Interindividual variations in susceptibility and sensitivity: linking risk assessment and risk management

In the past few years, our knowledge of mammalian genomes has increased enormously. Our understanding of the molecular basis of the normal cellular processes of DNA replication and repair and cell cycle control, together with how their fidelity malfunctions as part of tumor development, has increased in parallel. This has led to a clearer appreciation that there are subpopulations that have been generically described as being genetically or otherwise susceptible to the induction of cancer or birth defects. The term susceptibility is a default option, since there clearly will be a very broad range of sensitivities among the so-called susceptible populations, dependent upon the specific underlying mechanism. This could lead to the conduct of risk assessments for each specific situation, involving both genotypes of individuals and agents of concern. This would ideally take into account the effects on response of various modifying factors, genetic and other. One advantage to be gained from this approach is the ability to determine if a particular susceptibility places subpopulations at extreme risk as compared to the overall normal distribution of risk in the population, or whether such a susceptible population presents a slight extension of the upper bound of the risk distribution or lies within the normal distribution. In addition, the specific mechanism of the susceptibility as related to exposure scenarios and the magnitude and demographics of the susceptible populations need to be taken into account. Thus, the management of risk has to be linked to the specific risk assessment. For many of the so-called susceptible populations an uncertainty factor of less than 10, even including 1, would be predicted to bring the risk within the normal distribution. It is hoped that as more mechanistic information on susceptibility becomes available and a specific risk can be defined, the practice of risk management will be considerably improved.