Biological monitoring (biomonitoring)
Miklós Náray and Ferenc Kudász, Hungarian Institute of Occupational Health
- 1 Introduction
- 2 Definition of biomonitoring
- 3 Classification of biomarkers
- 4 Exposure and biotransformation
- 5 Sampling strategy, chemical analysis
- 6 Biomarker half-lives and timing of sampling
- 7 Biological matrices
- 8 Setting of biological limit values
- 9 Variability of results
- 10 Reference values
- 11 Use of biological monitoring
- 12 Interpretation of biomonitoring results
- 13 Ethical considerations
- 14 Information and consultation of workers
- 15 Advantages and disadvantages of biological monitoring
- 16 Future perspectives in biological monitoring
- 17 References
- 18 Links for further reading
Biological monitoring (biomonitoring) in occupational safety and health is the detection of substances (biomarkers) in biological samples of workers, compared to reference values. This article is limited to chemical exposures. Biomonitoring can help in exposure assessment of speciﬁc chemicals, characterisation of exposure pathways and potential risks. Biomarkers can detect the exposure, the effect, or reveal susceptibility. Biomonitoring may be interpreted at group or individual level. Most common media are urine and blood. While multitudes of substances can be measured, there are still only limited numbers of validated methods and limit values with scientifically proven background. The first paper on occupational biomonitoring was published in the USA, and worldwide mainstreaming started in the 1980s.
Definition of biomonitoring
Biomonitoring is the repeated measurement of certain exposure-related chemical/biochemical markers in biological samples of subjects. Biomarkers are early (reversible) signs of exposure, effect or susceptibility with possible adverse health outcome. Biomonitoring is aimed at health protection, exposure and risk assessment. Characteristics of biomonitoring and workplace air monitoring (also known as environmental monitoring) are summarised in Table 1.
Table 1: Comparison of biological and workplace air monitorings
|Biological monitoring||Workplace air monitoring|
|Quantifying||Internal dose||External dose|
|Absorption||All routes||Inhalation only|
|Confounders||Metabolic phenotype||Personal protective equipment, substances with similar structure/chemical properties|
|Measurement||Indirect (biomarkers)||Usually indirect (dangerous substance)|
Source: Manno, 2010
Classification of biomarkers
Biomarkers are classified into three categories depending on their use or the speciﬁc context in which the test is being used.
A biomarker of exposure is the substance, or its metabolite, or the product of an interaction that is measured in a compartment or a bodily ﬂuid. For example lead in blood may fairly represent the recent lead exposure of the individual.
A biomarker of effect is a measurable alteration (biochemical, structural, functional, behavioural, etc.) in an organism that can be associated with an established or potential health impairment or disease. Biomarkers of early disease indicate early biochemical or functional alterations, ranging from natural adaptation to disease. For example the value of Zinc protoporphyrin in blood is increased when lead exposure caused changes in the production of haemoglobin.
Biomarkers of genotoxicity (chromosomal aberrations, micronuclei, Comet test) are used to measure exposure to genotoxic chemicals, usually at group level. They are sensitive but not speciﬁc indicators and generally inadequate for occupational risk assessment purposes.
A biomarker of susceptibility is the marker of an ability to adversely respond to the challenge of exposure to a chemical. Genes can make certain individuals more vulnerable to toxins such as lead.  An example for a susceptibility biomarker is the type of genetic code for 6-aminolevulinic acid dehydratase (ALAD), an enzyme involved in the toxicity of lead that exists in two forms. These effect-modifying factors can be inherent or acquired. Biomarkers of susceptibility are not generally used in routine biomonitoring.
Exposure and biotransformation
The three main exposure pathways are inhalation (lungs), dermal (skin) and gastrointestinal (ingestion). Biological monitoring considers the overall systemic exposure (internal dose) and effect (biological effective dose) regardless of sources. Biomarkers may also reflect circumstances like change in atmospheric pressure, co-exposures and respiratory rate (e.g. heavy workload), which may all lead to higher (or decreased) uptake of the substance.
Once it enters the body the chemical (and its metabolites) can be:
- distributed among body compartments;
- undergo various modifications (biotransformation);
- cause functional changes and diseases;
- get excreted or deposited.
