Toward a Comprehensive Molecular Design Framework for Reduced Hazard Adelina M. Voutchkova, † Thomas G. Osimitz, ‡ and Paul T. Anastas* ,† Center for Green Chemistry and Green Engineering, Yale University, New Haven, Connecticut 06511, and Science Strategies LLC, 600 East Water St., Charlottesville, VA 22902 Received September 11, 2009 Contents 1. Introduction 5845 2. Scope of This Work 5846 3. The Present State of Toxicology and the Need for a Framework for the Design of Safer Chemicals 5847 4. Toxicology Resources for Chemists 5847 4.1. Explosion of New Information on Toxicity 5849 4.1.1. Toxicogenomics 5849 4.1.2. High-Throughput Screening (HTS) 5850 4.2. Mechanistic Toxicological Considerations for the Design of Safer Chemicals 5850 4.2.1. Toxicokinetics and Toxicodynamics 5850 5. Quantitative Structure-Activity (and Toxicity) Relationships 5862 5.1. Historical Development of QSARs 5862 5.2. Advancement of Whole-Organism QSTR Models 5863 5.3. QSARs for General Versus Specific Toxicity 5863 6. In Silico Approaches 5863 6.1. Estimation of Toxicity 5864 6.1.1. Automated Rule Induction (ARI) Systems Approach 5864 6.1.2. Knowledge-Based Systems (Expert Systems) 5865 6.2. Prediction of Metabolism and Biotransformation 5866 7. New Perspectives: Toward Property-Based Design Guidelines 5867 7.1. Toxicodynamic and Toxicokinetic Behavior and Chemical Properties 5867 7.1.1. Example: Do Highly Toxic Chemicals Share Common Physicochemical Properties? 5868 7.1.2. Structural Interventions That Reduce Absorption (Bioavailability) 5869 7.1.3. Structural Interventions That Reduce Distribution 5871 7.1.4. Structural Interventions That Can Reduce Bioactivation 5871 7.2. Designing Molecules That Do Not Interfere with CYP Regulation Pathways 5871 7.3. Structural and Property Modifications that Can Reduce Toxicity 5871 7.3.1. Reducing CNS Activity 5871 7.3.2. Reducing Carcinogenicity 5876 7.4. Strategies for Reducing Hazard beyond Human Toxicity 5877 7.4.1. Reducing Aquatic Toxicity 5877 7.4.2. Enhancing Biodegradability 5877 7.4.3. Minimizing Bioaccumulation 5879 8. Conclusion 5879 9. Acknowledgments 5880 10. References 5880 1. Introduction The history of chemistry has been one of understanding the properties and transformations of matter. Perhaps the most important aspect of this understanding is the properties that have an impact on human and environmental health and the transformations that take place in our bodies and in the biosphere. Only through a mastery of this understanding will chemistry be able to genuinely design molecules that perform their intended function (e.g., therapeutic or industrial) and are safer for humans and the environment. Knowledge about the nature of toxic effects comes from the field of toxicology. Once primarily a descriptive science, relying to a large extent on whole-animal toxicology studies, the field has developed an extensive understanding of many of the mechanisms by which chemicals can exert toxicity. 1 Application of this knowledge has made it possible to develop correlations, equations, and models that relate chemical structure and properties to biological responses. This has led to an increasingly sophisticated in silico predictive aspect of toxicology 2 and provides the basis for current work being pursued in the development of a comprehensive design strategy for safer chemicals. While there has been significant work in the field of chemistry in designing for various functions ranging from medicines to materials, there has been a lack of a compre- hensive framework for designing molecules to have a reduced impact on human health and the environment. A framework for the design of safer chemicals was originally published by the noted medicinal chemist E. J. Ariens in 1980, titled appropriately Domestication of Chemistry by Design of Safer Chemicals 3 and later revised in 1985. 4 An ACS Symposium Series book published in 1996 on Designing Safer Chemi- cals 5 puts forth a framework that draws on a variety of sources and contains chapters that illustrate how the frame- work can be applied. In light of the tremendous advances in toxicology and molecular science in the 25 and 14 years since these prior perspectives were written, this review seeks to incorporate the new knowledge and tools available to today’s chemist. In the final measure, the ultimate success of deeply studying a problem is not simply to admire the problem but rather to solve it. This review provides an overview of the excellent research that has been done in the evolution of the * To whom correspondence should be addressed. E-mail: Paul.Anastas@ yale.edu. † Yale University. ‡ Science Strategies LLC. Chem. Rev. 2010, 110, 5845–5882 5845 10.1021/cr9003105  2010 American Chemical Society Published on Web 09/27/2010