Occupational and Environmental Medicine 1997;54:361-366

METHODOLOGY Series editors: T C Aw, A Cockcroft, R McNamee

Biological monitoring: state of the art

Perrine Hoet, Vincent Haufroid

Exposure to chemical agents can be assessedeither by measuring the concentration of theagent in the air by stationary or personal sam-pling (ambient monitoring), or by measuringsome biological variables (biological monitor-ing). The term biomarker that has beenproposed for a few years is used in a broadsense to include almost any measurementreflecting an interaction between a biologicalsystem and an environmental agent, which maybe chemical, physical, or biological.' However,there is still some debate about the definition ofthe term and it is clear that interpretation oftheterm varies between authors. Strictly speaking,biological monitoring of exposure to chemicalagents means measurement of a substance orits metabolites in various biological media.Sometimes, the concept of biological monitor-ing is extended to include the detection of earlyreversible non-adverse effects (biologicalmonitoring of effect). The detection of anadverse effect-for example, increasedproteinuria-indicates that exposure is or hasbeen excessive and therefore such ameasurement is more logically included in aprogramme of early detection of health impair-ment due to industrial chemicals rather than ina biological monitoring programme for evalu-ating exposure. In view of differences betweenpeople in susceptibility to xenobiotics, thedetection of increased susceptibility to achemical hazard might also be considered. Thisimplies the use of biological markers able todetect endogenous aquired or inherent limita-tion of an organism to respond to a challenge ofexposure to a specific xenobiotic substance or agroup of such substances (biological monitor-ing of susceptibility).2(Occup Environ Med 1997;54:361-366)

Keywords: biological monitoring; methodology

Ambient monitoring, or biologicalmonitoring, or both? some considerationsAMBIENT MONITORINGAmbient monitoring is the most usual methodfor the assessment of exposure. As ambientmeasurements have been performed for somany years, analytical methods, exposure-effect and exposure-response relations, andlimits values are available for many of thechemicals encountered in the workplace. Am-bient monitoring is useful for the detection ofacute exposure to dangerous chemicals, theidentification of sources of emission, and the

evaluation of the efficiency of engineering con-trol measures.Ambient monitoring is not invasive and a

single ambient monitoring operation may pre-vent overexposure of many people. Atmos-pheric measurements are, moreover, more rel-evant than biological monitoring in cases ofexposure to substances exhibiting their effecton the site of contact-for example, skin, eye,or respiratory irritants, and respiratory tractcarcinogens-and those that are poorly ab-sorbed. Finally, it helps to separate theimportance of the contribution of an occupa-tional exposure from non-occupational sourcesof exposure (leisure activities, environment,cigarette smoking).

BIOLOGICAL MONITORINGBiological monitoring takes into account thefact that the exposure is not always constant: airconcentrations are seldom stable but fluctuateall the time, moreover the subject moves some-times from one place to another where theambient concentration is not necessarily thesame. It also takes into account absorption byother routes of exposure than the lungs. Manychemicals can enter the body by absorptionthrough the skin or the intestinal tract; asbiological monitoring data gives an estimate ofthe uptake by all routes of exposure (inhalation,ingestion, skin absorption), the measurement isrelated to the body burden and hence to theindividual risk. Biological monitoring reflectsall sources of exposure; not only occupationalbut also background exposure from dietaryhabits, smoking, residency, and hobbies. Fi-nally, it takes into consideration the variousphysicochemical and toxicokinetic factors-forexample, the solubility or the particle size of thecompound influencing the rate of absorption,the variation in workload entailing variation inthe absorption rate, and the capacity ofmetabolising the substance (absorption, bi-otransformation, excretion).

In conclusion, ambient and biological moni-toring are to be considered as two complemen-tary methods.

