Grandjean, Philippe

Clinical Chemistry

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 Biomarkers in epidemiology  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Grandjean P. 1995. Biomarkers in epidemiology. ClinicalChemistry 41 (12): 1800.Published Version http://clinchem.aaccjnls.org/content/41/12/1800.longAccessed April 17, 2018 3:01:35 PM EDTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:34776473Terms of Use WARNING: This file should NOT have been available fordownloading from Harvard University's DASH repository.CLIN. CHEM. 41/12, 1800-1803 (1995) #{149}European Beckman Conference1800 CLINICAL CHEMISTRY, Vol. 41, No. 12, 1995Biomarkers in EpidemiologyPhilippe GrandjeanA biomarker is a measurable event occurring in a biolog-ical system, such as the human body. In environmentalepidemiology, a biomarker represents a subclinical andreversible change; it is not a diagnostic test, but anindicator that an early change has occurred that couldlater lead to clinical disease. Although some biomarkersmay belong to more than one class, they are oftenseparated into biomarkers of exposure, biomarkers ofeffect, and biomarkers of suceptibility. Biomarkers canbe used to classify and quantify environmental exposuresand their related effects, and many methods may beapplicable in toxicological experiments as well as inepidemiology. Accordingly, biomarker epidemiology isundergoing rapid development and expansion and isbecoming one of the most promising areas of environ-mental research. Although expanded applications shouldbe encouraged, many biomarkers are poorly character-ized, and attention should be paid to defining theirproperties in detail.Indexing Terms: environmental toxicology/epidemiologyThe term biomarker has entered the epidemiologicaland environmental vocabulary as a short form forbiological marker or biochemical marker. The firstEuropean conference on biomarkers in environmentaltoxicology was held in 1993 (1). Biomarker refers to ameasurable event occurring in a biological system,such as the human body (2,3). This event is theninterpreted as a reflection of a more general state of theorganism or the life expectancy of an individual. Inaddition to biological marker (2, 4), other terms haveoccasionally been used with the same meaning. Forexample, a recent publication entitled “Biomarkers inecotoxicology” (5) was referred to as “Bioindicators inecotoxicology” in the table of contents. For the sake ofuniformity, biomarker would seem to be the mostappropriate term.To be useful in epidemiology, the measurable eventin the human body should represent a subclinicalchange only. A biomarker is not a diagnostic test, butan indicator that an early change has occurred thatcould later lead to clinical disease. Especially for use inpreventive medicine, the change should be completelyreversible. To trigger appropriate action, a biomarkerfinding should also be amenable to interpretation withregard to causal factors in the environment, and poten-tial preventive efforts should be realizable, at least inInstitute of Community Health, Odense University, Odense C,Denmark. Address correspondence to : Winslowparken 17, 5000Odense C, Denmark. Fax mt +45-65.91.14.58; e-mailp.grandjean@winsloew.ou.dk.Received June 12, 1995; accepted August 28, 1995.principle. Also, from an ethical viewpoint (6), the prac-tical use of the biomarker should be regarded asacceptable.A biomarker reflects an event or a sequence of eventsthat occur somewhere in the causal chain between anexposure to a hazardous factor and a related adverseeffect. Theoretically, these events can be separated intothose indicating “internal dose,” “effective dose,” etc.,but some of these terms themselves are difficult todefine, and a detailed classification of biomarkers maynot necessarily add to the understanding of their prop-erties. Nonetheless, three specific types of biomarkersare usually identified (Fig. 1) (2, 3). Although somebiomarkers may belong to more than one class, theyare often separated into biomarkers of exposure,biomarkers of effect, and biomarkers of suceptibility.As illustrated by papers presented at the BiomarkerConference in 1993 (1) and the present proceedings, allthree types of biomarkers are extremely useful inepidemiological studies.Exposure BiomarkersAn exposure biomarker may be a xenobiotic com-pound or metabolite within the body, an interactiveproduct between the compound (or metabolite) and anendogenous component, or another event related to theexposure (2, 3). Most commonly, biomarkers of expo-sures to stable compounds are assessed by measuringtheir concentrations in appropriate samples, such asblood, serum, or urine. The concentration of a volatilechemical may be assessed in exhaled breath. If thecompound is metabolized in the body, one or moremetabolites may be determined, e.g., in a urine sample.Especially with mutagenic chemicals, some promisinganalytical developments have been realized (7). Ad-ducts formed with DNA can now be detected in whiteFig. 