All these pathways are particular to the chemical substance concerned and may be specific to the individual. They may be influenced by internal or external non-occupational confounders (Figure 1).
Biomarkers can be used effectively if their toxicological background is understood:
- the fate of the chemical and/or its metabolites in the body (toxicokinetics);
- the mechanism of the disease/adverse effect (toxicodynamics);
- the way the individual factor promotes the chemical to cause disease/adverse effect (susceptibility).
In the process of biotransformation the external chemical substances are transformed in the body (metabolism). Enzyme activities are the fundamentals of susceptibility, including those involved in absorption and excretion. Individual varieties in the features of enzymes may result in different speeds and pathways in the metabolism of substances, modifying the dose-response curve. There are many modifiers in biotransformation: sex, age, body mass, co-exposures (workplace, non-occupational: e.g. diet, including fat, alcohol, medication, etc.). Compared to the original substance, its degradation products may be less or more harmful (the latter = activation). These metabolites may be used as biomarkers (of exposure or effect) as well.
Toxicokinetic features explain that many substances (although identifiable in the metabolic process) cannot be used for biomonitoring due to short half-life and/or disappearance from the accessible matrix, e.g. from the blood or the urine. Mathematical (such as physiologically-based toxicokinetic) models simulate metabolic processes in the human body to predict possible biological exposure parameters in a certain exposure scenario.
Sampling strategy, chemical analysis
Planning a biomonitoring program for specific purpose starts with the selection of an adequate sampling strategy. Ideally a biomarker of exposure is specific for the exposure concerned (single chemical substance or a group) and reliably detectable, using non-invasive sampling. Timing should be chosen accordingly (see chapter 4).
The analytical method is critical for the validity/reliability of a biomarker: accuracy, precision, reproducibility, recovery, sensitivity and specificity all have high influence to the consistency with the limit and reference values concerned. Several factors may affect the quality of the samples and the measurement of biomarkers: type of the matrix (see chapter 10), point in time of collection, containers and preservatives and other additives used to stabilise the sample, storage temperature and transport time. Adequate reference material should be applied in adequate concentration range and matrix. Reliable and validated analytical methods must be used supported by internal quality control (IQC) and external quality assurance schemes (EQA).
The success of a biomonitoring program highly depends on good cooperation of partners: workers, the employer and the engineer, the occupational physician/industrial hygienist, the laboratory.
Biomarker half-lives and timing of sampling
In the different matrices biomarkers have different half-lives, which is the time it takes the concentration to drop to half. Even a single biomarker may have different half-lives on different time scales: e.g. a quick concentration drop within days, followed by a slow decrease in years. Half-lives of biomarkers and the feasibility of single-compartment or multi-compartment model determine appropriate sampling strategy: the timing and the frequency of sample collection. For substances with long half-life, during continuous exposure, concentration reaches a certain value that remains stable (equilibrium) and reflects long-term intake. In such a case the timing of sample collection during a working day or even working week is not important. However, enough time must be left to reach equilibrium (e.g. lead, cadmium).
When the half-life is short (a few hours – a day) the concentration varies remarkably during the working day or week, thus timing of sampling is essential. Such a concentration reflects exposure over a short time and may not be representative of average long-term exposure. A meaningful picture of the average exposure may be obtained only from several samples.
Examples of different half-lives are illustrated in Figure 2. Usually sampling takes place
- at the end of shift for short half-live biomarkers (Fig. 2: green);
- at the end of the work-week for short half-live biomarkers with tendency to cumulate (Fig. 2: orange); and
- any time for highly cumulating biomarkers with long half-lives (Fig. 2: red).
Samples can be also taken prior to shift or during shift in certain circumstances.
As a general rule, sampling is to be undertaken at a time when the inner and the external exposures are in a state of equilibrium which is not to be expected in cases where exposures/activities are short (maintenance, etc.). In such cases, sampling shall be performed at the end of the relevant activity. In case of substances with short half-lives (<4 hours), validity of biomonitoring highly depends on the actual exposure profile during the shift.
Figure 3 illustrates the challenge of biomonitoring for different exposures to substances with short half-lives:
- If exposure takes place in the first two hours of the shift, subsequent sampling (Fig. 3: green arrow) assesses peak exposure, while end of shift sampling (Fig. 3: red arrow) misses detection.