Approaches in biological monitoringBiological monitoring has been defined as asystematic or repetitive measurement andassessment of workplace agents or their me-tabolites either in tissues, secretions, excre-tions, expired air, or any combination of theseto evaluate exposure and risk to health

University catholiquede Louvain, Faculte demedecine, Ecole desant6 publique, Unitede toxicologieindustrielle etmedecmne du travail,Clos Chapelleaux-Champs 30 bte 54,1200 Bruxelles,BelgiqueP HoetV Haufroid

Correspondence to:Dr P Hoet, Universit6catholique de Louvain,Faculty de medecine, Ecolede sante publique, Unite detoxicologie industrielle etmedecine du travail, ClosChapelle aux-Champs 30 bte54, 1200 Bruxelles, Belgique.

Accepted 3 September 1996

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compared with an appropriate reference.3 Itcan be divided into three sections: (a) biologi-cal monitoring of exposure; (b) biologicalmonitoring of effect; and (c) biological moni-toring of susceptibility.

BIOLOGICAL MONITORING OF EXPOSUREThe biological monitoring of exposure can beitself subdivided into biological monitoring ofinternal dose and biological monitoring ofeffective dose.

Biological monitoring of internal doseBiological monitoring of internal dose impliesthe assessment of the parent compound or itsmetabolites in biological samples. The mediamost commonly used are urine and blood but itis also possible to analyse exhaled air, faeces,adipose tissues, hairs, nails, saliva, and milk.These tests are classified into two subgroups:

Specific methodsThese methods rely on the direct measurementof the unchanged chemicals or their metabolitesin biological media. This category includes mosttests currently available in routine biologicalmonitoring of exposure to chemicals. Theresults reflect exposure to the chemical agentunder investigation only and indicate if exposureto a given compound has occurred-for exam-ple, the urinary measurements of mercury,muconic acid, and mandelic acid for the assess-ment of exposure to mercury, benzene, and sty-rene.

Assessment of body or organ burden in vivo-Recent methods have been developed to assessdirectly the amount of chemical stored at thesite of accumulation: (a) neutron activation-the cadmium content in the kidneys and theliver have been estimated by neutron activa-tion; (b) x ray fluorescence-the cadmiumcontent in the kidneys and the lead content inbones have been measured by x ray fluores-cence. Some findings suggest the existence of agood relation between the cumulative bloodlead index and the content of lead stored in thebones.

Non-specific methodsThese tests are used as non-specific indicatorsof exposure to a group of chemicals-forexample, measurement of diazopositive me-tabolites in urine for monitoring exposure toaromatic amines, the measurement ofthioethers in urine to assess exposure to muta-genic and carcinogenic substances, or of themutagenicity of urine to estimate exposure tosuch substances. Because of their lack ofspecificity and the existence of a large indi-vidual variability, these tests cannot usually beused to monitor exposure on an individualbasis. It is, however, possible that when anadequate control group is used as reference,they may be useful as qualitative tests to iden-tify exposed groups.

Biological monitoring of effective doseThese tests directly or indirectly estimate theamount of chemical interacting with the site ofaction (or toxicologically significant target).

The best known test of this category is themeasurement of carboxyhaemoglobin inducedby exposure to carbon monoxide (or dichlo-romethane metabolised into carbon monox-ide). However, it should be remembered thatexposure to carbon monoxide is certainly notspecific to occupational activities and thattobacco smoking is a major source of exposureto carbon monoxide.

Studies in this area have been mainly carriedout for exposure to potentially genotoxicsubstances and for development of themeasurement of macromolecular adducts. Pro-tein and DNA adducts can be used asindicators of exposure to reactive substances inthe DNA of target tissues. Although theamount of DNA resulting from white bloodcells or lymphocytes can be limited, proteins,such as haemoglobin or albumin are present inlarge quantities in human blood (see biologicalmonitoring of mutagenic or carcinogenicsubstances). DNA adducts can be removed byDNA repair processes or by cell death, butduring chronic exposure they often reachsteady state levels in carcinogen target tissues.

