Cancer Risk Reduction Through Mechanism-Based Molecular Design of Chemicals

Abstract

Increased understanding of the mechanistic basis of chemical carcinogenesis and the relationship between molecular structure and carcinogenic activity provides opportunities not only for identifying suspect carcinogens but also for designing chemicals with lower carcinogenic potential. One of the chemical classes in which the structural and molecular basis of carcinogenicity is the most clearly understood is the aromatic amines. This paper summarizes the bioactivation mechanisms and structural criteria for aromatic amine carcinogenesis; a strategic approach of risk reduction through mechanism-based molecular design of aromatic amine dyes with lower carcinogenic potential is discussed. With our increasing knowledge of the mechanisms and structure-activity relationships, it should be possible to develop safer products for other chemical classes using similar molecular design approaches. Mechanisms of Chemical Carcinogenesis and Structure-Activity RelationshipsConsiderable knowledge of the mechanisms of chemical carcinogenesis has accrued since the pioneer work by James A. and Elizabeth C. Miller at the University of Wisconsin beginning in the 1940's, particularly concepts on the metabolic activation of chemicals to reactive electrophilic intermediates that interact with cellular nucleophiles to initiate carcinogenesis (7,2). For many carcinogen classes, the molecular basis of carcinogenic activity is now known in considerable detail and the concept of electrophiles provides the most probable rationale for their carcinogenic action. Some of the electrophilic, reactive intermediates believed to be responsible for the carcinogenicity of genotoxic chemicals include: carbonium, aziridium, episulfonium, oxonium, nitrenium or arylamidonium ions, free radicals, epoxides, lactones, aldehydes, semiquinones/quinoneimines, and acylating moieties. The metabolic activation of various genotoxic chemicals to their ultimate carcinogenic metabolites has been reviewed (3).

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

“…The same approach has been used in design of safer chemicals (33) and pollution prevention (34). An expert system (OncoLogic) has been developed to systematize and codify the agency's SAR expertise in predicting carcinogenic potential of chemicals (26).…”

“…The DBPs were first reviewed to identify chemicals with low concern. Judgments of low cancer concern were based on structural similarity to chemicals with negative cancer data, a lack of structural alert for genotoxicity, or presence of structural features suggestive of low cancer risk via the oral route (26,27,33). Once the DBPs of low concern were removed from the list, a literature search was done for the remaining DBPs.…”

Structural motifs modulating the carcinogenic risk of aromatic amines

“…The case study selected for the present analysis is the aromatic amines. These chemicals have considerable environmental and industrial importance, and toxicological data have been reported for a large number of them [Lai et al, 1996;Sugimura, 1997;Vineis and Pirastu, 1997;Skog et al, 1998;Woo and Lai, 2001]. In previous work we have performed QSAR investigations on the activity and the potency of the aromatic amines, for both mutagenic (Salmonella) and carcinogenic (rat and mouse) endpoints [Benigni et al, 2000[Benigni et al, , 2007aFranke et al, 2001].…”

Quantitative structure‐activity relationships for predicting mutagenicity and carcinogenicity

“…Chemicals with two or more fused rings were all mutagenic. The mutagenic potency was found to increase in the order single ring < diphenyl methane < biphenyl < fused rings, suggesting that perhaps multiring systems do provide a longer conjugation path for the stabilization of intermediate metabolites as proposed by Lai et al [11]. The results indicated that mutagenic activity was influenced by different molecular characteristics in different subclasses of aromatic amines.…”