1. Three major types of biomarkers have been recognized, butoverlapping may occur.CLINICAL CHEMISTRY, Vol. 41, No. 12, 1995 1801blood cells or tissue biopsies, and specific DNA frag-ments may be identified in the urine. Hemoglobinadducts may be a feasible biomarker, but no repairoccurs, and they may not accurately reflect the effectsin the target organ. On the other hand, hemoglobinadducts indicate the integrated event during the4-month lifetime of red blood cells. One may speculatethat adducts with other proteins, such as collagen,could become useful as indicators of exposures duringmuch longer exposure periods. Although such adductsare the result of a biological effect, they are usuallyconsidered exposure biomarkers.Temporal aspects are important for all exposurebiomarkers, not only for adducts. Evidence must beobtained to show the extent to which short-term vari-ations in the exposure affect distribution, retention,and interaction with the target molecules. Sometimes,such toxicokinetic evidence is used to classify a bio-marker as an indicator of (total) absorbed dose or anindicator of effective dose (i.e., the amount that hasreached the target tissue). Although few biomarkershave been fully characterized in this regard, extendedapplication in epidemiology should be encouraged toassist in the elucidation of these aspects.Effect BiomarkersA marker of effect may be an endogenous component,or a measure of the functional capacity, or some otherindicator of the state or balance of the body or organsystem, as affected by the exposure. Such effect mark-ers are generally preclinical indicators of abnormali-ties. These biomarkers may be specific or nonspecific.The specific biomarkers are useful because they indi-cate a biological effect of a particular exposure, thusproviding evidence that can potentially be used forpreventive purposes. The nonspecific biomarkers donot point to an individual cause of the effect; rather,they indicate the total, integrated effect that could bedue to a mixed exposure.As discussed, e.g., by Harris et al. (7), biomarkersmay be crucial for the evaluation of genotoxic effects ofenvironmental chemicals. In particular, methods usedfor assessing genotoxicity in humans may also beapplied in animal experiments in which they can becompared with data on target tissues that cannot beexamined in human subjects. Such studies of causalchains may provide new insight into disease pathogen-esis. In this way, biomarkers constitute a commonground to be explored jointly by toxicologists and epi-demiologists. Not surprisingly, this research area hasattracted much attention, although predominantly inrelation to cancer.A recent publication from the International Programon Chemical Safety (IPCS) (8) reviews the applicationsof biomarkers, including those that indicate effects ondifferent organ systems. Although very useful in thisregard, it includes the following adverse health effectsas examples of biomarkers: liver cell necrosis, de-creased pulmonary function, low birth weight, andmental retardation. Thus, according to IPCS, certainmedical diagnoses could be used as biomarkers. How-ever, this application of the term may lead to confusion.The medical diagnoses mentioned should instead bereferred to as sentinel events (9). A biomarker in thestricter sense of the word does not represent thediagnosis or the sentinel event itself, but rather reflectsa risk that such pathology could develop at a laterstage.A biomarker therefore is like a symbol, which has adepth of meaning (regarding risk) greater than thatrepresented by its immediate appearance (the changeper se). Epidemiological evidence is of key importanceto document the interpretation of the biomarker withregard to such risk.Susceptibility BiomarkersA