treated as an indicator of possible carcinogenicity. Testing requirements for pesticides and pharmaceuticals include in vivo studies in rodents to test for chromosomal aberrations and micronuclei, and in vitro tests for mutations in mammalian cells and bacteria. Tests based on mechanisms other than genotoxicity are also used. The goal is to target an agent’s ability to modulate pathways that underlie the basic mechanisms of toxicity. While regulatory agencies typically do not label chemicals that have tested positive in genotoxicity tests as possible carcinogens in the absence of supporting human or animal data, product development programs for pesticides and pharmaceuticals often avoid chemicals with strong signals of genotoxic potential, mostly out of concerns for potential carcinogenicity and mutagenicity.

Because the current standard whole-animal testing approach for carcinogenicity (as well as other endpoints) is time- and resource-consuming, initiatives to move toward reliance on in vitro and structure–activity relationships have been advocated and are under way (NRC, 2007; Krewski et al., 2009; EPA, 2011). The National Research Council (NRC) has envisioned a new toxicity testing system, focusing on upstream events: chemical perturbations of cellular response networks (i.e., complex biochemical interactions that maintain normal cellular function) (NRC, 2007). For example, testing might identify perturbation of estrogen signaling and the subsequent events that potentially result in cancer. The NRC vision was made possible because of the emerging scientific understanding of cellular response networks, and high-throughput technology that enables the exploration of the structure of these networks and rapid conduct of in vitro tests. NRC (2007) proposed the development of suites of predictive, high- and medium-throughput assays, emphasizing those based on cells of human origin, to evaluate perturbations. These would be complemented by assays of more integrated cellular responses and in vivo assays to cover uncertainties in the testing regimen, to test prototypic compounds, and to address metabolism. Other components of the framework include the use of physiologically based pharmacokinetic studies, human biomonitoring data, and epidemiologic data to evaluate and fine-tune the predictive ability of the tests. The NRC vision was accompanied by a long-term strategy for its realization, involving a substantial multidisciplinary research program.

Subsequently, in 2008, various federal institutions entered into a Memorandum of Understanding to “research, develop, validate and translate innovative chemical testing methods that characterize toxicity pathways” (EPA, 2011). The current “Tox21 collaboration,” renewed for 5 years in 2010, includes EPA, the NTP, the National Human Genome Research Institute and the Chemical Genomics Center of the National Institutes of Health, and the FDA. The main work will be to explore high-throughput screening assays and tests using phylogenetically lower animal species (e.g.,



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