The Need for, and the Role of the Toxicological Chemist in the Design of Safer Chemicals

Abstract

During the past several decades, there has been an ever increasing emphasis for designers of new commercial (nonpharmaceutical) chemicals to include considerations of the potential impacts a planned chemical may have on human health and the environment as part of the design of the chemical, and to design chemicals such that they possess the desired use efficacy while minimizing threats to human health and the environment. Achievement of this goal would be facilitated by the availability of individuals specifically and formally trained to design such chemicals. Medicinal chemists are specifically trained to design and develop safe and clinically efficacious pharmaceutical substances. No such formally trained science hybrid exists for the design of safer commercial (nonpharmaceutical) chemicals. This article describes the need for and role of the "toxicological chemist," an individual who is formally trained in synthetic organic chemistry, biochemistry, physiology, toxicology, environmental science, and in the relationships between structure and commercial use efficacy, structure and toxicity, structure and environmental fate and effects, and global hazard, and trained to integrate this knowledge to design safer commercially efficacious chemicals. Using examples, this article illustrates the role of the toxicological chemist in designing commercially efficacious, safer chemical candidates.

Computer-Aided Discovery and Redesign for Respiratory Sensitization: A Tiered Mechanistic Model to Deliver Robust Performance Across a Diverse Chemical Space

“…While the primary use of CADRE has been to provide robust hazard predictions for commodity and specialty chemicals, the recent regulatory emphasis on green chemistry has spurred demand for in silico safer chemical design. This initiative is in line with the long-recognized need to transform our “reactive approach” to chemical safety (i.e., chemical testing) to a “proactive strategy” that ensures systems-based considerations of chemical properties in the upstream of new product development. − In contrast to traditional SAR and (Q)­SAR approaches (as well as modern statistical tools based on machine learning and artificial intelligence), the mechanistic underpinning of CADRE can facilitate rational design of safer chemicals for its end points. ,, Here, the ‘rule of 2’, based on cutoffs in log P w/g and Δ E HOMO–LUMO , can steer structural modifications of existing compounds into part of the chemical space where safety is more likely (Figure ). While these methods are not intended to be deterministic, they are useful vectoring tools that prod the chemist to consider perturbations that would yield the desired outcome in the broader context of the role the specific chemical must play to achieve its commercial potential …”