Toxicity testing in the 21st century.

This month’s lead is a summary and review of the National Research Council’s “Toxicity Testing in the 21st Century: A Vision and A Strategy.”1 In this article, Daniel Krewski, Melvin Andersen, Ellen Mantus, and Lauren Zeise summarize a vision to advance toxicity testing and human health assessment of environmental agents. They describe how scientific advances can transform toxicity testing to allow additional assessments of potentially toxic chemicals by using more timely and more cost-effective methods, including highand medium-throughput in vitro screening assays, computational toxicology and systems biology, along with other emerging highcontent testing methodologies, such as functional genomics and transcriptomics. Suresh Moolgavkar, our Area Editor for Health Risk Assessment, asked six experts with different perspectives to comment on the paper. Each praises the vision and offers suggestions for making it more useful. Rory Connolly argues that if we expect risk assessment to maintain high throughput and be accurate, then there is need to address the issues of microdosimetry, adaptive responses and homeostasis. E. Donald Elliott focuses on the regulatory perspective, wondering why a regulator would ever take the political and legal risk to be the first to base an actual regulatory decision on the new model, and then he wonders if a judge would uphold a regulatory decision based on the new vision. Elliott argues for a legally sophisticated group or institution to take up the issues where the NAS Committee left off and fill in the gaps so that Toxicity Testing in the 21st Century can actually be used by regulatory authorities. Dale Hattis notes that while high-throughput testing may ultimately be of substantial value, for higher profile decisions on major agents in commerce involving complex tradeoffs of risks and economic impacts for different policy options, the findings of high-throughput tests will not be sufficient. For these, a system that quantitatively assesses actual health risks and the large associated uncertainties will be essential. A commentary by Robert H. Kavlock and colleagues acknowledges the challenges laid out in the Krewski et al. perspective, and describes the NIH/EPA collaboration called Tox21. With four focus groups devoted to different components of the NRC vision, the Tox21 consortium constitutes a concerted, long-term effort to identify mechanisms of chemically-induced biological activity, prioritize chemicals for more extensive evaluation and develop more predictive models of in vivo biological response. Lorenz R. Rhomberg urges Risk Analysis readers to read the full NRC report, focusing on a careful consideration of the ways that risk assessment will have to change to deal with the new testing approaches. He highlights his view that the new vision consists of more than new testing technologies, but is based on a change in the questions that toxicology addresses, that is, a shift toward identifying causes and then inferring possible effects. The final commentary by Joyce Tsuji stresses the difficulties of developing in vitro assays that can predict in vivo outcomes with adequate sensitivity and specificity and discusses challenges for public health decisionmakers in dealing with uncertainty. Krewski et al. briefly reply to each commentary and encourage us to use their paper and the accompanying commentaries as a starting point for thinking about a more complete evaluation of the future directions for toxicity testing as set out in the full NRC report. We’re pleased with this set of papers and hope that you will consider proposing similar sets of papers to us. The other papers in this issue examine terrorism, food contamination, endangered species, and other risk-related challenges. Yacov Haimes, our Area Editor for Engineering, had discussed the meaning of “vulnerability” in a 2006 article in Risk Analysis.2 His perspective article in this issue examines what we mean by “resilience.” He considers existing definitions and arrives at one that will prove useful to practitioners. Terje Aven and Ortwin Renn, funded by Norway’s Research Council, consider the utility of