A look at the European Union's REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) legislation, enacted to address public demand for the control of toxic chemicals used in manufacturing and agriculture. (Titled "Are in Vitro and in Silico Toxicity Testing Finally Within REACH?" in print version.)
An increasingly aware and educated public is demanding better determination and control of the toxicity of chemicals commonly found in manufacturing, agricultural and other uses. In response, the European Union introduced the REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) legislation in June 2007 (1). REACH applies to chemicals manufactured or imported into the EU in quantities equal to or greater than one metric ton.
About 86 percent of chemicals in current use in the EU, many of which were first produced prior to 1981, do not have REACH-compliant safety assessments (1). Assessment under REACH is tiered according to production or importation volume so that the degree of physicochemical and toxicological information required under REACH increases with each quantity band (2). As of December 2008, 65,000 companies have submitted more than 2.7 million preregistrations for about 144,000 substances (3). Eventually, up to one million chemicals and mixtures may be assessed (4).
The current approach to toxicological testing using animal-based methodologies provides regulators and industry with a defined testing regimen with internationally agreed testing guidelines. This regimen enables costs, timelines and outcomes to be predictable while limiting liabilities (5). However, in addition to the ethical dilemma of using large numbers of animals to adequately evaluate chemicals under REACH, current methodologies using long-term and maximum-dosing experiments on animals are imperfect and slow (1). The U.S. National Toxicology Program, in 1996, estimated that a thorough assessment of chemicals may take several years and cost $2 to $4 million (6). The current paradigm cannot generate the required data for toxicological risk assessments within a reasonable timeframe and at a reasonable cost. Therefore, a new approach is required “if science is going to maintain a significant role in environmental and public health policy” (6).
Significant efforts are underway internationally to develop new approaches to identify toxicants and determine which biological pathways they perturb— approaches that are based on in vitro and in silico technologies, many of which are specific for human biology. Experimental platforms include established and developing “omics” technologies, chemical and biochemical studies. In vitro platforms may employ “subcellular fractions, tissue slices or perfused organ preparations, through primary cultures and cell line to 3-D organotypic cultures, which include reconstructed tissue models” (7).
REACH places significant burdens on industry and regulatory agencies. Industry must assume responsibility for the safety of substances throughout their life cycles as well as manage the uncertainties associated with the proposed shift in testing platforms (2). This will bring about greater exposure to liabilities and will increase regulatory discomfiture in many cases; for example, the reference dose for many chemicals may be increased based on these same studies (5).
The changes to toxicology testing methods and analysis ultimately will be defined by a concomitant increase in our understanding of underlying toxicological principals, the continued development of effective in vivo and in vitro test platforms and computational modeling capabilities and finally an acceptance of the new risk assessments by the community, regulatory authorities and industry.
1. Hartung, T. (2009) Toxicology for the Twenty-first Century. Nature 460, 208–212.
2. Lahl, U., and Gundert-Remy, U. (2008) The use of (Q)SAR Methods in Context of REACH. Toxicology Mechanisms and Methods 18, 149–158.
3. Hartung, T. (2009) Pathway Based Approaches: A European/REACH Perspective. Toxicity Pathway-Based Assessment: Preparing for Paradigm Change, a Symposium of the Standing Committee on Risk Analysis Issues and Reviews— May 11–13, 2009. National Research Council, Washington, D.C.
4. Preuss, P. W. (2009) The Changing Landscape of Risk Assessment. Toxicity Pathway-Based Assessment: Preparing for Paradigm Change, a Symposium of the Standing Committee on Risk Analysis Issues and Reviews. May 11–13, 2009. National Research Council, Washington, D.C.
5. Schmidt, C. W. (2009) Tox 21: New Dimensions in Toxicity Testing. Environmental Health Perspectives 117, A349–A353.
6. Thomas, R. S., et al. (2001) Identification of Toxicologically Predictive Gene Sets Using cDNA Microarrays. Mol. Pharmacol. 60, 1189–1194.
7. Bhogal, N., et al. (2005) Toxicity Testing: Creating a Revolution Based on New Technologies. Trends in Biotechnology 23, 299–307.
Tertius de Kluyver (firstname.lastname@example.org) is an adjunct professor of biology and environmental science at Hood College.