Structural and Toxic Mechanism‐Based Approaches to Designing Safer Chemicals

Abstract

The sections in this article are Toxicophores Electrophilic Toxicophores Designing Safer Electrophilic Substances Structure–Activity Relationships Aliphatic Carboxylic Acids Organonitriles Quantitative Structure–Activity Relationships ( QSARs ) Isosteric Substitution as a Strategy for the Design of Safer Chemicals Isosteric Substitution in the Design of Safer Drug Substances Isosteric Substitution in the Design of Safer Pesticides Isosteric Substitution in the Design of Safer Commercial Chemicals Conclusion Disclaimer

Toward a Comprehensive Molecular Design Framework for Reduced Hazard

“…Dissociation constant (p K a ) and ionization: organic salts are absorbed better than neutral organics; neutral molecules are better absorbed by passive diffusion.…”

On the design of safer chemicals: a path forward

“…1 Over the past 35 years many comprehensive treatises devoted to the design of safer chemicals have been published, [2][3][4][5][6][7][8][9][10][11][12][13] and some chemical companies devote considerable resources to the development of safer commercial chemicals. 10,15,16 These examples illustrate use of: biochemical mechanisms of toxicity to infer molecular modifications that mitigate toxicity; qualitative structure-activity (toxicity) relationships; quantitative structure-activity (toxicity) relationships; isosteric substitution; and retrometabolic principles, among others, and provide structural representations of chemicals known or believed to be safer than other chemicals. 10,15,16 These examples illustrate use of: biochemical mechanisms of toxicity to infer molecular modifications that mitigate toxicity; qualitative structure-activity (toxicity) relationships; quantitative structure-activity (toxicity) relationships; isosteric substitution; and retrometabolic principles, among others, and provide structural representations of chemicals known or believed to be safer than other chemicals.…”

“…16,17 For optimal impact the concept must be accepted and applied as the general practice throughout industry in the development, production and use of commercial chemicals. 16,17 For optimal impact the concept must be accepted and applied as the general practice throughout industry in the development, production and use of commercial chemicals.…”

“…9,14 Many specific and detailed examples on how timehonored approaches used by medicinal chemists to design safer, clinically efficacious pharmaceutical substances can be applied to the design of safer commercial chemicals are provided in publications by Ariëns 2,4,7 and DeVito. 10,15,16 These examples illustrate use of: biochemical mechanisms of toxicity to infer molecular modifications that mitigate toxicity; qualitative structure-activity (toxicity) relationships; quantitative structure-activity (toxicity) relationships; isosteric substitution; and retrometabolic principles, among others, and provide structural representations of chemicals known or believed to be safer than other chemicals.…”

“…Yet for a variety of reasons, or more specifically because of a variety of impediments, the concept of designing safer chemicals has not yet been fully adopted by industry as a routine and necessary component of new chemical design. 16,17 For optimal impact the concept must be accepted and applied as the general practice throughout industry in the development, production and use of commercial chemicals. Moreover, a concerted effort must be made on the part of governmental regulatory agencies, funding institutions and academic institutions to eliminate the many challenges that impede application of the concept or, as a minimum, help chemical companies surmount them.…”