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Non-animal Methods for Toxicity Testing

Overarching Challenges & Opportunities

Last Updated: May 4, 2009
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Any field of research faces challenges, and the field of non-animal methods of toxicity testing is no exception. New methods of testing need to be developed, validated, accepted, and implemented. These diverse steps present an array of scientific, practical, and policy challenges. At the end of the day, the concerns of diverse stakeholders in industry, government, animal protection, academia, and nongovernmental organizations need to be addressed.

The alternatives literature has numerous compilations of these challenges or "barriers" to progress (see, for example, Becker, et al., 2006; Blaauboer, 1998; Daston & McNamee, 2005; Goldberg & Hartung, 2006). Here we provide a brief summary of many of these concerns. Most of the publications discussing challenges and barriers to progress also provide recommendations to overcome them. These recommendations are not summarized here; they essentially constitute the subject matter for the related Way Forward commentaries and Overarching Challenges & Opportunities forum discussions.

The 2005 workshop of the International Society of Regulatory Toxicology and Pharmacology (ISRTP), Progress and Barriers to Incorporating Alternative Toxicological Methods in the US, provided an extensive compilation of challenges based on presentations by diverse stakeholders. The ISRTP workshop focused on the US situation, but many of the considerations discussed there are common across countries.

The publication resulting from the ISRTP workshop, which serves as a primary reference for the information provided here, grouped barriers to progress into three categories: scientific/technical; economic/financial; and regulatory/policy (Becker, et al., 2006). We follow the same categories here, except for characterizing economic/financial barriers more broadly as practical/logistical. We summarize these challenges in the following three tables.

The European Partnership for Alternative Approaches to Animal Testing (EPAA) Working Group 5 held a workshop on barriers to validation in September 2006, and the resulting report provides an inventory of the barriers they identified (Ahr, et al., 2008). They describe barriers to validation as "factors which might delay or hamper the validation of alternative methods," and the barriers they identified are included in the tables below.

Readers interested in further information on these and other challenges are invited to consult relevant sections of AltTox.org's Toxicity Testing Resource Center, as well as the scientific literature, including specific ECVAM publications.


Table 1: Scientific and technical challenges to replacing animal tests with non-animal methods.

 Challenge

Details

References

Lack of focused research There is insufficient research of alternatives, especially in key areas such as elucidating mechanisms of action, identifying and collecting reference data on biomarkers, validating new methods, and translating new methods for use in risk assessment ISRTP, 2005
Insufficient participation of academic scientists across all aspects of alternatives R&D   Becker, et al., 2006
Lack of applied research needed to generate reference data and proof-of-concept models   Becker, et al., 2006
Lack of publicly accessible databases to facilitate access to existing data   Becker, et al., 2006
Lack of fundamental toxicological research Lack of sufficient research and analysis of the predictive capability and reproducibility of existing animal models/data Blaauboer, et al., 1998; Becker, et al., 2006; Daston & McNamee, 2005
Traditional tests used as gold standards against which to compare in vitro results are not always useful for that purpose   Becker, et al., 2006; Daston & McNamee, 2005; Goldberg & Hartung, 2006
Capturing the complexity of the toxic response of an intact organism with an in vitro or in silico system Regulatory agencies need proof-of-concept Becker, et al., 2006; ISRTP, 2005
Lack of mechanistic understanding of the biology and the resulting toxicological processes in tissues or organs of interest Basic research is needed to develop this type of information Daston & McNamee, 2005; Blaauboer, et al., 1998; Ahr, et al., 2008
Lack of sufficient in vitro models/platforms to express critical aspects of a mechanism and a measurable output for that mechanism These aspects are required for the successful validation of an in vitro method Daston & McNamee, 2005
Challenge of compiling and validating a test battery when no single non-animal method will suffice to replace an animal method   Daston & McNamee, 2005
Lack of clarity on the purpose and uses of the test method   Ahr, et al., 2008


Table 2: Practical and logistical challenges to replacing animal tests with non-animal methods.

Challenge

Details on this barrier

References

Funding/resources Government agencies typically have not prioritized funding for alternative methods Becker, et al., 2006; ISRTP, 2005; Goldberg & Hartung, 2006; Ahr, et al., 2008
Problems with accessing existing toxicology (animal) data
  • Data not available - companies consider data as proprietary
  • Lack of uniformity and formatting of existing industry data
  • Insufficient data provided in the published toxicology literature for use in statistical models for validation studies
  • Lack of quality assurance
Becker, et al., 2006 (but listed as a scientific barrier); ISRTP, 2005; Goldberg & Hartung, 2006; Ahr, et al., 2008
Education/training on use of alternative methods for researchers/toxicologists Insufficient methods/platforms for educating toxicologists on alternative methods to promote the translational research needed to move methods from the bench to use in risk assessments Blaauboer, et al., 1998; ISRTP, 2005
Clarity and coordination of objectives Short and long-term objectives not clarified; need for coordination and prioritization of US agencies' alternatives research and programs ISRTP, 2005
Communications Scientists from agencies, industry, and academia need to collaborate during all phases of research and validation so that the methods developed are useful for a regulatory framework Becker, et al., 2006 (implied)
Unavailability of test substances that were used to generate reference data   Ahr, et al., 2008


Table 3: Policy and regulatory challenges to replacing animal tests with non-animal methods.

Challenge

Details on this barrier

References

Low level of comfort with alternative assays in regulatory community   Becker, et al., 2006; ISRTP, 2005
Conservatism in current US regulatory frameworks for the substitution of new, validated methods
  • Certain testing requirements entail a long list of animal tests
  • Lack of regulatory approaches for using integrated or tiered testing strategies
  • Lack of procedure(s) for removing animal test from federal guidance once a validated replacement method is available
Becker, et al., 2006; ISRTP, 2005; Goldberg & Hartung, 2006
US regulatory agency acceptance processes
  • Differences among US agencies in acceptance
  • Unclear processes and agency requirements
Becker, et al., 2006; ISRTP, 2005
NICEATM/ICCVAM have not received or reviewed a sufficient number of new methods Possible "issue with outreach" noted Becker, et al., 2006; ISRTP, 2005
Methods development and standardization not always tied to ultimate regulatory uses Regulators need to educate and collaborate with researchers so they develop and validate methods useful for a regulatory framework Becker, et al., 2006
Ability to convince the scientific and regulatory communities that an alternative method fulfills its intended purpose and has been rigorously validated   Daston & McNamee, 2005
Length of time required to move a method through development to validation and acceptance   Daston & McNamee, 2005; Goldberg & Hartung, 2006; Ahr, et al., 2008
Legal requirements for testing vary widely around the world Need for greater international harmonization Blaauboer, et al., 1998; Goldberg & Hartung, 2006
Delays in regulatory acceptance after a method is validated   Goldberg & Hartung, 2006
Need for overarching US agency strategy Lack of overall coordination by one organization (such as NTP) to coordinate all government research and encourage development and use of alternative methods Becker, et al., 2006; ISRTP, 2005
When agencies encourage submission of alternative methods in parallel with traditional animal data, information on the utility of the alternative data needs to be captured and made public to facilitate its use and refinement of new methods   Becker, et al., 2006
Deadlines imposed by the European Parliament Legislation calls for a ban of most animal testing for substances used in cosmetic products by 2009 and a ban on all animal testing by 2013 Daston & McNamee, 2005
Lack of a regulatory reference test for certain endpoints such as immunotoxicity   Ahr, et al., 2008
Lack of established validation process for complex methodologies or approaches   Ahr, et al., 2008


References