it may be that exposure from diverse sources or by various rates is not covered by environmental monitoring. For example, classification of residents by distance from an arsenic smelter may not adequately reflect the arsenic concentrations in their diets, and environmental monitoring may not provide good estimates of total arsenic exposure.

Biologic markers are often assumed to be good indicators of exposure because they represent the integrated exposure from various sources and through various routes. However, to assess this assumption requires correlation of the marker with the potentially less-adequate environmental measure. There is no "gold standard." Perfect correspondence between the marker and the exposure could mean that neither is better than the other or that there are no other routes, sources, or host factors that intervene. On the other hand, it may mean that the marker is not an accurate reflection of these other intervening factors. It is important to determine whether the marker shows an exposure-response relation, whether all potential routes are accounted for, and whether susceptibility or host factors are addressed.

Host factors, including behavioral factors and genetic characteristics, may influence the amount of a toxic agent that interacts with critical macromolecules in cells and tissues. This is the "biologically effective dose." The biologically effective dose assesses exposure from all routes and sources as well as some aspects of effect modification, possibly including host characteristics for uptake, metabolism, absorption, and excretion. However, the marker may not necessarily encompass all these factors. Thus, even when biomarkers are useful, the best appraisal of exposure may still include ambient and environmental measurements as well as biologic measurements.

Numerous biomarker-related issues may arise during the conduct of studies, including questions of specimen collection, transport, storage, and assay; measurement error of technical variables in the assay; biologic variability; and assay interpretation and communication of results.

In cohort studies, biologic markers may be measured in subsets of populations, such as in a nested case-control or case-cohort approach, to assess etiologic questions and mechanisms and to identify high-risk subpopulations. In these situations, biologic markers of exposure may be useful to (1) distinguish exposure subgroups, (2) determine whether there is a relation between exposure and dose, or (3) evaluate the relation between exogenous exposure and internal or biologically effective dose.

Biologic markers may also be useful to identify the effect of an intervention. For example, does reduction of environmental emissions result in a reduction in the level of DNA adducts? Research studies to assess interventions need to include assessment of baseline levels of biomarkers in order to interpret the effect of the interventions.



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