- If exposure takes place in the last two hours of the shift, sampling at the end of the shift (Fig. 3: orange arrow) detects peak exposure. If exposure is erroneously reckoned as all-day, the total daily exposure will be overestimated.
Biomonitoring is available in many kinds of biological media (matrices): urine, blood, exhaled air, saliva, sweat, semen, faeces, and several tissues. The appropriate matrix depends on the type of biomarker (exposure, effect, susceptibility) and the type of chemical (parent compound or metabolite, volatile or non-volatile, hydrophilic or hydrophobic, unstable or persistent, etc.). The most important biological samples used in the everyday practice are urine, blood, and occasionally exhaled air.
Urine collection is more readily accepted by workers (easy and not invasive). Concentration in urine usually reflects the mean plasma level of the substance since last urination. Rapidly excreted substances (e.g. solvents) are detected in end-of-shift samples. Timed collected specimens may be more representative. In routine urinary biomonitoring spot samples adjusted for dilution (by creatinine or relative density) are adequate alternatives. Highly diluted or very concentrated urine (creatinine: <0.3, >3.0g/litre; relative density: <1.010, >1.030) are not suitable for such adjustment, thus new specimens should be collected.
Most absorbed substance and active metabolites can be found in blood, which is the second most common biological matrix used in routine biomonitoring. Unlike urine, composition of blood is regulated within narrow limits (e.g. pH, concentrations of natural substances), thus it seldom needs adjustment. Blood sampling is useful for inorganic chemicals (e.g. metals) and for organic chemicals that are poorly metabolised and have a sufficiently long half-life.
Exhaled air analysis is non-invasive and most appropriate to estimate exposure to volatile organic substances (e.g. solvents), although it is much less frequently used.
Hair has become an important biological sample in forensic, environmental and clinical toxicology (reconstructing past exposures), its use in routine occupational biomonitoring is not advisable due high contamination risk.
Setting of biological limit values
Different approaches of scientific bodies resulted in various value definitions, also determining their application: BLVs, BATs and BEI®s are set by the above mentioned scientific bodies, and are equally used in European countries. However, the recommended limit values are not necessarily mainstreamed into national legislations. The diversity is huge in Member States’ policies, applications, values and measures. The sole specific mandatory EU-wide policy on biomonitoring is on lead, set in Council Directive 98/24/EC.
The International Commission on Occupational Health (ICOH) defined Biological Limit Value as the biomarker level that can be directly associated with (the lack of) a biological effect or disease. The European Scientific Committee on Occupational Exposure Limits (SCOEL) defined: ‘A Biological Limit Value (BLV) is a reference value for the evaluation of potential health risk in the practice of occupational health. [...] Exposure concentrations equivalent to the BLV generally do not affect the health of the employee adversely, when they are attained regularly under workplace conditions (8 hrs/day, 5 days/week), except in cases of hypersensitivity.’ ‘It is presented as the concentration in the appropriate biological medium of the relevant agent, its metabolite, or indicator of effect.’.
Health-based Biological Limit Values (BLVs) are obtained in biological effect monitoring or linking no-observed-adverse effect-level to adverse effects human studies. Although these values are preferred, the number of such biomarkers is limited. Many SCOEL BLVs are obtained from the corresponding Occupational Exposure Limits (OELs) by matching the ‘mean’ level of a biological index with the corresponding OEL (concentration limit in the workplace air). These values are calculated from studies comparing exposures (OEL) and the corresponding biological concentrations observed. For non-traditional working schedules (not 8 hours/day, 5 days/week) BLVs can be derived from toxicokinetic and toxicodynamic bases. When an OEL serves as protection against non-systemic effects (e.g. respiratory irritation), and also for substances with significant non-inhalatory exposure routes, the BLV is set to avoid systemic effects (e.g. intoxication), and is not derived from the OEL.
BAT (biological tolerance) values are based either on the relationship between external exposure and internal dose, or between the internal dose and the resulting effect of the substance, using the average of internal dose. BLVs and BAT can be used at group level and, with certain restrictions, at the individual level too.