marker of susceptibility, whether inherited orinduced, is an indicator that the individual is particu-larly sensitive to the effect of a xenobiotic or to theeffects of a group of such compounds. Most attentionhas focused on heterogeneities of enzymes involved inthe metabolism of xenobiotics (7), although other non-genetic factors are likely to be at least as important.Hypersusceptibility is a well-known but insufficientlyexplored phenomenon in epidemiology. It may be dueto an inherited trait, to the constitution of the individ-ual, or to environmental factors (10).A particularly promising aspect relates to hypersus-ceptibility caused by depletion of the reserve capacity.The human body seems to possess a certain capacity towithstand potentially adverse effects of chemical expo-sures. However, an individual’s resistance towardchemical toxicity may be decreased by a preexistingdisease or by additional environmental exposures, in-cluding those associated with diet and life-style (10). Aprevious exposure may not necessarily have resulted inrecognized toxicity, but could conceivably have causeda weakening of body defenses, i.e., a decrease in thereserve capacity. Biomarkers of reserve capacity couldtherefore reflect both effect and susceptibility, e.g.,related to the immune system, the hemopoietic system,or the kidneys. Such biomarkers would be particularlypromising for epidemiological studies.Applications in EpidemiologyAs indicated above, biomarkers have important ap-plications in epidemiology as well as in preventivemedicine and environmental health. A major aim ofepidemiological studies is to identify and evaluate riskfactors associated with disease. Because of insufficientconsideration of pathogenesis, risk-factor epidemiologyhas sometimes been referred to as black-box epidemi-ology (11). Biomarkers therefore fill a substantial needin modern epidemiology (Fig. 2). Hulka and Wilcosky(4) outlined the following purposes of using variousbiomarkers: (a) elucidation of pathogenic mechanisms;(b) improvement of etiologic classification of environ-mentally related diseases; and (c) recognition of earlyeffects. In addition, some exposure biomarkers can beapplied in groups of exposed workers to assess the1802 CLINICAL CHEMISTRY, Vol. 41, No. 12, 1995Black-box epidemiologyBiomarker epidemiologyFig. 2. The “black box” often apparent in risk-factor epidemiologymay be effectively explored by the use of biomarkers as indicatorsof pathogenetic steps.extent of compliance with pollution abatement regula-tions or effectiveness of preventive efforts in general.Biomarkers can also be applied to document the com-munity impact of an environmental hazard. In healthysubjects, a biomarker may reflect individual hypersus-ceptibility to specific chemical exposures and maytherefore serve as a basis for risk prediction. On anindividual basis, a biomarker may be used to support orrefute a diagnosis of a particular type of poisoning orother chemically induced adverse effect. These applica-tions clearly relate to central issues in environmentalepidemiology.Conventional epidemiology has low sensitivity whenexposure is assessed indirectly, or when assessment ofthe effects is based on crude indicators, such as diag-noses from death certificates. Because of the poorprecision, misclassification is likely to occur, thus de-creasing the sensitivity. Also, since major diseases takeyears to develop, conventional epidemiology concernsexposures of the past and may relate only partly to theproblems of exposures today. In addition, environmen-tal health research has to confront the thorny questionof extrapolation from studies in experimental toxicol-ogy. Biomarkers represent an important instrument totackle these problems.Because biomarkers can be used in epidemiologicalstudies to classify and quantify environmental expo-sures and related effects by methods that may even beapplicable in toxicological experiments, biomarker ep-idemiology is currently undergoing rapid developmentand expansion and is becoming one of the most prom-ising areas of environmental research. Again, someconfusion has clouded the literature. Thus, papers ongenotoxicity biomarkers first used the term “mutationepidemiology” (12), and subsequent publications usu-ally referred to this area as “molecular epidemiology”(7). The molecules referred to were generally markersof genotoxic