Written by Stanley R. Milstein, Ph.D.
This blog (posted in a 3 part series) is in no way intended to be a formal scholarly treatise on the subject of “quantitative structure-activity relationships (QSAR)” and their evolution to a battery of “in-silico” methods within the overarching “umbrella” that has come to be known as “integrated strategies” of Tox 21.
Rather, it is simply a curious and personal tale of how one organic-medicinal chemist, originally steering towards a career in the pharmaceutical or agricultural chemicals industry, found himself, instead, seeking a path to introduce the QSAR Paradigm to the cosmetic industry and, later, to the cosmetic regulatory environment at the U.S. FDA.
“Structure-Activity Relationships or (Q(SAR)” (qualitative or quantitative) postulate that systematic trends in relative biological activity (RBR) or potency in a set of chemical compounds related through chemical and/or biological “similarity” (i.e., analogs or congeners) can be understood through some rational function of their chemical structure and “mechanism of action (MoA).
Originally envisioned by Professor Corwin H. Hansch (“Father of QSAR”) in the early 1960s as a science-based technology geared to “optimize” biological activity of ‘lead compounds’ in a congeneric series of pharmaceutical or agricultural compound ‘actives’ through rational computer-guided organic synthesis, the QSAR Paradigm evolved from turn-of-the 20th Century hypotheses of Crum-Brown, Fraser, Meyer-Overton, and Ferguson, and grew over a period of four decades to a cutting-edge scientific discipline that is still evolving today, to encompass environmental structure-toxicity relationships, substance structure-property relationships (QSPR), and explorations of “safer chemical alternatives” of institutional and industrial (I&I) as well as consumer commodity chemicals.
As an integral component of the growing field of 3R- “Predictive Toxicology” (i.e., Tox21), the QSAR Paradigm seeks to fill “information gaps” in safety assessments, and to jointly utilize the best validated science-based “integrated strategies” of in-vitro, in-chemico, and in-silico approaches to answer questions related to (cosmetic) ingredient safety assessment, while promoting international efforts to “reduce, refine, replace” the use of sentient animal-based toxicity testing of cosmetic ingredients with more accurate and human-relevant validated alternative test methods and tools! In this context, QSAR is referenced in the 9th Revision (2016) of the European Commission advisory committee, the Scientific Committee on Consumer Safety (SCCS) publication, “Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation, click here.
For an in-depth discussion of what came to called ‘classical QSAR, please consult the following sources:
- 1) C. Hansch, “A Quantitative Approach to Biochemical Structure-Activity Relationships”, Accts Chem. Res., 2 (8), 232-239, !1969);
- 2) C. Hansch and A. Leo, Exploring QSAR: Fundamentals and Applications in Chemistry and Biology, ACS Professional Books, (1995);
- 3) C. D. Selassie, . “History of Quantitative Structure-Activity Relationships”, in D.J. Abraham, Ed., Burger’s Medicinal Chemistry and Drug Discovery (6th Edition), Volume 1- Chapter 1 (2003)
In the next post, Stanley details his journey along the ‘Yellow Brick Road” – from Academia to Industry.
STANLEY R. MILSTEIN, Ph.D. retired as Acting Deputy Director in FDA’s Office of Cosmetics and Colors at the FDA Center for Food Safety and Applied Nutrition (CFSAN) in Washington, D.C. in 2017. He continues to be available to the Agency for short term consultation assignments, but the comments in the current blog reflect only his own personal experiences over the past four decades and are neither reflections of FDA agency policy or positions. Prior to joining the FDA in 1991, Dr. Milstein held several senior scientific and regulatory affairs positions in the R&D Division of the Andrew Jergens Company (Cincinnati, OH). Prior to his retirement he represented FDA as a member of the U.S. delegation to the International Cooperation on Cosmetics Regulation (ICCR) and as the agency’s non-voting liaison to the PCPC International Nomenclature Committee (INC), which he continues to serve as an Emeritus non-voting member (Consultant, since June 2017).
Professionally, Dr. Milstein has served the Society of Cosmetic Chemists (SCC) in several local and regional elected capacities over the past 40 years. He served as Chair, Ohio Valley Chapter (OVCSCC) in 1984, Area II Director (1985), and a term as President of the National SCC in 1992. He served as 2014 Chair, Mid-Atlantic Chapter SCC (MACSCC) and is currently the SCC Senior Area IV Director (Mid-Atlantic, Southeast, Florida, and Carolinas Chapters) (2016-2018). He has also held several visiting and adjunct faculty appointments in general and organic chemistry, as well as in cosmetic science in the Departments of Chemistry at Adelphi University (Garden City, NY) and the University of Cincinnati, respectively. He recently joined the faculty of the UC College of Pharmacy as Adjunct Professor, Cosmetic Science. Dr. Milstein has frequently addressed foreign regulatory delegations to FDA-CFSAN and has also spoken to audiences at CTFA, PCPC and ICMAD industry conferences. He was also an invited presenter at the FDA Office of Regulatory Affairs University course on Import Operations and Entry Review (2005-2017) and the Widener University-Delaware School of Law (2018).. He is currently a member of the FDA Alumni Association (FDAAA) Activities Committee.
Dr. Milstein has published in the peer review literature of organic and medicinal chemistry, cosmetic science, and regulatory affairs, as principal co-author of two chapters on cosmetic regulation in the Handbook of Cosmetic Science and Technology (Marcel Dekker/ Taylor-Francis, 2001, 2006) and. most recently, co-author of a chapter on the analysis and regulatory aspects of color additives in cosmetics in Analysis of Cosmetic Products (Elsevier, 2007, 2018).
Dr. Milstein holds a B.S. degree in Biology from Rensselaer Polytechnic Institute, an M.S. degree in Pharmaceutical Sciences (Cosmetic Science) from the University of Cincinnati College of Pharmacy, and a Ph.D. in Organic Chemistry from Adelphi University (Garden City, NY). He also completed two post-doctoral research fellowships in medicinal chemistry and QSAR at Pomona College (Claremont, CA) and at the University of Cincinnati College of Pharmacy (Cincinnati, OH).