Traditionally, carcinogenic substances are excluded from setting BAT levels as no safe level can be set. However, a BLV could theoretically be derived for carcinogens with an OEL or based on correlation of workplace air concentration and body burden (e.g. Germany, Expositionsäquivalente für krebserzeugende Arbeitsstoffe EKA: exposure equivalents for carcinogenic substances). Carcinogens may have a BLW value (see above).
Differences between BLV and BAT (Biologischer Arbeitsstoff-Toleranzwert or Biological Tolerance Value by the Deutsche Forschungsgemeinschaft – DFG, Germany) disappeared following the harmonisation of definitions. Initially BATs used to be maximum permissible values.
In certain circumstances proper BLV cannot be established because of missing data. In this case setting of limit value for intervention for substances is based on occupational-medical information together with toxicological data. However, it does not exclude a risk of adverse health effects (e.g. BLW – Biologischer Leit-Wert by the Deutsche Forschungsgemeinschaft – DFG, Germany). E.g. BLW may refer to the non-carcinogenic effect of an otherwise carcinogenic chemical.
Biological Exposure Indices (BEI®) of the American Conference of Governmental Industrial Hygienists (ACGIH) are indirect guidance values based mainly on the correlation between the biomarker concentration and the airborne concentration of the original substance.
The benchmark dose approach uses a mathematical model including all the dose-response data.
In the USA, most BEI®s are also derived from the corresponding OELs (Threshold Limit Values, TLV®) on the basis of mean values. These results can be interpreted only at the group level: some individuals may exceed the value due to variables other than exposure. Intervention is required only if BEI® values are exceeded for a longer period of time or by a substantial group of exposed.
Variability of results
Only accurate and reproducible analytical results should be used for biomonitoring and health surveillance. The predictive value of an effect biomarker is the extent to which that particular biomarker is capable of correctly separating subjects with a likelihood of impairment or disease from those without it and it may be influenced by different factors.
Biomarker concentration levels decrease when moving on from exposure to disease: this increases measurement uncertainty. Measuring the actual chemical can limit biological variability, but the advantage is that the measurement is not confounded by intermediary biological steps or by identical metabolites of other reactions. However, measuring the metabolite(s) may be better if the parent chemical is unstable or volatile, or the metabolite is directly involved in the mechanism of toxicity (needs activation).
There may be a substantial variation among values obtained from different workers on the same day and also from day to day for a single worker: this may make dose-response relationships harder to assess.
Biological limit values in occupational medicine are set for healthy adults. There is no general rule for setting biological limit values for workers with certain health impairments. The disease may influence the biomarker level directly (e.g. biomarkers of effect), or the disease may alter the uptake, metabolism or excretion of the chemical. For these workers biomonitoring needs to be reconsidered and an individual approach may be necessary.
Biomarker concentration values in the general (occupationally not exposed, but otherwise identical) population are useful reference intervals in the assessment of thresholds concerning occupational exposure. Although distinguishing between occupational and environmental exposure is very difficult (if possible at all), these reference values can help identifying subjects with an increased exposure.
The International Union of Pure and Applied Chemistry (IUPAC) recommends the highest concentration (usually 95th percentile) of the biomarker in the unexposed population as reference limits (same as biological guidance values as defined by SCOEL and Biologische Arbeitsstoff-Referenzwerte of DFG). Reference values are influenced by: local environmental exposure levels, genetic polymorphisms, biological conditions (sex, age, fatty mass and diseases), and metabolic interferences due to lifestyle (tobacco and alcohol consumption, diet, medications). Thus it is recommended that reference values should be defined at the local level (country, region). Due to improvement in chemical analysis methods, a decreasing trend in occupational exposure levels and the change in concentrations of environmental pollutants (including air, water, food, soil, etc.), reference values are continuously being adapted.
Use of biological monitoring
Only highly speciﬁc, validated biomonitoring tools should be used as part of routine medical surveillance programs, especially when individual decisions have to be made. Selection of appropriate biomarkers depends on the targeted aims and possibilities. The benefit to workers is highest if the biomarker is close to the target organ and the test has high predictive value.
Biological monitoring plays a key role in occupational risk assessment, complementing workplace air monitoring. It can be used as a part of medical health surveillance. Biomonitoring can be used to perform or validate risk assessment when other approaches are unavailable or inadequate.
