Toxcity and Prioritizing Chemicals for Further Screening and Testing
Relationship Reason: EPAs ToxCast Program for Predicting Toxcity and Prioritizing Chemicals for Further Screening and Testing197866DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ACToR-Aggregated Computational Resource
Relationship Reason: ACToR-Aggregated Computational Resource196203DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
The Toxicity Data Landscape for Environmental Chemicals
Relationship Reason: The Toxicity Data Landscape for Environmental Chemicals196163DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Understanding Mechanisms Toxicity: Insights from Drug Discovery Research
Relationship Reason: Understanding Mechanisms Toxicity: Insights from Drug Discovery Research196083DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPA's ToxCast (TM) Program for Predicting Hazard and Prioritizing Toxicity Testing of Environmental Chemicals
Relationship Reason: EPA's ToxCast (TM) Program for Predicting Hazard and Prioritizing Toxicity Testing of Environmental Chemicals195243DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ToxCast (TM): A New Paradigm for Predicting Hazard and Prioritizing Toxicity Testing
Relationship Reason: ToxCast (TM): A New Paradigm for Predicting Hazard and Prioritizing Toxicity Testing187405DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ACToR-Aggregated Computational Toxicology Resource (I)
Relationship Reason: ACToR-Aggregated Computational Toxicology Resource (I)186944DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity
Relationship Reason: ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity186763DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ToxRefDB: Classifying ToxCast™ Phase I Chemicals Utilizing Structured Toxicity Information
Relationship Reason: ToxRefDB: Classifying ToxCast™ Phase I Chemicals Utilizing Structured Toxicity Information186291DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ACToR A Aggregated Computational Toxicology Resource (S)
Relationship Reason: ACToR A Aggregated Computational Toxicology Resource (S)186287DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPA's ToxCast Program for Predicting Hazard and Prioritizing the Toxicity Testing of Environmental Chemicals
Relationship Reason: EPA's ToxCast Program for Predicting Hazard and Prioritizing the Toxicity Testing of Environmental Chemicals186284DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPA TOXCAST PROGRAM
Relationship Reason: EPA TOXCAST PROGRAM170703DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
TOXMINER: DEVELOPING COMPUTER SYSTEMS AND DATABASES FOR HIGH THROUGHPUT TOXICITY TESTING PRIORITIZATION.
Relationship Reason: TOXMINER: DEVELOPING COMPUTER SYSTEMS AND DATABASES FOR HIGH THROUGHPUT TOXICITY TESTING PRIORITIZATION.170423DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
COMPUTATIONAL TOXICOLOGY-WHERE IS THE DATA?
Relationship Reason: COMPUTATIONAL TOXICOLOGY-WHERE IS THE DATA?170043DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ACToR-AGGREGATED COMPUTATIONAL TOXICOLOGY RESOURCE
Relationship Reason: ACToR-AGGREGATED COMPUTATIONAL TOXICOLOGY RESOURCE169983DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
ACToR A Aggregated Computational Toxicology Resource
Relationship Reason: ACToR A Aggregated Computational Toxicology Resource166383DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
TOXREFDB: LINKING REGULATORY TOXICOLOGICAL INFORMATION ON ENVIRONMENTAL CHEMICALS WITH HIGH-THROUGHPUT SCREENING (HTS) AND GENOMIC DATA.
Relationship Reason: TOXREFDB: LINKING REGULATORY TOXICOLOGICAL INFORMATION ON ENVIRONMENTAL CHEMICALS WITH HIGH-THROUGHPUT SCREENING (HTS) AND GENOMIC DATA.166186DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPA'S TOXCAST PROGRAM FOR PREDICTING HAZARD AND PRIORITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS
Relationship Reason: EPA'S TOXCAST PROGRAM FOR PREDICTING HAZARD AND PRIORITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS166065DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
INTRODUCTION: PREDICTIVE TOXICOGENOMICS AS A COMPONENT OF THE TOXCAST PROGRAM
Relationship Reason: INTRODUCTION: PREDICTIVE TOXICOGENOMICS AS A COMPONENT OF THE TOXCAST PROGRAM166004DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
DEVELOPMENT OF EPA'S TOXCAST PROGRAM FOR PRIORITIZING THE TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS.
Relationship Reason: DEVELOPMENT OF EPA'S TOXCAST PROGRAM FOR PRIORITIZING THE TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS.162611DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
TOXCAST: A NOVEL APPROACH FOR PRIORITIZING POTENTIAL FOR HAZARD OF ENVIRONMENTAL CHEMICALS.