BIOLOGICAL MONITORING OF NON-ADVERSEREVERSIBLE EFFECTSThere are many potential biomarkers forassessing the biochemical effects of chemicalagents. Schematically, these tests can bedivided into two broad categories. The firstcategory includes the variables that indicatepathological damage-such as biomarkers ofliver dysfunction (transaminases) or kidneydysfunction (albumin in urine). The secondcategory comprises those detecting early bio-chemical changes or responses which areconsidered as reversible and not adverse.These are often considered to be biomarkers

of exposure. Biological effect monitoring hasbeen defined as the measurement of a rever-sible biochemical change caused by the absorp-tion of the substance; the degree of chancebeing below that associated with toxic injuryand not associated with a known irreversiblepathological effect.4 Thus, in this framework,biological monitoring of effects relies on theidentification and the measurement of rever-sible, non-adverse biological effects related tothe internal dose. These tests should predictthe adverse effects but are to be distinguishedfrom the tests identifying the adverse effects.However, the distinction between adverse andnon-adverse biological effects is not alwaysclearcut and is sometimes arbitrary as it may bedifficult to evaluate the health significance ofaneffect. The inhibition of enzymes-such as the6-aminolaevulinic acid deshydratase (inhibitedby lead) or the pseudocholinesterase (inhibitedby organophosphates)-are examples of wellvalidated methods.The measurement of the activity of numer-

ous enzymes in blood has also been widelyused, specially with the development of separa-tion techniques of isoenzymes-for example,lactate dehydrogenase (LDH)-but in thesecases they usually indicate adverse effects ratherthan reversible biochemical changes and aretherefore better indicated for early detection of

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a health impairment programme-for example,the measurement of the hepatic enzymesreleased into the blood to detect liver damage.The urinary excretion ofnumerous proteins,

enzymes, and biochemical markers-for exam-ple, al and 02-microglobulins, N-acetyl-glucosaminidase, 0-galactosidase, sialic acid,retinol binding protein, thromboxan,kallikrein-has been investigated by manyauthors in subjects exposed to nephrotoxicsubstances such as cadmium, lead, andmercury.5'-0 However, the potential healthsignificance of some of these variables is stillunknown. Are they to be considered as rever-sible non-adverse effects or should they beincluded in the programme of early detectionof health impairment?

BIOLOGICAL MONITORING OF SUSCEPTIBILITYA biomarker of susceptibility is an indicator ofan inherent or acquired ability of an organismto respond to the challenge of exposure to aspecific xenobiotic substance.'For example, the ability to acetylate aromatic

amines is genetically determined and showsvariation with ethnic origin. It has beensuggested that slow acetylators with mutationswhich result in less functional N-acetyl-transferase enzymes, are at increased risk ofdeveloping bladder cancer but decreased riskof colorectal cancer when exposed to carcino-genic aromatic amines." 12 The measurementof such polymorphism in metabolising genesrequires the administration of a relevant testdrug (sulphamethazine and caffeine have beensuggested) and the subsequent measurementof its clearance from the body. An alternative tothese metabolic methods relies on direct geneanalysis based on new methods in molecularbiology (including the polymerase chain reac-tion) with DNA from lymphocytes and othercells. These techniques allow the detection ofgenotypes of known polymorphisms involvingvarious enzymes that metabolise xenobiotics.Among these, enzymes associated with cyto-chrome P-450 are of particular interest forinterpreting the results of biological monitor-ing especially if metabolites are responsible forthe toxicity of the chemical-for example,alkoxyacetic acid metabolites of ethylene glycolethers.A genetically based low level of a-antitrypsin

activity increases the risk of emphysema fromcigarette smoking."' 14 Such biomarkers shouldbe used preventively rather than after an expo-sure event.Many ethical issues, that will not be

discussed in this article, have been raised aboutthe use of biological markers, especially aboutmarkers of susceptibility.

An example: biological monitoring ofmutagenic or carcinogenic substancesConsiderable efforts have been made todevelop biological markers associated withexposure to potentially carcinogenic chemicalsand to establish a relation between the markerand the future health risk. As well as the detec-tion of mutagenic or carcinogenic substancesor their metabolites in blood and urine-that

is, biological monitoring of internal dose(measurement of the urinary concentration ofinorganic arsenic and its methylated metabo-lites, muconic acid, 4,4'-methylene-bis(2-chloroaniline) (MOCA), 1-hydroxypyrene forthe assessment of exposure to inorganicarsenic, benzene, MOCA, and polycyclicaromatic hydrocarbons)-different types ofbiological analyses can be considered fordetecting exposure to carcinogens.