Biological monitoring may assess individual exposure to chemicals by different routes, providing additional information for occupational risk assessment from hazard identification to the control of prevention measures. It can be used to identify exposed workers, providing strong indirect evidence for the presence of the chemical in the workplace. Several factors contribute to the disruption of expected correlations between biomonitoring and workplace air monitoring, but biomonitoring, not workplace air monitoring, actually reﬂects systemic exposure. Biomonitoring may better assess the degree of recent and, also past exposure to chemicals from all routes and clarify dose-response relationships. Use at compounds with a skin notation may benefit the most, because it allows monitoring of dermal uptake of the substance.
Biomonitoring can help in the correct interpretation of doubtful clinical tests if the dose-response relationship is known. However, this has been controversially discussed (see Ethical considerations).
There may be varied consequences of biomonitoring results above the reference value. Depending on the exposure, biomarker concerned and Member State policies it may result in:
- a more frequent biomonitoring;
- detailed health surveillance of the affected or all exposed workers;
- revision of the risk assessment;
- removal of the worker from the exposure/job.
Furthermore, biological monitoring data can be used very fruitfully when setting DNEL/DMEL (Derived No-effect Level/ Derived Minimal Effect Level) and preparing the exposure scenario according to REACH. If a reliable dose-response relationship exists between biomarker concentration and effects in human, the ‘No Observed Adverse Effect Level’ (NOAEL) expressed as the biomarker level may directly serve as a basis for the DNEL .
Interpretation of biomonitoring results
Biomarker concentration is compared to appropriate reference values, but the user should be aware of all the uncertainty of the results and how the reference is defined. A biomarker above the reference value does not mean disease or hazard but potentially higher exposure than the reference population. This, however, may not necessarily mean increased health risk, but only if confirmed with repeated measurements and analysis of circumstances (SCOEL). Collective biomarker data (e.g. BEI®) should be used only for the assessment of exposure at group level while individual data (e.g. BAT) are appropriate for drawing conclusions on personal exposure.
Dose-response relationships of effects (Fig. 4: blue, orange and red curves – scientifically established) can be compared to the cumulated frequency distribution of the biomarker (Fig. 4: green area – containing the values of all actual measurements). The probability to observe a certain effect (blue, orange or red) is achieved by projecting 100% of the cumulated frequency distribution (Fig. 4: grey broken line) to intersect the dose-response curves (Fig. 4: orange, blue broken lines): 80% for blue effect, 35% for orange effect, and 0% for red effect. Using an individual result (Fig. 4: crossed circle), the probabilities (Fig. 4: yellow arrow) can be calculated for a single worker.
Interpretation can be easier if variability factors are taken into consideration: uncovering and explaining variability may become a resource more than a limitation and may provide useful information for the interpretation of the results. Special attention should be paid to the thorough explanation of the use of biomarkers of carcinogenicity, emphasising that they are neither biomarkers nor direct predictors of cancer disease.
Individual biomonitoring results are medical data, thus should be handled accordingly. Interpretation of the results is the task of a physician trained in the field of occupational health and informed on the entire situation (workplace exposures and worker's health). Data handling, storage and communication are specified in Directive 98/24/EC and in further European and national legislations. Communication (and interpretation) of individual results should be made only towards the worker concerned. Group data can be communicated towards the employer and workers' representatives. The ethical considerations must be regarded during the entire process of a biomonitoring study.
ICOH’s code of ethics states that ‘Biomarkers must be chosen for their validity and relevance for protection of the health of the worker concerned, with due regard to their sensitivity, their specificity and their predictive value’. Principles of this internationally agreed document are:
- Biomonitoring should not be used as screening tests or for insurance purposes’.
- Current knowledge in biomonitoring of susceptibility does not justify job opportunity discrimination of affected workers.
- Priority should be given to non-invasive (urine) and easily collected sampling (spot). In these cases informed consent is usually not required for routine procedures using validated biomarkers.
- Invasive tests or tests posing a health risk calls for a risk-benefit analysis, and informed consent of the worker .
