Emerging stratgies for the determination of human carcinogens: detection, identification, exposure monitoring, and risk evaluation

Introduction

It is now generally accepted that most chemical carcinogens and probably all chemicals that induce cancer, de novo, i.e. cancer initiators, operate via a genotoxic mechanism. DNA is regarded as the key target of genotoxic carcinogens although many chemicals classified as genotoxic are in fact inactive precursors requiring metabolic conversion into reactive forms in order to undergo chemical reactions with DNA. Primary products of these reactions are generally promutagenic and their occurrence leads to an increased risk of mutation and cancer. Among the reaction products. DNA adducts have been singled out for special attention not only because of their mutagenic propensity but also because of the sensitivity and specificity of the methods for their analysis. DNA adducts and generalized DNA damage can also arise indirectly, e.g. via the agency of reactive oxygen species formed as a consequence of chemical or radiation-induced perturbations in normal cellular metabolism. Chemicals that induce coding errors by interactions with DNA replication or repair functions provide an additional category of indirect genotoxic agents.

Cancer prevention

These developing mechanistic insights have important practical applications not least in the field of cancer prevention. In particular, the compelling evidence of a sequential mechanism linking electrophile reactivity with the induction of primary chemical damage in DNA leading to mutation and cancer fuelled the development and widespread application of rapid, in vitro genotoxicity assays for the prediction of carcinogenic activity. The trend is towards increasingly prospective and sensitive technology. The major emphasis is on the development of generic and specific molecular approaches designed to detect genotoxic action and discriminate between the causative agents at the low concentrations encountered in the environmental or occupational setting. For example, advances in molecular biology now permit the direct determination and analysis of mutation at the level of individual bases in DNA with no prior requirement for phenotypic selection. Furthermore, ultrasensitive techniques, based on the analysis of DNA and protein adducts, have been introduced to detect and monitor human exposures to both known and, as yet, unidentified genotoxic chemicals. Indeed, a key feature of the emerging technology is tat it can be applied directly in a man of the chemical agents responsible for the initiation of human cancer. Specifically, the new methods serve to focus attention on the real hazards to which humans are exposed as opposed to potential hazards which may or may not penetrate to and damage human DNA. The emerging technology is, therefore, central to new strategies for cancer prevention.

The trend towards increasingly prospective sand sensitive technology satisfies an important need to provide an early warning of the hazard to man. However, the high sensitivity of the new methods highlights an additional requirement, i.e. a need to quantify the risk to man.