Integrated Testing Strategies & Risk Assessment

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Integrated Testing Strategies & Risk Assessment

Last updated: November 22, 2009

The potential hazard of a chemical or other substance is evaluated to determine whether it presents a risk to humans, animals, and/or the environment. Chemicals have traditionally been tested using the set of toxicity tests, primarily animal tests, described in the Toxicity Endpoints & Tests sections. We have provided some background in each of those sections on efforts to develop and validate predictive alternative methods, including in vitro assays and computational methods such as (Quantitative) Structure Activity Relationships ((Q)SARs) and expert systems, as well as approaches to combining these methods into test batteries or tiered testing schemes along with some form of decision-making criteria.

Typically, data for many of the toxicity endpoints are needed for a regulatory submission on a chemical or other new substance. In addition to the testing required for new chemicals and products, there is growing realization that the safety information we have on many existing chemicals is insufficient. This has been the basis of a number of voluntary testing programs, and most recently the European Union’s REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) legislation. While it is desirable to have only safe chemicals and products in the marketplace, the traditional means of testing cannot keep pace with the demand.

The conduct of traditional toxicity testing for all of these chemicals and products would be economically impractical and ethically unacceptable, and it would delay innovation and new products reaching the marketplace. Furthermore, even the results of animal tests can be regarded as preliminary given that they are not conducted in the species of interest, which is the human. Therefore, the need exists for faster, cheaper, and scientifically superior methods for toxicity testing to meet industry’s needs and protect the public health, as well as to satisfy the growing numbers of stakeholders concerned with animal welfare. While these new test methods are being developed and validated—efforts that will take years—additional approaches such as integrated testing strategies are being developed to meet the concurrent needs for faster throughput, animal-reduction approaches.

Integrated Testing Strategy vs. Tiered Test Scheme or Test Battery

Toxicity testing composed of tiered test schemes and/or test batteries, where certain components may be statistically weighted, can be used to provide a final assessment of a toxicity endpoint that is more predictive of the in vivo response than could be obtained from any individual component of the testing system. Just like an individual toxicity test, a test scheme and/or test battery can be validated for use in regulatory decision making.

Test batteries and tiered test schemes are sometimes called “integrated testing” or an “integrated approach,” but they differ somewhat from the use of “integrated testing strategies” as discussed in this article. This clarification in terminology is being made here just to alert readers of the sometimes interchangeable use of the terms that can be found in the toxicology literature.

Proposed definitions:
Test battery: a group of assays conducted together for a specific purpose, usually to provide a prediction for a toxicity endpoint. The results of each individual assay could be equally weighted, or a statistical weight could be used as an attempt to better model the in vivo response.

Tiered test scheme: testing approaches based on sequential assessments, where a result at one tier is used to determine the next step, if any. It is usually a decision-tree type of assessment; after each step, the information is evaluated to determine whether a prediction for the toxicity endpoint can be made or whether further testing/analysis needs to be conducted. A tiered approach might progress as follows: a preliminary review of existing literature and data, to a review of data for related chemicals or formulations, to perhaps a SAR/(Q)SAR analysis, to simple in vitro screening assays, to the use of more complex in vitro three-dimensional models, to testing in lower species, to the traditional animal test.

Integrated testing strategy (ITS): approaches that integrate different types of data and information into the decision-making process. In addition to the information from individual assays, test batteries, and/or tiered test schemes, integrated testing strategies may incorporate approaches such as weight-of-evidence and exposure/population data into the final risk assessment for a substance.

Hazard Assessment and Risk Assessment

The US EPA’s Risk Characterization Handbook (2000) defines risk assessment as “an analysis of scientific information on existing and projected risks to human health and the environment.” Risk assessments are conducted for both ecological and human health risks. A risk assessment for human health can be described in the following four steps:

  • Hazard Identification – the determination of whether a particular chemical is or is not causally linked to particular health effects
  • Dose-Response Assessment – the determination of the relation between the magnitude of exposure and the probability of occurrence of the health effects in question
  • Exposure Assessment – the determination of the extent of human exposure before or after application of regulatory controls
  • Risk Characterization – integrates information from the preceding components of the risk assessment and synthesizes an overall conclusion about risk that is complete, informative, and useful for decision makers.

The hazard assessment is conducted to determine whether, and under what circumstances, a substance may be hazard to human health. It can involve the analysis of a variety of types of data ranging the animal tests described in the Toxicity Tests & Endpoints sections to computational methods such as (Q)SARs. “To the extent that data permit, hazard assessment addresses the question of mode of action of an agent as both an initial step in identifying human hazard potential and as a component in considering appropriate approaches to dose-response assessment.”

A risk assessment is most simply expressed by the following formula:

Risk = Hazard x Exposure

Although risk assessments are the ultimate outcome of toxicity testing/hazard assessment, the details of carrying out a risk assessment can vary for the type of substance being evaluated and the agency or national government undertaking the analysis. The primary focus of is the toxicity tests themselves: the development, validation, regulatory acceptance, and implementation of non-animal toxicity test methods. Since these developments will constitute a lengthy process, other practices in the overall risk assessment process that contribute to reducing or eliminating animal testing, such as integrated testing strategies, are also of significant interest.

Integrated testing strategies involve the use of multiple approaches for obtaining the information necessary for a regulatory assessment that circumvents the laundry-list of animal toxicity tests, where possible. The continued exploration of new and innovative approaches is warranted. Potential benefits of integrated testing strategy approaches include:

  • Better protection of human and animal health and the environment by the rapid prioritization of more toxic materials for additional testing
  • Reductions in animal testing requirements
  • Time and cost savings