ANALYSIS OF THE MUTAGENIC ACTIVITY OF URINE

OF EXPOSED WORKERS (SEE NON-SPECIFIC TESTS)Mutagenic activity of urine is considered to beamong the non-specific tests-for example,mutagenic activity of nurses handling cyto-static drugs.'5 '7 This test shows large variationsbetween people and is prone to interferencefrom smoking, diet, and drugs. Another pointto be underlined is that only mutageniccarcinogens can possibly be detected by thismethod. Moreover, the mutagenic activitymeasured in urine is not necessarily a reflectionof the genetic alteration in the target organ. Itshould also be stressed that the compoundresponsible for the mutagenicity in urine maynot be involved in the genotoxic effect in thetarget organ and conversely, the lack ofincreased mutagenic activity in urine does notnecessarily mean the absence of genotoxiclesions.

ANALYSIS OF THIOETHER DETOXIFICATIONPRODUCTS IN URINE (SEE NON-SPECIFIC TESTS)Urinary thioethers are mainly derived from thereaction of electrophilic chemicals with glu-tathione. The glutathione conjugates formedare then degraded to yield N-acetyl-S-alkylcysteine or mercapturic acids which areexcreted in the urine. Several authors haveevaluated the possibility of measuring urinaryexcretion of thioethers to detect exposure toelectrophilic substances and their precursors- for example, in petroleum retailers, workersoccupied in the petoleum industry, in cokeovens, in asphalt producing or using plants,workers exposed to styrene, and workersexposed to pesticides.'"" There are large vari-ations between and within subjects due mainlyto the influence of the excretion of endogenousthioethers, diets, and cigarette smoking.2' 24Moreover, it seems that a value within the nor-mal range does not exclude exposure to anelectrophilic substance.25 Therefore, the pri-mary value of this test is its signal function,meaning that when an increase in thioetherexcretion is found it may be concluded thatexposure to such a substance has occurred.

DETERMINATION OF MACROMOLECULAR ADDUCTS

(SEE BIOLOGICAL MONITORING OF EFFECTIVE

DOSE)Macromolecular adducts are used both asmolecular dosimeters (biomarker of exposure)and to assess the genotoxic potential of chemi-cals (biomarker of effect). They can be consid-ered as biomarkers of effective dose, the effec-tive dose at a relevant site being the preferredmeasure over internal dose.

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DNA adducts are formed during the bio-transformation of chemical agents to reactiveintermediates that are electrophilic and bindcovalently to DNA. Unless repaired, suchDNA lesions may result in mutations at criticalsites during DNA replication, ultimately lead-ing to cancer. Thus, accurate measurement ofDNA adducts formed from a (suspected)genotoxic agent in the target organ is expectedto indicate its initiating potential. The bindingof carcinogens to DNA and the resultingformation of DNA adducts can be directlyshown by identifying these adducts either incellular DNA (in white blood cells or lym-phocytes), in its degradation products excretedin urine, or indirectly by measuring the adductsformed with non-target macromolecules suchas proteins (albumin, haemoglobin). It hasindeed been suggested that monitoring of thereaction products formed with amino acids inproteins might provide an indication of theextent ofDNA alkylation."6 The amino acids inhaemoglobin that may react with genotoxicagents are those with nucleophilic side chains(lysine, histidine, cysteine) and the N-terminalamino acid (valine). As they are not repairedhaemoglobin adducts reflect the cumulativeexposure during the lifetime of the protein(four months). However, as carcinogens mayvary in their ability to cross the erythrocytemembrane, the degree of alkylation of serumalbumin (lifetime 21 days) might constitute abetter index of exposure, at least to some elec-trophilic compounds.Macromolecular adducts have been largely

used in recent years for the biomonitoring ofoccupational exposure-for example, to aro-matic amines, ethylene oxide, styrene, 1,3-butadiene, complex mixtures of polycyclic aro-matic hydrocarbons (PAHs) in iron foundries,coke ovens, aluminium plants, and amongroofers and surface coating workers.26 28They seem very promising methods but

much research is still needed before they can beintroduced in the routine biological monitoringof industrial workers.