Information and consultation of workers
According to Directive 98/24/EC, workers have a privileged right to be informed and know of the results of any biological monitoring in the framework of health surveillance . The individual worker shall, at his request, have access to the health and exposure records relating to him personally. Where, as a result of health surveillance:
- a worker is found to have an identifiable disease or adverse health effect which is considered by a doctor or occupational health-care professional to be the result of exposure at work to a hazardous chemical agent, or
- a binding biological limit value is found to have been exceeded,
the worker shall be informed by the doctor or other suitably qualified person of the result which relates to him personally, including information and advice regarding any health surveillance which he should undergo following the end of the exposure.
Stricter requirements apply, especially as regards record-keeping and information of workers, when carcinogens or mutagens´ exposure occur, laid out in Directive 2004/36/EC (carcinogens and mutagens at work). For example, all cases of occupational cancers shall be notified to the competent authority. Records shall be kept for at least 40 years following the end of exposure,
Advantages and disadvantages of biological monitoring
A unique advantage of biomonitoring as compared to air monitoring is that it takes into consideration:
- all exposure routes (including inhalation, ingestion and dermal absorption) and circumstances (physical activity, multiple and uneven exposures);
- the individual response (variability in absorption/metabolism/excretion).
Biomonitoring is also an adequate tool in the assessment of the efficacy of protective equipment, ventilation and other hygiene measures. Biomonitoring may help estimating past exposure and assessing individual susceptibility. Specific and sensitive biomarkers may enable intervention in due time, thus preventing the development of a disease.
The above mentioned advantages also have some drawbacks. Biomarkers:
- are usually unable to specify the source of the exposure (occupational or non-occupational);
- may not be sufficiently specific to a particular chemical;
- are not suitable for identification of workplace contaminations in general;
- may be interfered by other chemicals in the biological medium (e.g. medications);
- are not useful at all for the assessment/monitoring of acute and/or local toxic effects (e.g. irritation);
- and the provision of samples for biomonitoring may be a burden for workers (e.g. blood samples).
The integrated use of both workplace air and biological monitoring is considered still to be the best approach to individual exposure assessment.
Future perspectives in biological monitoring
Currently there are only 60-90 chemicals (FIOH) (IPASUM) with validated methodologies in biomonitoring in contrast to the thousands of chemicals used in workplaces. This calls for the development of biomonitoring. There is a strong demand to develop non-invasive sampling methods. Besides urine, exhaled air and saliva may become more common. However, even urine analysis of unchanged solvents is not widespread enough in current occupational applications.
The decreasing trend in occupational exposure levels and better analytical methods enable investigation of unchanged volatile compounds in urine, minor metabolites and adducts (reaction products of foreign compounds and body’s own substances) in matrices.
Adducts are products of the interaction between a reactive chemical/metabolite and a target molecule of the body. Currently adducts are mostly used in research studies. Haemoglobin adducts may provide insight on the molecular mechanism of toxicity, and reflect long-term exposure. DNA adducts can be considered as biomarkers of exposure, of effect and of susceptibility too. They are envisaged in the future as markers of carcinogen exposure (but not markers of cancer).
The ‘omic’ (genomics, transcriptomics, proteomics, etc.) technologies detect early molecular responses and signals at cellular level, like the change in the profile of gene expression in cells caused by the investigated exposure. Although in the research phase, this methodology is a very promising possibility for future biomonitoring.
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Links for further reading
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Biomarkers In Risk Assessment: Validity and Validation (United Nations Environment Programme, the International Labour Organization, the World Health Organization). Retrieved 22 June 2015, from: 
Bolt, H. M. & Thier, R., 'Biological monitoring and Biological Limit Values (BLV): The strategy of the European Union', Toxicology Letters 162, 2006, pp. 119-124.
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Eurotox – Federation of European Toxicologists & European Societies of Toxicology (2011). Carcinogenesis Speciality Section. Retrieved 22 June 2015, from: 
FIOH – Finnish Institute of Occupational Health (2015). Biomonitoring Services. Retrieved 22 June 2015, from: 
FIOH – Finnish Institute of Occupational Health(2010). The Eighth International Symposium on Biological Monitoring in Occupational and Environmental Health (ISBM 2010). Round table discussion: The Future Role of Biomonitoring in Chemicals Management. Retrieved 22 June 2015, from: 
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