Biomarkers and disease prevention
Unit of Chemoprevention, International Agency for Research on Cancer, Lyon, France
“We are under no illusion that preventive strategies will be easy to implement. For a start, the costs of prevention have to be paid in the present, while its benefits lie in the distant future. And the benefits are not tangible – when prevention succeeds, nothing happens. Taking such a political risk when there are few obvious rewards requires conviction and considerable vision.” — Kofi Annan, Secretary General of the United Nations (1) The objective of epidemiological investigations is to estimate the distribution and determinants of disease in populations, with the ultimate goal of disease prevention. Use of biomarkers in occupational epidemiology requires a multidisciplinary approach in which molecular genetics, cell biology, toxicology, biochemistry, statistics and bioethics are incorporated into a traditional research frame. Recently, both genetic and epigenetic abnormalities have been detected in lesions in people who are clinically free of disease, and these could be used in assessing the risks and monitoring the health of working populations. Use of biomarkers to monitor exposure in a work environment was pioneered in the 1970s, first with respect to metals and organic solvents, then gradually expanding to a larger, more varied spectrum of exposures. The use of biomarkers expanded with the availability of techniques to measure effects at the molecular level: for instance, structural chromosome and gene damage, gene variation and gene products in cells and body fluids (2). Use of these biomarkers improved our ability to understand causality by allowing more direct and more accurate measurement of exposure and outcome. The aim of occupational epidemiology is to study the causal relations between exposure to exogenous agents and the development of clinical disease. The mechanisms by which exposures lead to disease are still, however, often unknown. Direct observation of a relationship between disease and exposure was considerably easier when exposure levels were high, such as in the 1960s and the beginning of the 1970s. With changing environments and decreasing exposure levels, we beed to evaluate subtler exposures and smaller risks. It has also been suggested that use of biomarkers also enhances quantitative risk assessment, by providing more accurate data for establishing dose–response relationships and measuring exposure and by facilitating the extrapolation of results for experimental animals to human populations. Individual susceptibility to a particular exposure can also theoretically be mapped genetically. Such studies have progressed rapidly because of the rapid advances in methods for molecular genetics that occurred in the 1980s and 1990s. Information about the distribution of ‘preclinical’ lesions or markers of susceptibility has also contributed to the characterization of high-risk populations (3). In order to design a successful disease prevention programme, we should ideally understand the natural history of the disease. Use of molecular markers in toxicology and epidemiology holds promise for elucidating the mechanisms of disease development and progression. Many of the factors in gene–environment interactions are modifiable and would provide a good starting point for primary prevention. It appears inevitable that various genetic polymorphisms will be identified at an increasing pace. Whether that will improve our ability to control occupational diseases is unclear. The number of genes that contribute to susceptibility to many diseases is likely to be large, and the effects of each gene on an allele will be weak. For example, if there are a dozen or more genes that contribute to myocardial infarct or to lung cancer, attempting to identify susceptible subgroups for public health interventions would be too complex to be of practical value. Thus, for myocardial infarct and lung cancer, and for most other chronic diseases, it is likely that more persons will benefit from modifications to their lifestyle or to environmental factors than from knowledge about their genotypes. If scientists conduct a comprehensive search for the genetic basis of every health outcome and ignore environmental exposures and attributable risks, we are likely to miss opportunities to prevent disease. Undoubtedly, overoptimistic expectations about the ability of genomics research to solve chronic disease problems emerged in the period of excitement that followed the sequencing of the human genome. This stemmed in part from a lack of understanding of the complexity of disease causation and in part from a tendency of some scientists to overemphasize the immediate medical importance of their work to the media and to granting agencies. References 1.Annan K. Preventing conflict in the next century. In: Fisburn D, Ed. The World in 2000. London: Economist Publications, 1999:91. 2.Aitio A. Biomarkers and their use in occupational medicine. Scand J Work Environ Health 1999;25:521–8. 3.Buffler P, Rice J, Bird J, Boffetta P, Ed. Mechanisms of carcinogenesis. Contributions of molecular epidemiology. IARC Scientific Publications No. 157, Lyon: IARCPress, 2004.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 803 (Risk & assessment).