ANALYSES OF GENOTOXICITY (SEE BIOLOGICALMONITORING OF EFFECT)These methods aim to detect the consequencesof the interaction of the mutagenic or carcino-genic agent and the genetic material. The vari-ous possible methods involve the measurementof chromosomal aberrations, sister chromatidexchanges, unscheduled DNA synthesis, singlestrand breaks, point mutations, and micronu-clei in peripheral blood lymphocytes.29 31 Aswith mutagenic activity in urine and themeasurement of thioethers in urine, because ofthe wide variations between and within sub-jects and the many potential confounding fac-tors, these tests can only be used at the grouplevel, to detect a group at risk.

DETECTION OF ONCOGENIC PROTEINSThe identification in urine or plasma ofproteins resulting from the activation of anoncogene has been suggested to detect specificmutations. For example, PAHs have beenshown to cause specific mutational lesions that

can lead to the activation of the ras oncogeneand expression of its p21 protein product.32Much research is still needed before this testcan be introduced in the routine biologicalmonitoring of industrial workers.

Main prerequisites for the developmentofbiological markers and theirinterpretationKNOWLEDGE OF THE TOXICOKINETICS OF THE

CHEMICALBiological monitoring mainly relies on theknowledge of toxicokinetic data. This includesinformation on the rate of absorption, distribu-tion, sites of accumulation, biotransformation,and routes of excretion to make the best choiceabout the substance to be measured as well asthe biological media and the time of sampling.The toxicokinetics of an agent are influenced

by many physiological and pathological factors(age, sex, food, drink, smoking, state of health,intake of drugs) that must be taken intoaccount when interpreting a result. For exam-ple, chronic intake of ethanol usually stimulatesdrug metabolising enzymes and hence thebiotransformation of other absorbed chemicalagents, whereas during or shortly after a largealcohol intake entailing a high concentration ofalcohol in the body, there seems to be aninhibitory effect on the metabolism ofxenobiotics.33

Perturbation of renal clearance, or large orrestricted beverage intake, may also be respon-sible for misinterpretation of urinary results(urine samples that are too dilute or tooconcentrated).

It is also important to underline thatphysicochemical factors also play an importantpart in the rate of absorption of a substance.For instance, measurement of nickel in urine isonly a qualitative indicator of exposure to solu-ble nickel compounds but certainly not toinsoluble compounds. However, the importanthealth effects caused by exposure to nickel aremainly local (skin, respiratory tract), and thereal interest of the dosage of nickel in urinemight be questionable.

Practically, the variable most often used tocharacterise the behaviour of the biologicalmarker in the body is the elimination half life-that is, the time needed to excrete half theamount of the substance. A substance with ahalf life of less than two hours is not suitable formonitoring as timing is too critical. When thehalf life lies between two and 10 hours theoptimum sampling time is at the end of theshift or the beginning of the next shift (lessinfluenced by peak exposure). When thesubstance under investigation has a half lifebetween 10 and 100 hours, it provides anevaluation of the total amount of the chemicalabsorbed during the preceding day (samplingafter 16 hours) or during the week (end ofweeksampling). For cumulative substances-such asheavy metals-the time of sampling is notcritical."4 In this case, there is indeed a slowrelease from a deep compartment that hasaccumulated the chemical substance over along period and that may result in anendogenous exposure of target organs-for