Relationship Reason: TOXCAST: A NOVEL APPROACH FOR PRIORITIZING POTENTIAL FOR HAZARD OF ENVIRONMENTAL CHEMICALS.161629DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
LINKING REGULATORY TOXICOLOGICAL INFORMATION ON ENVIRONMENTAL CHEMICALS WITH HIGH-THROUGHPUT SCREENING (HTS) AND GENOMIC DATA
Relationship Reason: LINKING REGULATORY TOXICOLOGICAL INFORMATION ON ENVIRONMENTAL CHEMICALS WITH HIGH-THROUGHPUT SCREENING (HTS) AND GENOMIC DATA159658DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
THE TOXCAST PROGRAM FOR PRIORITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS
Relationship Reason: THE TOXCAST PROGRAM FOR PRIORITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS 157347DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
EPA'S TOXCAST PROGRAM FOR PREDICTING TOXICITY AND PRIORITIZING ENVIRONMENTAL CHEMICALS
Relationship Reason: EPA'S TOXCAST PROGRAM FOR PREDICTING TOXICITY AND PRIORITIZING ENVIRONMENTAL CHEMICALS157326DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
TOXCAST: A PROGRAM FOR PRIORTITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS
Relationship Reason: TOXCAST: A PROGRAM FOR PRIORTITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS156414DOCUMENT1.0NONEREVIEWEDPUBLICORDNCCT
Project Information:
Progress: At this point in time, ToxCast is nearly the end of its conceptual design phase. The information domains have been identified, and a number of potential contributing data sources have been investigated (e.g., Iconix, MDS Pharma, CEREP, Amphora, PASS). Recruitment actions are underway to add two staff members to the NCCT who will be responsible for the biological and information processing components of ToxCast. Communications have been established with the NTP/NIEHS which has similar interests and which is beginning to work with the NIH Molecular Libraries Initiative (see also the DSSTox implementation plan). Outreach to the OPPTS, ACC, EDF and other external groups has also begun to help develop a consensus on the specific directions and contents of ToxCast.Approach: Modern computational chemistry and molecular biology tools bring enabling technologies forward that can provide information about the physical and biological properties of large numbers of chemicals. The essence of the proposal is to conduct a demonstration project based upon a rich toxicological database (e.g., registered pesticides, or the chemicals tested in the NTP bioassay program), select a fairly large number (50-100 or more chemicals) representative of a number of differing structural classes and phenotypic outcomes (e.g., carcinogens, reproductive toxicants, neurotoxicants), and evaluate them across a broad spectrum of information domains that modern technology has provided (i.e., physical-chemical properties, predicted biological activities based on existing structure-activity models, biochemical properties based on high throughput screening assays, cell based organotypic assays, and genomic analysis of cells or organisms). These domains represent increasing biological relevance, as well as increasing resource requirements. The ultimate goal of the project would be to mine the resulting data for association between and among the various domains and the known toxicological properties of the base set of chemicals in order to provide a structured strategy to identify potential toxicity pathways, and to prioritize chemicals them for subsequent testing based on that information.
The underlying hypothesis is that whether is concerned with the off target effects of drugs, as desired to be understood by the pharmaceutical industry, or toxicity in case of environmental agents of interest to the EPA, the response is driven by interactions with biomolecular targets of one form or another. One needs only to identify those receptors of concern and identify tools for assessing the likelihood of interaction with the chemicals of concern. In moving from the drug development arena (which can be compared to working along one or just a few vectors) to the environmental toxicology arena (which can be likened to working on a matrix instead of a vector), one needs to shift from a specific screening target to a more global agenda, and it becomes necessary to vastly expand the number of potential biomolecular targets, be these obtained from in silico assays, biochemical assays, cell based in vitro assays, surrogate animal models, or short term studies in traditional species. Hence, a wider net of endpoints and information sources will be applied, at least initially, as the concept transgresses from a concept to a reality.
Of course, a number of hurdles would need to be addressed before launching such an effort, including: (1) identification of a subset of chemicals for serving as the proof of concept models; (2) developing a chemical inventory management and distribution system; (3) identifying an upper cap on the per chemical cost of obtaining screening level data: (4) selecting assays within the available resources; (5) flexibility, or tiering, of domains based upon pre-existing knowledge; (6) perhaps initially targeting only a few manifestations of toxicity rather the all possible ones to decrease the complexity of the task; (7) evaluating the impact of metabolizing capability, or lack thereof, on the efficiency of the screening assays; (8) developing a bioinformatic approach to mining the resulting data and identifying signatures of concern; and (9) carrying out a prospective assessment of the bioinformatic approach using chemicals currently entering a traditional testing process. These hurdles would be the subject of considerable discussion as the potential feasibility of this concept proposal is discussed further.
Relevance: The availability of a biologically and chemically based system to begin to associate chemicals of like properties and activities will provide a number of EPA Program Offices with an extremely useful tool that heretofore has been seriously lacking. The tool may be one of the first broad scale products of the NCCT that addresses the mission of improving the efficiency and effectiveness of hazard identification and risk assessment methodologies employed by the EPA.
Project IDs:
ID Code: IIC-3Project type: Partner Specific