NAMs Training: Getting Started

NAMs Background

Reducing the use of vertebrate animals for toxicity testing is a priority for the U.S. Environmental Protection Agency (EPA) and, as such, the Agency is working on the development and application of New Approach Methodologies (NAMs). NAMs are defined as any technology, methodology, approach, or combination that can provide information on chemical hazard and risk assessment to avoid the use of vertebrate animal testing. Examples of NAMs are in vitro tests or assays, in chemico assays and in silico algorithms. 

• In vitro studies are experiments which use human or animal cells. 
• In chemico studies are experiments which do not use any human or animal cells, but simply evaluate how a chemical interacts/reacts with certain materials.
• Finally, in silico is the term used for computer-driven predictive tools.

CompTox Chemicals Dashboard

The Comptox Chemicals Dashboard contains environmental chemical data to support EPA and partner decision making. Here, one can find legacy and NAM information on chemistry, hazard, bioactivity, dosimetry, and exposure data, as well as navigate to other online tools, such as the read-across tool, GenRA. The dashboard also provides downloading capability. These data may help inform hazard prediction for weight-of-evidence, screening, and new approach methodologies-based points-of-departure for risk assessment.

Ecotoxicology

EPA researchers are developing, integrating, and evaluating ecological models to predict effects of pesticides and other chemicals on endangered species and wildlife populations. High-level assessments include quantitative estimates of ecologically relevant risk and identification of risk mitigation options. Many chemicals have little or no data on which to base these decisions, so risk assessments rely on ecological models to estimate exposure and subsequent effects. The ECOTOXicology Knowledgebase (ECOTOX) is a source for locating single chemical toxicity data for aquatic life, terrestrial plants and wildlife. Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) is a fast, online screening tool that allows researchers and regulators to extrapolate toxicity information across species. SeqAPASS extrapolates from data rich model organisms to thousands of other non-target species to evaluate their specific potential chemical susceptibility. 

Exposure

As part of its ongoing efforts to support implementation of the Toxic Substance Control Act as revised by the Frank R. Lautenberg Chemical Safety for the 21st Century Act, EPA researchers are developing innovative methods to collect and predict exposure estimates for thousands of chemicals. These type of quantitative exposure data are combined with toxicity data to help thoroughly evaluate chemicals for potential health effects.

Measured Data

Exposure data are collected from the public domain and collated into databases for use. Consumer product information: CPDat (Chemical and Products Database) is a database containing information on consumer products and the chemicals they contain. The database’s primary intended use is for exposure, risk, and safety assessments. Exposure data are also measured using non-targeted screening approaches to identify unknown chemicals in the environment.

Predictions

In general, we do not have a good understanding of the potential to be exposed to chemicals for non-pharmaceuticals or non-occupational situations. Rapid exposure prediction models have the potential to provide quick estimates for thousands of chemicals where no measured data exist. Exposure models can estimate far-field exposures, such as those where chemicals are released into the outdoor environment. The ExpoCast model estimates global daily exposures from a consensus prediction, which can be found in the CompTox Chemicals Dashboard. Nearfield exposure models provide estimates of exposure to chemicals used in consumer products and in-home products. The Stochastic Human Exposure and Dose Simulations– HT Model is a probabilistic human exposure model that estimates everyday exposures where detailed use patterns drive the exposures. The output produces population-level distributions by dermal, inhalation, and ingestion routes.

Databases Relevant to Toxicity and Bioactivity

The ToxCast program generates data and predictive models on thousands of chemicals of interest to the EPA.

Screening

Automated chemical screening technologies called high-throughput screening assays are used to expose living cells, isolated proteins, or other biological molecules to chemicals. The cells or proteins are then screened for changes in biological activity that may suggest potential toxic effects. These innovative methods have the potential to limit the number of required laboratory animal-based toxicity tests while quickly and efficiently screening thousands of chemicals for potential health effects. ToxCast data is available for download, as well as viewing and download via the CompTox Chemicals Dashboard

In vivo legacy data

Toxicity Reference Database (ToxRefDB) and ToxValDB are devoted to collecting legacy in vivo animal-based toxicology study data from several sources to provide a comprehensive collection of publicly available data. These data can be accessed via the CompTox Chemicals Dashboard.

Toxicokinetics and Dosimetry

Toxicokinetics (TK) provides a bridge between toxicity and exposure assessment by predicting tissue concentrations due to exposure. Chemical-specific in vitro data have been obtained from relatively high-throughput toxicokinetic (HTTK) experiments. HTTK in vitro experiments include measuring the fraction of a chemical bound to plasma (Fup) and measuring intrinsic metabolic clearance (CLint) typically in primary human liver cells. In silico HTTK approaches include predicting Fup and CLint using a computer and predicting the amount of chemical in an animal based on the exposure dose (forward dosimetry) and predicting the amount of exposure dose given to an animal based on an assumed internal steady state plasma concentration (reverse dosimetry, aka reverse toxicokinetics (RTK). An EPA open-source R package (“httk”) is freely available and allows for forward and reverse dosimetry and other statistical analyses of chemicals. When performing RTK, we use the in vitro NAM data as the assumed internal steady state plasma concentration in the “httk” R-package to estimate an Administered Equivalent Dose (AED).

Chemical Safety Proof of Concept (POC) Workflows

Regulatory agencies world-wide are looking to efficiently integrate information on chemical substances to inform priorities for decisions and data requests. The Public Information Curation and Synthesis (PICS) approach integrates publicly-available hazard, exposure, persistence, and bioaccumulation information for chemical substances and aims to increase efficiency and focus expert review on substances that may have a greater potential for selection as a high- or low-priority.

A Proof-of-Concept Case Study Integrating Publicly Available Information to Screen Candidates for Chemical Prioritization under TSCA

Chemistry

Advanced chemical evaluation techniques have allowed scientists to utilize new approach methods and reduce the use of vertebrate animal testing. These techniques include non-targeted analysis (NTA),  General Read-Across (GenRA) and the Toxicity Estimation Software Tool (TEST) and WebTEST. GenRA allows one to fill a toxicological data gap whereby a chemical with existing data is used to make a prediction for a ‘similar’ chemical. The TEST software can predict measures of toxicity from physical characteristics of the structure of the chemical, as it contains a compilation of Quantitative Structure Activity Relationship (QSAR) models.