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Integrated Approaches to Testing and Assessment

Integrated approaches to testing and assessment (IATAs) provide a means by which all relevant and reliable information about a chemical is used to answer a defined hazard characterization question. Information considered can include toxicity data, computational model predictions, exposure routes, use cases, and production volumes. This information is used to characterize outcomes that can inform regulatory decision-making. There is increasing interest in replacing tests using laboratory animals with human cell-based, biochemical, and/or computational methods to predict chemical toxicity. But because of the complexity of toxicity mechanisms, data from several of these alternative methods usually need to be considered in combination to adequately predict toxicity. IATAs provide a means by which these data can be considered in combination. When necessary, IATAs can guide generation of new data, preferably using non-animal approaches, to inform regulatory decision-making.Read More

A defined approach to testing and assessment can be used as part of an IATA or on its own to satisfy a need for hazard information. While IATAs may rely on expert judgment, defined approaches are structured and reproducible, and therefore provide objective outputs. NICEATM, in collaboration with other scientists, has developed defined approaches for skin sensitization and endocrine disruption. Work is in progress to develop a defined approach for identification of eye irritants.

A defined approach to testing and assessment relies on:

  • Input data generated from identified methods.
  • A data interpretation procedure that is used to translate data produced from a defined set of information sources into a prediction.
Examples of defined approaches: 
  • Sequential testing strategies use a fixed, stepwise approach to obtain and assess test data. They include interim decision points at which the user may either proceed to additional testing steps or stop testing and make a hazard prediction.
  • Integrated testing strategies use an approach in which multiple sources of data or information are assessed at the same time to arrive at either a hazard prediction or a decision that more testing is needed.

More information about IATAs and defined approaches is available on the OECD website.

Defined Approaches for Eye Irritation

List of defined approaches for eye irritation
Project Description Publication
Classification of eye irritation potential of agrochemical formulations NICEATM is collaborating with PETA-ISC, EPA, and member companies of the trade association CropLife America to identify promising methods that could be used in an in vitro defined approach for classification of eye irritation potential of agrochemical formulations.
  • Clippinger et al. (submitted)
  • NTP report in preparation

Defined Approaches for Skin Sensitization

In 2018, EPA released a draft Science Policy to reduce animal use by using defined approaches to identify potential skin sensitizers. The draft policy is the result of national and international collaboration among ICCVAM, NICEATM, Cosmetics Europe, EURL ECVAM, and Health Canada’s Pest Management Regulatory Agency.  These collaborations included the following projects:

List of defined approaches for skin sensitization
Project Description Publication
Guideline for defined approaches for testing and assessment for skin sensitization NICEATM and international collaborators convened a 2016 workshop on skin sensitization that produced a proposal for an OECD project to develop an international harmonized guideline for defined approaches for skin sensitization.
  • Casati S, et al. Standardisation of defined approaches for skin sensitisation testing to support regulatory use and international adoption: position of the International Cooperation on Alternative Test Methods. Arch Toxicol. 2018;92(2):611-617.
  • Test guideline in development.
Open-source tools to implement defined approaches to skin sensitization testing and assessment NICEATM and industry scientists from Cosmetics Europe wrote open-source code to reproduce defined approaches submitted as case studies to OECD for skin sensitization testing and assessment. Data on 128 substances to evaluate these defined approaches were also developed as part of this project.
  • Hoffmann S, et al. Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database. Crit Rev Toxicol. 2018;48(5):344-358.
  • Kleinstreuer N, et al. Non-animal methods to predict skin sensitization (II): an assessment of defined approaches. Crit Rev Toxicol. 2018;48(5):359-374.
Defined approach using non-animal data to predict skin sensitization hazard

NICEATM and ICCVAM developed a defined approach that uses non-animal data to predict three skin sensitization endpoints:

  • Murine local lymph node assay (LLNA) hazard
  • Human skin sensitization hazard
  • Human or animal skin sensitization potency (enables classification of skin sensitizers as "weak" or "strong" without animal tests)
  • Prediction of murine local lymph node assay outcomes:
    Strickland J, et al. Integrated decision strategies for skin sensitization hazard. J Appl Toxicol. 2016;36(9):1150-62.
  • Prediction of human skin sensitization hazard:
    Strickland J, et al. Multivariate models for prediction of skin sensitization hazard. J Appl Toxicol. 2017;37(3):347-360.
  • Prediction of human or animal skin sensitization potency:
    Zang Q, et al. Prediction of skin sensitization potency using machine learning approaches. J Appl Toxicol. 2017;37(7):792-805.
Open-source software to implement an integrated testing strategy based on a Bayesian network NICEATM and collaborators with Procter & Gamble developed open-source software to implement an integrated testing strategy (a type of defined approach) for skin sensitization potency based on a Bayesian network. The model provides a numerical probability that a substance belongs in each of  four potency classes.
  • Pirone JR, et al. Open source software implementation of an integrated testing strategy for skin sensitization potency based on a Bayesian network. ALTEX. 2014;31:336-340.

Defined Approaches for Endocrine Disruption

List of defined approaches for endocrine disruption
Project Description Publication
Identification of substances with the potential to interact with the androgen receptor NICEATM and EPA developed a defined approach that combines data from 11 high-throughput screening tests with a computational model to identify substances with the potential to interact with androgen receptors in a cell. Androgens are a class of hormones, produced largely by the testes, that serve as the primary male hormones.
  • Kleinstreuer N, et al. Development and validation of a computational model for androgen receptor activity. Chem Res Toxicol. 2016;30(4):946-964.
Identification of substances with the potential to interact with the estrogen receptor NICEATM validated a defined approach developed by the EPA that combines data from 18 high-throughput screening tests with a computational model to identify chemicals with the potential to interact with the estrogen receptors in a cell. Estrogens are a class of hormones, produced largely by the ovaries, that serve as the primary female hormones.
  • Browne P, et al. Screening chemicals for estrogen receptor bioactivity using a computational model. Environ Sci Technol. 2015;49:8804-8814.
Selecting a minimal set of assays to screen chemicals for estrogen and androgen receptor interaction NICEATM and EPA analyzed the high-throughput screening based models described above to identify a subset of assays that would provide similarly accurate predictions of endocrine disruption while minimizing the resources required to run defined approaches. For detecting estrogenic substances as few as four assays could be used. For substances interacting with the androgen pathway as few as five assays provided similar performance as the full model.
  • Judson RS, et al. On selecting a minimal set of in vitro assays to reliably determine estrogen agonist activity. Regul Toxicol Pharmacol. 2017;91:39-49.
  • Judson R, et al. Selecting a minimal set of androgen receptor assays for screening chemicals. Regul Toxicol Pharmacol. 2020;117.