Biomarker categories

Biomarkers can be classified into a number of categories according to the type of information obtained.

Biomarkers of exposure indicate whether exposure to an agent has taken place, and they include measurement of specific metabolites and/or adducts formed by reaction of the compound or its metabolites with macromolecules, such as DNA, RNA, and protein. Measures of a biologically effective dose include DNA adducts, and as a surrogate indicator of the amount of the reactive chemical or metabolite circulating in the blood, hemoglobin adducts and albumin adducts. Biomarkers of exposure can also aid in performing interspecies extrapolations when data are available from experimental animals and humans.8 In addition, in some circumstances, biomarkers can provide insights into the potential shape of the dose response curve below levels where tumors have been observed.9,10 One of the challenges in developing a biomarker of exposure is demonstrating that the marker is indeed specific and does not reflect a nonspecific response that could arise from a number of different compounds.

Markers of effect provide an indication of early events in the etiology of disease or in toxicologic or carcinogenic processes. Markers of effect for

Markers of Exposure

EXPOSURE

Markers of Exposure

EXPOSURE

i

k Chemical or ' Metabolites in blood, tissues, urine

k DNA Adducts ' Protein Adducts (hemoglobin, albumin)

IDNA Strand Breaks t Sister Chromatid Exchanges Micronuclei

Chromosomal Aberrations hprt Mutations

(LacI Mutations)

Oncogene Activations

Tumor Suppressor Gene Mutations

k

SUSCEPTIBILITY

Cytochromes P-450 GSTs

N-Acetyltransferases Oncogenes

Tumor Suppressor Genes DNA Repair

Cytochromes P-450 GSTs

N-Acetyltransferases Oncogenes

Tumor Suppressor Genes DNA Repair

Figure 25.1 Biological markers of exposure, effect, and susceptibility that are important in chemically induced carcinogenesis. (From Fennell, T.R., CIITAct., 16, 11, 1996. With permission.

carcinogens include endpoints that can be measured in the tissue of concern with regard to particular stages of carcinogenesis. In most cases, measurements are made in surrogate cells such as blood cells, which can be readily obtained from human subjects. The markers may include sister chromatid exchanges, micronuclei, chromosomal aberrations, and mutations at several genes such as hprt and glycophorin A. A confounding factor in measuring these markers in people is that they are not chemical specific and may be elevated by lifestyle factors. More specific measures of effect that may be critically linked to the carcinogenic process include the measurement of mutations in oncogenes and tumor supressor genes. Mutations in the ras oncogene and the p53 tumor suppressor gene are frequently detected in human tumors, and with polymerase chain reaction for sensitive detection may provide early markers of events in human carcinogenesis.11

Markers of susceptibility can be used to identify specific individuals at greater risk than the general population due to a genetic or other predisposition to the effects of exposure to a particular compound. These can involve enzymes involved in the metabolism of carcinogens, activation and detoxi-cation, DNA repair enzymes, oncogenes, and tumor supressor genes. Markers can be measured at various stages in the progression from exposure to the end effect, and represent a continuum of the events involved (Figure 25.1). The biomarkers presented in Figure 25.1 are particularly relevant to chemical carcinogenesis.1213 However, biomarkers are of interest in the molecular epidemiology of other diseases.6

There are many issues in toxicology that can be addressed with bio-markers. Among these are the following: the comparison of routes of expo sure (e.g., dermal vs. inhalation exposure to chemicals); the sources of exposure (e.g., lifestyle vs. workplace); endogenous generation of chemicals vs. exogenous exposure; comparisons between species; interindividual differences in sensitivity and susceptibility; and gaining insights on the mode of action of a given chemical. Making effective and efficient use of biomarkers to address the above issues requires that we understand the relationship among exposure, effects, and a biomarker, the specificity and sensitivity of a biomarker, and the role of timing between exposure and measurement on the level of a biomarker. For humans, exposure to mixtures and the potential for exposure by multiple routes and sources adds a significant degree of complexity to the development and interpretation of biomarkers. In subsequent section of this chapter, we examine the potential dual role that the Ah Receptor (AHR) can play in establishing the mode of action of dioxin, an ubiquitous compound arising as a contaminant of a variety of industrial processes and for which considerable controversy exists concerning potential effects in humans.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment