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.
These 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 term "integrated" 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 testing; after each step, the information is assessed to determine whether a prediction for the toxicity endpoint can be made or whether further testing/analysis needs to be done. A tiered approach usually progresses from a 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: 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 defines risk assessment as "a process for organizing and analyzing information to determine if an environmental chemical or other agent might cause harm to exposed persons and ecosystems." The EPA describes a risk assessment as having the following four components:
- Hazard assessment: Determining "whether a particular chemical is or is not causally linked to particular health effects" (the intrinsic toxicity of a substance)
- Dose-response assessment: Determining "the shape and form of the relationship between exposure and the health effects in question"
- Exposure assessment: Determining or estimating human exposure to the potential hazard (such as type and extent of exposure; who and how many will be exposed)
- Risk characterization: Steps include "summarize all data, strengths and weaknesses, integrate information from previous steps, discuss uncertainties and assumptions, develop estimates of risk for public health and ecological integrity, and provide tools for risk managers who make decisions"
A hazard assessment is traditionally based on animal tests, like those described in the Toxicity Tests & Endpoints sections. The EPA's Guidelines for Carcinogen Risk Assessment notes that "current approaches to hazard characterization include consideration of evaluation of mechanism(s) of action and biologically-based models" and that an analysis of the weight of the evidence (all pertinent information) is an important component of hazard 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 AltTox.org is the toxicity tests themselves&Mdash;in support of the development, validation, and implementation of non-animal alternative 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. A number of approaches have been successful, and 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
- Rime and cost savings
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