Systems Toxicology

Accordingly, research in toxicology has moved into a new systems-ori- ented phase called systems toxicology, which involves the study of complex molecular response networks initiated by exposure (both intentional and unintentional) to chemical substances. At the heart of systems toxicology approaches are the development and usage of quantitative mechanistic models that create a predictive toxicology aspect relevant to all toxicology fields, including drug research and development and environmental research. the overall approach involves the integration of classical toxicology with the quantitative analysis of large networks of chemically-induced molecular and functional changes, which occur across multiple levels of biological organization.5 Examples of key influential events in this transition since the year 2000 include the release of human genome sequencing data including specific signal transduction domains, the development and issuance of the report Toxicity Testing in the Twenty-first Century by the National Research Council (NRC),9 which has influenced all sectors of the toxicology field, and the development and publication of the adverse outcome pathway (AOP) approach,6,10,n which has highlighted the realities that exist as the science moves away from an overdependence on in vivo testing and makes greater use of computational, molecular, and focused in vitro tools. Additional drivers of change include the European Union (EU) report from the Scientific Committee on Health and Environmental Risks, the EU’s Registration, Evaluation, Authorisation and Restriction of Chemical Substances (REACH) program, and the International Programme on Chemical Safety (IPCS).7,;12 The paradigm shift can also be seen in the drug research and development sector, but rather than focusing on drugs during late stages of development or on marketed drugs, the systems-related efforts are positioned at the front end of research, both on safer chemical design and extensive target research.

While the drug industry is required to conduct animal toxicology studies by regulatory agencies and international guidelines, the major effort underway is to determine chemical liabilities early in the drug discovery pipeline, both to reduce the time and cost of failures later in the process, but also to avoid costly failures once a drug reaches the market.5 Currently, there is an International Consortium for Innovation and Quality in pharmaceutical Development (IQ), where several pharmaceutical and biotechnology companies have created a Nonclinical to Clinical Translational Database (WG1) to allow analysis of the reliability and potential limitations of nonclinical data in predicting clinical outcomes, including the evaluation of conventional biomarkers of toxicity.13 Current screening approaches applied to the front end of drug research are described below.

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