IVD Technology Magazine | IVDT Article Index
Originally published May 1996
Commentary
Biomarkers of chemical exposure: A new frontier in clinical chemistry
Steven M. Rosen
The major goal of environmental toxicology research has been to predict and prevent human disease resulting from chemical exposure and other environmental risk factors. Until about 15 years ago, the health risk associated with exposure to environmental chemicals was determined by calculations of external exposure. Such exposure, however, correlates only roughly with the amount of internal exposure and individual risk.
The introduction of molecular approaches to toxicology research has led to the discovery of biological and biochemical markers, which are increasingly valuable for predicting and preventing diseases with environmental etiology. Through recombinant DNA techniques, researchers can detect the environmentally induced changes in the structure and sequence of DNA indicated by biomarkers. Automated immunoassay technology currently in development can detect biomarkers of specific disease-causing compounds in biological fluids. Also, clinical laboratories are beginning to use biomarker-detection tests to evaluate individual risk for environmental disease.
A biomarker is the result of a subclinical event in the body caused either directly or indirectly by exposure to an environmental factor, such as a chemical or radiation. It is an indicator of disease susceptibility. Ideally, the increased risk for disease associated with the presence of the biomarker should be reversible by appropriate medical intervention. Common sample materials for biomarker assays are blood, urine, feces, hair, and saliva. DNA samples are usually derived from white blood cells, and the presence of chemical metabolites is usually determined from urine.
Biomarkers have been categorized into three types: biomarkers of exposure, effect, and susceptibility. Biomarkers of exposure are foreign compounds or their metabolites found within the body--for example, an adduct formed by the interaction of polyaromatic hydrocarbons with DNA. The formation of these adducts has been linked to the transformation of cells to a cancerous phenotype.
Another type of biomarker of exposure is the metabolic product of an environmental toxin. The metabolites of many chemicals, such as some pesticides, are measured instead of the parent compound either because the metabolite is the more toxic or because the parent compound is completely metabolized in vivo.
Biomarkers of effect result from changes in the homeostasis of an organ system that precede clinical disease. Examples of such effects are liver necrosis, low birth weight, and changes in pulmonary function. A biomarker of effect may be specific to a particular environmental toxin or it may imply a mixed exposure to a number of environmental agents.
A biomarker of susceptibility indicates whether a person is more likely to be sensitive to a xenobiotic than are most other members of the population (Cullen et al., Clin Chem, 41:18091813, 1995). Degrees of susceptibility to environmental disease vary with hereditary and acquired metabolic variation, mutations, the functional status and the genetic composition of a person's immune system, and variation in his or her nutritional status. For example, the levels of ß-carotene, selenium, and retinoids have been associated with the predisposition to cancer. Some individuals are known to exhibit multiple chemical sensitivities.
Epidemiological studies indicate that many diseases and most cancers are due to human exposure to environmental toxins. In recent years, there has been a great deal of interest in defining the intermediate steps of carcinogenesis. This work has been facilitated by novel molecular diagnostic techniques that enable the quantitation of changes in cellular biochemistry.
Researchers are exploring the possibility that giving chemopreventative drugs to biomarker-positive persons might reverse damage to cellular biochemistry. For example, cytologic examinations of human sputum have found that the administration of folate and vitamin B12 suppressed the development of squamous metaplasia and atypia in smokers' airways (Kamei et al., Cancer, 71:24772483, 1993). In addition, folate has been associated with reduced risk for invasive cervical cancer in patients with cervical dysplasia (Potischeman et al., J Nutrition 123 [2 suppl], February, pp 424429, 1993).
Some major reference laboratories, such as LabCorp, Inc., Analytics Laboratory (Richmond, VA), already offer tests for chemical-exposure biomarkers to help monitor exposure to toxic substances in the workplace (see Table I). The entry of leading reference laboratories into the environmental toxicology field suggest that this area will see accelerated growth in the future.
Several roadblocks obstruct the application and commercialization of biomarkers for the detection of toxic chemical exposure. The analytical, diagnostic, and etiologic validity of many of the new markers has yet to be established (Tockman et al., Cancer Res, 52, pp 2711s2718s, 1992). Recognized disease end points need to be more clearly associated with them. Standardized criteria for the quantitative measurement of these new markers must be established, and the predictive values of each of them must be determined by population studies.
At the present time, little is known about how FDA will greet the use of the new biomarkers in the clinical laboratory to predict disease risk. In the past, the agency has approved tests that help predict the risk for heart disease, such as those for high- and low-density lipoproteins. However, it has been slower to accept changes in biomarker levels as end points in clinical trials for infectious-disease drugs. FDA's stance on biomarkers will depend upon their epidemiological significance.
In addition to the technical challenges, the social impact of biomarker assays must be considered. New diagnostic tests will have the capability of identifying predisposition to serious and life-threatening diseases. In many cases, there will be a lag between the time a marker is identified and the availability of treatment to prevent the onset of disease. Information on increased risk may be especially undesirable if potential employers or life insurance companies could access it. Legislation should be enacted to prevent the use of this technology in a manner contrary to societal goals. However, such legislation should not defeat the ability of this technology to predict and prevent environmental disease.
Further issues may exist in tort law. In Ayers v. Jackson Township (106 NJ 557), the courts ruled that persons who had been exposed to aromatic hydrocarbon solvents but at the time of the trial exhibited no disease were entitled to damages for medical surveillance and the enhanced, although not quantified, risk of disease. The availability of biomarker assays may influence litigation such as this case and cause potential polluters to be more cautious.
The potential for early treatment and disease prevention should justify the extensive cost and effort of commercializing biomarkers. The benefit of such tests greatly outweighs any negative societal impact. Biomarker-based diagnostic tests may offer opportunities to intervene effectively with relatively inexpensive treatments before environmen-tally induced disease advances to a stage where more costly therapy is required.
Steven M. Rosen, PhD, is a senior scientist for the Drug Monitoring Business Unit of Roche Diagnostic Systems, Inc. (Somerville, NJ).