effects. Because genotoxicity could also bereflected by changes in morphology (e.g., aneuploidy),and because molecular biology methods may also beapplied for other types of biomarkers, a more appropri-ate term for this field of research is obviously bio-marker epidemiology.Research NeedsRecent research has demonstrated the complexity ofsome dose-response relations and the considerabledifficulty in identifying no-effect concentrations. Forexample, for most organic compounds, quantitativeassociations between exposures and the correspondingadverse health effects are not yet available; in manycases, even the primary target organs are not knownfor sure. Biomarkers are likely to be of crucial value incharacterizing doses and effects in such studies. Ex-trapolation from animal experiments is becoming asophisticated specialty within toxicology, and determi-nation of comparable biomarkers in different speciesmay provide important evidence in this regard. How-ever, evaluation of toxicity data and biomarker resultsis often complicated by exposure to mixtures of sub-stances, rather than exposure to a single compound ata time.As already indicated by the proceedings (1) of thefirst Biomarker Conference in this series, multidisci-plinary research is burgeoning and is likely to affect ina profound way both environmental epidemiology andtoxicology, as well as preventive medicine. However,biomarkers, new and old, must be evaluated carefullywith regard to their analytical, diagnostic, and etiologicvalidity. Toxicokinetic aspects, effects of other factors,and standardization of methodology must also be con-sidered. These aspects have been clarified for only ahandful of biomarkers so far, and the need to obtainsuch basic information is pressing. Schulte (13) re-cently asserted that “application of these markers hasbeen less than optimum because of the failure ofinvestigators to be precise about the type of markerthat is needed or the specific purpose for which it isused.” This criticism is somewhat harsh, but it doesreflect the fact that in the beginning of a new researchera insufficient attention is sometimes paid to charac-terizing the study variables. Given the growth in bio-marker research of high quality and relevance, futureresearch will hopefully remedy this problem.Biomarker research at the author’s department is supported bythe Danish Medical Research Council.References1. Biomarkers of chemical exposure. Proceedings of the Arnold 0.BeckmanIIFCC European Conference on Environmental Toxicol-ogy. Clin Chem 1994;40:1359-476.2. Committee on Biological Markers of the National ResearchCouncil. Biological markers in environmental health research.Environ Health Perspect 1987;74:1-191.3. Grandjean P, Brown SS, Reavey P, Young DS. Biomarkers ofchemical exposure: state of the art. Clin Chem 1994;40:1360-2.CLINICAL CHEMISTRY, Vol. 41, No. 12, 1995 18034. Hulka BS, Wilcosky T. Biological markers in epidemiologicalresearch. Arch Environ Health 1988;43:83-9.5. Lopez-Barea J. Biomarkers in ecotoxicology. Arch Toxicol1995;Suppl. 17:57-79.6. Ashford NA. Monitoring the worker and the community forchemical exposures and disease: legal and ethical considerationsin the US. Clin Chem 1994;40:1426-37.7. Harris CC, Weston A, Willey JC, Trivers GE, Mann DL.Biochemical and molecular epidemiology of human cancer: indi-cators of carcinogen exposure, DNA damage, and genetic predis-position. Environ Health Perspect 1987;75: 109-19.8. International Programme on Chemical Safety. Biomarkersand risk assessment: concepts and principles (EnvironmentalHealth Criteria 155). Geneva: WHO, l993:82pp.9. Rutstein DD, Mullan RJ, Frazier TM, Halperin WE, MeliusJM, Sestito JP. Sentinel health events (occupational): a basis forphysician recognition and public health surveillance. Am J PublHealth 1983;73:1054-62.10. Grandjean P. Individual susceptibility to toxicity. ToxicolLett 1992;64165:43-51.11. Skrabanek P. The emptiness of the black box. Epidemiology1994;5:553-5.12. Miller JR. Perspectives in mutation epidemiology: 4. Generalprinciples and considerations. Mutat Res 1983;114:425-47.13. Schulte PA. Introduction: the role of biomarkers in theprevention of occupational disease. In: Mendelsohn ML, PeetersJP, Normandy MJ, eds. Biomarkers and occupational health,progress and perspectives. Washington, DC: Joseph Henry, 1995:1-6.

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