Validation of Biological Markers for Quantitative Risk Assessment

Abstract

The evaluation of iolgia markers is recoied as necsry to the future oftokcOy , epideniology, and q Iive risk assment. For bio cl nmrkes to becm widely accepted, their validity must be ascertained. This paper explores the range ofconsiderations that compose the concept of validiBt as it applies to the evaluation of bioogical markers. Three broad categories of validity (meaem ent, internal study, and external) are discussed in the context of evWaluating data for use inquantitative risk at. Frticular attention is given to the importnce ofmeuement validity in the consideration ofwhether to use biological markers in epidemiologic studies. The Three broad categories of validity can be distinguished: measurement validity, internal study validity, and external validity. Measurement validity has been defined as an expression ofthe degree to which ".. . a measurement measures what it purports to measure" (9). Internal study validity is the degree to which inferences drawn from a sample are warranted when account is taken of the study methods, the representativeness of the study sample, and the nature ofthe population from which the sample is drawn (9). External study validity is the extent to which the findings of a study can be generalized to other populations (9). likely that the risk assessments constructed from those measurements will also be invalid. Measurement validity characterizes the extent to which a marker ofa phenomenon has content validity (i.e., pertains to the underlying phenomenon); construct validity (i.e., correlates with other relevant characteristics of the underlying phenomenon); and criterion validity (i.e., predicts some component of the underlying phenomenon). In general, these three components ofmeasurement validity are best assessed in terms of the extent or degree to which they apply to the underlying phenomenon, rather than as an all-or-none condition (JO). Content ValidityContent validity is the extent to which a marker "incorporates the domain ofthe phenomenon under study" (9). For example, a marker of internal dose will have content validity if it reflects the dose contributed by all routes of exposure. A marker of effect will have content validity if it encompasses the essential characteristics of the disease it represents. In other words, the marker must pertain to the appropriate target organ, or its relationship to the natural history ofthe disease in question must be unambiguous. For example, a DNA adduct of benzo(a)pyrene (BaP) will have content validity as a marker of exposure in a study ofBaP-induced lung cancer, since the involvement ofDNA in BaP-induced carcinogenesis is well documented. In contrast, the development of DNA adducts in the N7 position might not have content validity as a marker of biologically effective dose ifthe 06 methylguanine adduct is shown to be that which is most clearly related to the carcnogenic process. However, the N7 adducts might be reasonably valid markers ofBaP biologically effective dose ifthe production of06 and N7 adducts are directly proportion...

Assessment of exposure to environmental tobacco smoke

“…The validation is, thus, based on comparing results obtained with one method to those obtained with the other "nonideal" methods [18]. Measurement validity comprises three dimensions [17,19]. 1) Content validity describes the extent to which the measurement incorporates the domain of the phenomenon under study.…”

“…Reliability encompasses the nonsystematic, random variation observed upon repeated measurements [17,19].…”

Human Biomonitoring – An overview on biomarkers and their application in Occupational and Environmental Health

“…Ideally, biomarkers should be accessible (non-invasive), non-destructive, and easy and cheap to measure. Identification of biomarkers that are on causal pathways, have a high probability of reflecting health or the progression to clinical disease, and have the ability to account for all or most of the variation in a physiological state or the preponderance of cases of the specified clinical outcome have largely remained elusive, as one is never quite sure if they fulfill such requirements [13,14].…”

“…Biological markers can contribute to quantitative risk assessment by helping to: determine the forms of dose-time-response relationships; assess the biologically effective dose; make interspecies comparisons of effective dose, relative potency, and effects; resolve the quantitative relationships between human interindividual variability; and identify subpopulations that are at enhanced risk [13]. Nowadays, most research on biomarkers is concerned with markers which will increase our ability to identify long-term risks due to toxicant exposure, in particular the risk of developing cancer, and identify early markers of toxicity in the field of environmental or ecotoxicology.…”

“…The traditional, generally accepted classification of biomarkers divides them into three main categories -biomarkers of exposure, effect, and susceptibilitydepending on their toxicological significance [4,13,17]. A biomarker of exposure is defined as "an exogenous substance or its metabolite or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a compartment within an organism" [4,11].…”