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example, the release of lead from the bones thatis increased in some circumstances-such asosteoporosis and bone fracture.Animal studies can be used to show

toxicokinetic patterns of a chemical butconfirmatory studies in humans are neededbefore extrapolation of these patterns fromexperimental data. Physiologically based phar-macokinetic models taking account of the vari-ability ofnumerous exposure and physiologicalfactors (intensity and duration of exposure,workload, body build, liver and renal function)may also provide valuable tools when trying toestablish relations between external exposureand internal dose.'5

KNOWLEDGE OF THE TOXICODYNAMICSThe knowledge of the non-adverse biologicalchanges and the potential harmful effectsshould also be considered as a prerequisite forthe accurate determination of a tolerablebiological action level and the interpretation ofthe results. The determination of the concen-tration of the substance at which the effect isexpected to occur (dose-effect relation) and thepercentage of people showing these effects ateach dose level (dose-response relation) arealso fundamental data.

In the occupational setting exposure is oftento a mixture of substances. This may entailvariations in terms of toxicokinetic and toxico-dynamic processes, which must be taken intoaccount when interpreting the results (the pos-sible physicochemical interactions between thesubstances, the effects that one agent may haveon the absorption, biotransformation, andexcretion of the other).

REFERENCE LEVELSResults are to be interpreted by comparisonwith reference limits values.

Reference value observed in an unexposedpopulationThe substance under investigation may bepresent in the biological fluids in the generalpopulation without any occupational exposure.These reference values must be derived from apopulation similar in terms of race, age, sex,and environmental factors-such as air pollu-tion, smoking habits, drugs, and dietaryfactors. Such an approach is largely used inclinical chemistry and allows identification ofexposed people. It needs a sufficiently largesample of the population. Failure to know themain sources of variation limits the validity.Another limitation is that for some chemi-

cals, the detection limit of the analytical meth-ods available is not sufficiently low to assess theconcentration in non-occupationally exposedpeople.

Biomonitoring action level for an exposedpopulationBiomonitoring action levels allow the uptake ofa certain amount of a chemical agent which isconsidered to be acceptable for the preserva-tion of the health of the subject.For most substances these levels are derived

from the occupational exposure limits in air,

and are the concentration of the agent that willoccur in the body fluids after an eight hour timeweighted average exposure at the occupationalexposure limit. Biological monitoring per-formed under these conditions is much morean assessment of the exposure intensity than ofthe potential risk to health.For chemicals that are extensively absorbed

through the skin, biological action value basedon the relation between the occupational limitvalue in the air and the concentration in thebiological media may underestimate the im-portance of exposure-for example, glycolethers.

Ideally the biological action levels should behealth based derived from long term follow upstudies ofworkers exposed to eight hours a day,five days a week, over a working life withoutadverse effects. In some situations, a quantita-tive relation between internal dose and adversehealth effect has actually been identified-forinstance, for lead in blood, cadmium in urine,or carboxyhaemoglobin. In these cases, thebiological variable can be considered as anindicator of health risk. When the internal doseis quantitatively related to both adverse effectsand external exposure, the biological variableprovides information on both exposure andhealth risk.The biological action level may also be

derived from good working practices. In thisapproach, the limit reference is established incomparison with the concentration of thechemical (or its metabolites) found in biologi-cal specimens of workers exposed to thesubstance under investigation when goodworking practices are adhered to. This ap-proach is largely used, for practical reasons, forsubstances extensively absorbed through theskin.

ConclusionIdeally, the biological variable:* Specifically assesses the exposure to the

chemical substance under investigation* Is sufficiently sensitive to detect people

exposed to low level of chemicals* Varies quantitatively with the intensity of

exposure and the risk of development ofadverse effects and there is a clear cut relationwith the degree of exposure* Yields more information on potential

health risk than information obtained by ambi-ent monitoring* Is stable enough to allow storage of the

sample for a certain period* Does not entail sampling methods involv-

ing too much discomfort or any health risk forthe subject* Can be measured by an analytical method

with sufficient accuracy, specificity, sensitivity* Does not need too time consuming, com-

plex, or expensive methods.

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3 Berlin A, Yodaiken R, Hennman B, eds. Assessment of toxicagents at the workplace. Role ofambient and biological monitor-

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