ITS – Emerging Science & Policy

Integrated Testing Strategies & Risk Assessment

Emerging Science & Policy

Last updated: December 6, 2007

New technologies such as toxicogenomics, cell-based methods, and mechanism-based mathematical models are contributing to our knowledge of the mechanisms of toxicological effects. Ways to incorporate these new types of data into risk assessments are being evaluated (Simmons & Portier, 2002). The incorporation of decision theory into regulatory analysis was proposed as “a sound scientific way explicitly to account for new knowledge and its effects on eventual policy choices” (Ricci et al., 2006). Jardine, et al. (2003), proposed that “the incorporation of new evidence requires that risk management be a flexible, evolutionary, and iterative process… [but that] each agency must continue to employ a process that meets the needs of their specific application of risk management.”

Integrated approaches based on combinations of in vitro and in silico methods have had various levels of success in predicting the in vivo toxicities while reducing animal use (Gubbels-van Hal et al., 2005). The European Centre for the Validation of Alternative Methods (ECVAM) has a research program on (Q)SAR modeling and integrated testing (Worth, 2002), and is supporting several programs such as ReProTect and ACuteTox that involve integrated approaches to the development of predictive in vitro/in silico systems for specific toxicity endpoints.

Scientists from the Fund for the Replacement of Animals in Medical Experiments (FRAME) have proposed integrated testing approaches for the REACH program for a number of years. They have defined decision-tree style strategies for each of the major toxicity endpoints required by REACH that maximize the use of non-animal approaches to hazard identification (Grindon et al., 2006) and have refined this approach for mutagenicity and carcinogenicity testing (Combes et al., 2007).

The report from an Organisation for Economic Co-operation and Development (OECD) Focus Session, Experiences Using Integrated Approaches to Fulfill Information Requirements for Testing and Assessment (2006), provides good examples of the various approaches to using integrated testing strategies in regulatory decision making. The OECD described the use of chemical categories, which is a testing reduction approach based on evaluating the similarity of chemical structures and then not testing (or conducting less testing on) chemicals that have structural similarity to ones with complete datasets. The recently released OECD guidance document Guidance on Grouping of Chemicals provides for greater testing efficiency and animal reduction by the use of chemical categories. This approach is discussed in more detail in the Emerging Technologies: (Q)SAR section.

The European REACH legislation requires the assessment of many chemicals marketed in the EU. The European Commission described REACH as emphasizing an integrated approach that includes all available data.

Additional testing may not be necessary when one or more of the following methods provide data indicating the chemical does not present a hazard:

  • Existing data
  • Weight of evidenceinformation from several sources
  • (Q)SARmodel that meets specific requirements such as validation
  • In vitro methodsthat meet specific requirements including validation
  • Grouping of substances and read-across approach based on: 1) a common functional group, 2) common precursors and/or likelihood of common breakdown products, which result in structurally similar chemicals, or 3) a constant pattern in the changing of the potency of the properties across the category

The US Environmental Protection Agency (EPA) presentation at the OECD Focus Session described the current paradigm for pesticides as extensive hazard testing using in vivo animal data. The EPA also described their vision for the future as “a hypothesis-driven paradigm where existing data, in silico (computer simulated) models (e.g., structure activity relationships or SARs), and in vitro data, combined with estimates of exposure, are used to determine what specific in vivo tests are required…. The approach would use screening and priority setting to eliminate the need for requiring a battery of tests focused on all possible adverse outcomes.” The new approach reportedly would save money and animals, while improving health and environmental protection. Implementation of the EPA’s integrated approach to testing and assessment of pesticides is expected to take up to 10 years.

A committee of distinguished scientists assembled by the National Research Council (NRC) (2007) proposed a vision for a new toxicity testing paradigm that essentially is an integrated testing strategy that would help inform a risk assessment. The NRC developed the report at the EPA’s request. The committee’s vision for the future of toxicity testing has two components—cellular toxicity-pathway assays and targeted testing. Predictive toxicity-pathway assays will serve as the primary type of data collected to provide information on cellular toxicity mechanisms and pathways. “Targeted testing will serve to complement the assays and support evaluation…. Over time, the need for traditional animal testing should be greatly reduced and possibly even eliminated.”

New Perspectives

For some new perspectives on integrated testing strategies and risk assessment, read the following invited commentaries: