# A harmonized occupational biomonitoring approach

Nancy B. Hopf, Christophe Rousselle, Devika Poddalgoda, Farida Lamkarkach, Jos Bessems, Kaspar Schmid, Kate Jones, Koki Takaki, Ludwine Casteleyn, Maryam Zare Jeddi, et al.

► To cite this version:

Nancy B. Hopf, Christophe Rousselle, Devika Poddalgoda, Farida Lamkarkach, Jos Bessems, et al. A harmonized occupational biomonitoring approach. Environment International, 2024, 191, pp.108990. 10.1016/j.envint.2024.108990. anses-04691673

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Full length article

A harmonized occupational biomonitoring approach

Nancy B. Hopf<sup>a</sup>, Christophe Rousselle<sup>b</sup>, Devika Poddalgoda<sup>c</sup>, Farida Lamkarkach<sup>d</sup>,
Jos Bessems<sup>e</sup>, Kaspar Schmid<sup>f</sup>, Kate Jones<sup>g</sup>, Koki Takaki<sup>h</sup>, Ludwine Casteleyn<sup>i</sup>,
Maryam Zare Jeddi<sup>j</sup>, Michael Bader<sup>k</sup>, Michael Koller<sup>l</sup>, Patience Browne<sup>m</sup>, Rex FitzGerald<sup>n</sup>,
Susana Viegas<sup>o</sup>, Thomas Göen<sup>p</sup>, Tiina Santonen<sup>q</sup>, Virpi Väänänen<sup>r</sup>, Radu - Corneliu Duca<sup>i,s,*</sup>,
Robert Pasanen-Kase<sup>f,*</sup>

ARTICLE INFO

Handling Editor: Adrian Covaci

Keywords:

Biological monitoring

Exposure biomarkers

Effect biomarkers

Risk assessment

Risk management

Toxicokinetics

A B S T R A C T

Biomonitoring has been widely used in assessing exposures in both occupational and public health com-
plementing chemical risk assessments because it measures the concentrations of chemical substances in human
body fluids (e.g., urine and blood). Biomonitoring considers all routes and sources of exposure. An occupational
biomonitoring guidance document has been elaborated (OECD Occupational Biomonitoring Guidance) within
the OECD framework and specifically, the Working Parties on Exposure and Hazard Assessment by scientific
experts from 40 institutes and organizations representing 15 countries. The guidance provides practical infor-
mation for assessing chemical exposures in occupational settings including the three common routes of exposure:
inhalation, skin absorption and ingestion due to hand to mouth contact. The elaborated stepwise approach for
conducting biomonitoring is tailored for occupational health professionals, scientists, risk assessors, and regu-
lators. It includes methods for selecting appropriate biomarkers, devising sampling strategies, and assessing
laboratories for validated analytical methods for the biomarker of interest, and ensuring timely feedback of
results. Furthermore, it describes procedures for setting up efficient biomonitoring programs based on the Similar
Exposure Group (SEG) approaches. Derived health-based human exposure biomarker assessment values called

<footnote><sup>a</sup> Center for Primary Care and Public Health (Uniséité), University of Lausanne, Route de la Corniche 2, 1011 Epalinges-Lausanne, Switzerland</footnote>

<footnote><sup>b</sup> French Agency for Food, Environmental and Occupational Health and Safety (ANSES), 94701 Maisons-Alfort, France</footnote>

<footnote><sup>c</sup> Existing Substances Risk Assessment Bureau, Healthy Environment and Consumer Safety Branch, Health Canada, Government of Canada, Canada</footnote>

<footnote><sup>d</sup> French Agency for Food, Environmental and Occupational Health and Safety (ANSES), 94701 Maisons Alfort, France</footnote>

<footnote><sup>e</sup> VITO Nv, Boeretang 200, 2400 Mol, Belgium</footnote>

<footnote><sup>f</sup> State Secretariat for Economic Affairs (SECO), Section Chemicals and Occupational Health, Holzkofenweg 36, 3003 Bern, Switzerland</footnote>

<footnote><sup>g</sup> Health and Safety Executive, Harpur Hill, Buxton, SK17 9JN, UK</footnote>

<footnote><sup>h</sup> Ministry of the Environment, Japan</footnote>

<footnote><sup>i</sup> Katholieke Universiteit Leuven, Belgium</footnote>

<footnote><sup>j</sup> Shell Global Solution International, BV., Netherlands</footnote>

<footnote><sup>k</sup> BASF SE, ESG/CB - Medical Center Z130, Carl-Bosch-Str. 38, 67056 Ludwigshafen am Rhein, Germany</footnote>

<footnote><sup>l</sup> SUVA, Fluhmattstrasse 1, 6002 Luzern, Switzerland</footnote>

<footnote><sup>m</sup> OECD, 2, rue André Pascal, 75775 Paris Cedex 16, France</footnote>

<footnote><sup>n</sup> Universities of Basel and Geneva, Switzerland</footnote>

<footnote><sup>o</sup> ENSP/UNI, NOVA National School of Public Health, Public Health Research Centre, Comprehensive Health Research Center, CHRC, NOVA University Lisbon, Portugal</footnote>

<footnote><sup>p</sup> University of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nuremberg, Schillerstrasse 25, 91054, Erlangen, Germany</footnote>

<footnote><sup>q</sup> Finnish Institute of Occupational Health, Helsinki, Finland</footnote>

<footnote><sup>r</sup> European Chemicals Agency, Telakkakatu 6, P.O. Box 400, FI-00121 Helsinki, Finland</footnote>

<footnote><sup>s</sup> Laboratoire National de Santé (LNS), Environmental Hygiene and Human Biological Monitoring, Department of Health Protection, 1, Rue Louis Rech, L-3555</footnote>

<footnote>Dudelange, Luxembourg</footnote>

<footnote>* Corresponding authors.</footnote>

<footnote>E-mail addresses: Nancy.Hopf@unisante.ch (N.B. Hopf), christophe.rousselle@anses.fr (C. Rousselle), devika.poddalgoda@hc-sc.gc.ca (D. Poddalgoda), farida.lamkarkach@gmail.com (F. Lamkarkach), jos.bessems@vito.be (J. Bessems), Kaspar.Schmid@seco.admin.ch (K. Schmid), Kate.Jones@hse.gov.uk (K. Jones), Koki.takaki@env.go.jp (K. Takaki), ludwine.casteleyn@icloud.com (L. Casteleyn), Maryam.ZareJeddi@shell.com (M. Zare Jeddi), michael.bader@basf.com (M. Bader), michael.koller@suva.ch (M. Koller), Patience.BROWNE@oecd.org (P. Browne), rex.fitzgerald@unibas.ch (R. FitzGerald), susana.viegas@ensp.unl.pt (S. Viegas), thomas.goeen@fau.de (T. Göen), Tiina.Santonen@ttl.fi (T. Santonen), virpi.vaananen@echa.europa.eu (V. Väänänen), Radu.DUCA@lns.etat.lu (R.C. Duca), robert.pasanen-kase@seco.admin.ch (R. Pasanen-Kase).</footnote>
Occupational Biomonitoring Levels (OBLs) are proposed for use in occupational exposure and risk assessment. It also helps with the interpretation of biomonitoring results routinely collected and procedures for communicating biomonitoring results at individual, collective, and workplace levels. Ethical considerations associated with biomonitoring are also discussed. The ultimate goal of this biomonitoring approach is to promote harmonized application and interpretation of biomarkers as well as evidence-based occupational risk management measures.

# 1. Introduction

Human biomonitoring, biological monitoring or biomonitoring is an approach to assess exposures by quantifying biomarkers in biological material from humans. Urine and blood are commonly used biological materials, but other matrices such as hair, saliva or exhaled breath are also sometimes considered for specific purposes and applications. The biomarker represents either a hazardous compound, one of its metabolites, or an addition product ('adduct') of a reactive metabolite to proteins or DNA, whose concentration corresponds to possible or identified health hazards (exposure biomonitoring) or a marker of an early biochemical, physiological, or behavioral effect (effect biomarker), which has been associated with an established or possible developing health impairment or disease ((WHO, 2023) (Council, 2006)). Biomonitoring accounts for all routes of exposure (inhalation, oral, and skin exposure) and to all sources of exposure (e.g., water, air, diet, consumer products, and industrial products). This approach is especially beneficial for assessing exposure to chemical substances with several possible exposure routes, or when the applicability and significance of workplace air monitoring is limited.

Although, biomonitoring is an excellent tool for assessing systemic exposures to many chemicals, and especially for chemicals with a skin notation. Biomonitoring is not systematically integrated into national regulations leading to a lack of available assessment values. One reason for this is that there is a need for a harmonized biomonitoring protocol. Harmonizing the biomonitoring method and implementing a standardized biomonitoring program in exposure assessment should lead to a greater transparency as well as regulatory inclusion and thus, better worker protection.

Occupational biomonitoring is used to assess workers' exposures to hazardous chemicals encountered at work and implement exposure reduction strategies where necessary (Galea et al., 2021; Guseva Canu et al., 2021; Hines et al., 2012; Hines et al., 2008; Hopf et al., 2010; Jones et al., 2022; Santonen et al., 2019; Santonen et al., 2022; Scheepers et al., 2021). Identifying exposure generating tasks or impaired exposure reduction measures, such as malfunctioning personal protective equipment, is essential for an efficient exposure monitoring and if needed, an exposure mitigation strategy. Biomonitoring can lead to an increased awareness of risks to chemical exposures among workers.

A common chemical exposure assessment procedure starts by developing exposure profiles based on temporal exposure patterns related to particular jobs or tasks. Exposure profiles describe exposures generated from each task performed by workers within a given job and are used to group workers in jobs with similar exposure patterns. These Similar Exposure Groups (SEGs) include jobs with similar exposure intensity, frequency, and duration as well as materials and processes used, along with the pre-existing risk management measures (RMM). SEGs also enable us to measure exposure and assess effectiveness of risk management reductions for workers within a particular SEG by analyzing data from a subset of workers within the same SEG. SEGs play a crucial role in determining the necessary RMM and in assessing compliance with occupational exposure limit values (CEN 2020).

The major advantage of biomonitoring over air monitoring is that it integrates several exposure routes over time offering integrative exposure assessments (Viegas et al., 2020). Biomonitoring is useful for chemical exposures that result in systemic exposure and a tool for exposure assessors in addition to external exposure measurements (air

measurements and surface wipe sampling). Biomonitoring is recommended when assessing dermal uptake from chemicals that cross the skin barrier, in explosive environment, after a chemical accident, complex chemical mixture exposures, and assessing the efficacy of personal protective equipment.

Chemicals are absorbed, distributed, metabolized, and eliminated based on their interaction with the human body resulting in a wide variability in apparent half-lifes. Some chemicals, such as polychlorinated biphenyls (PCBs), are fat soluble and resistant to degradation thus, have half-lifes measured in years. Conversely, many metals, volatile organic compounds, and water-soluble compounds have half-lives of a few hours to a few days. The sampling interval is therefore determined by the half-life of the chemical of interest in the biological media, and in addition, the feasibility of obtaining the sample at that time given a worker's work schedule. For example, a spot urine sample can be collected at the end of a work-shift that reflects a defined exposure interval based on a short apparent urinary elimination half-life. Biomonitoring requires little field equipment e.g., only a urine cup and identification labels and a questionnaire. Some typical occupational situations where biomonitoring is preferred to other exposure assessment approaches are for chemical substances:

(1) absorbed through the skin in toxicologically relevant amounts (normally these substances have a skin notation);

(2) ingested because of contaminated hands, tools/equipment and surfaces (poor occupational hygiene, hand-to-mouth contact);

(3) with high biological persistence (long half-life);

(4) that are carcinogens, mutagens or reprotoxic substances (CMR substances);

(5) where air monitoring may be impossible or impractical (e.g., substances with low volatility);

(6) where exposure control relies largely on personal protective equipment (e.g., gloves or respirators) or human behavior i.e., doing a task in a particular way;

(7) where internal exposures may increase as a result of enhanced physical workload and environmental stress (elevated temperatures, exposure to chemical mixtures); and

(8) accidental exposures or short-time peak exposures.

The biomonitoring measurement value is the concentration of a biomarker or a set of biomarkers in a single biological sample that is specific and sensitive for the chemical exposure in question. Suitable biomarkers for assessing occupational exposures have convenient sampling procedures and validated analytical methods. Furthermore, they should be based on known Adsorption, Distribution, Metabolism, and Elimination (ADME) kinetics. The resulting biomarker concentrations are then compared to established Occupational Biomonitoring Levels (OBLs) to evaluate the biomonitoring data in a health risk context.

Occupational biomonitoring programs are implemented in workplaces to monitor workers' chemical exposures routinely, or during specific work such as maintenance or turnarounds. These programs require a defined purpose and sampling strategy with established biomonitoring methods. The occupational health practitioner should use these established harmonized biomonitoring methods when setting up the biomonitoring programs. Furthermore, they also need instructions on how the results should be communicated as well as recommendations for actions. Procedures to keep results confidential are vital and should be addressed before implementation of the biomonitoring programs.
Ethical considerations such as confidentiality and the right a worker has to know or decline to know their individual biomonitoring results need to be addressed and respected. Competent occupational health or hygiene professionals (OHP) need to manage the biomonitoring programs and communicate with the workers regularly. Based on exposure findings and informed consent of workers a good collaboration with health surveillance professionals should be envisaged. Competence refers to both technical and organizational aspects.

This occupational biomonitoring approach is based on the recently published ‘Occupational Biomonitoring Guidance Document’, elaborated in a joint activity including experts from more than 40 institutes and organizations in collaboration with the OECD Working Party on Exposure Assessment and the OECD Working Party on Hazard Assessment (Occupational Biomonitoring Guidance Document). The guidance document draws mainly upon exposure- and partially on effect-biomonitoring approaches and gained experiences from the regulatory context. The Occupational Biomonitoring Guidance Document should facilitate the generation of high quality and sound occupational biomonitoring programs. This guidance provides instructions on implementing biomonitoring in exposure assessment and risk management based on existing biomonitoring methods and with the overall goal to harmonize biomonitoring programs. It assumes that a biomonitoring method exists for a specific compound. These biomonitoring methods define the specific exposure biomarkers for the chemical exposure being measured, and also sampling media (usually urine and to a lesser extent blood), sample collect time (i.e., pre-shift or post-shift). Although, the OECD occupational guidance document includes the guidance on biomarker derivation for biomonitoring, the main aim here is to provide instructions on implementing biomonitoring in exposure assessment and risk management.

The novelty of this biomonitoring protocol is the agreement from more than 75 global biomonitoring experts from 15 countries on the definition and content of an occupational biomonitoring program. The finalized guidance is exceptional in that it has two parts: a scientific part for research such as assessing biomarkers for chemicals that have been approved for production but does not yet have a validated biomonitoring method; and a second part for compliance. In a following publication the authors intend to add: A Harmonized Methodology to Derive Occupational Biomonitoring Levels (OBL) to stimulate the derivation and use of OBLs according to OECD guidance.

## 2. Biomonitoring program

Exposures to harmful substances which cannot be addressed appropriately by air measurements due to dermal or oral uptake might pose a higher risk to workers' health than ethical reservations. Implementation

of a biomonitoring program should aim to use less invasive sampling methods and include ethical consideration such as workers' right to decline participation in the biomonitoring program. Biomonitoring should be used if it provides added information, relevant for health protection and that cannot be obtained with traditional occupational hygiene methods. Harmonized approaches, as suggested here, allow for more and better collaboration between experts, with sharing of knowledge and expertise, improving interpretation and supporting regulatory decision making.

Biomonitoring results should provide the relevant and necessary information for the occupational health and hygiene professionals (OHP) to evaluate the chemical exposures and the effectiveness of implemented RMMs. Furthermore, the biomonitoring results should be used to prioritize collective and individual control measures. For example, if only the results of certain individuals repeatedly show increased exposure, response remains on an individual level, while if a group workers of a similar exposure group (SEG) shows increased exposures, a comprehensive response to workplace hygiene measures is required. Here, we provide a practical stepwise approach to develop a suitable and reliable biomonitoring program. Fig. 1 shows the seven steps. Before the seven steps are initiated, it is important that the workers receive an introduction of the biomonitoring program and the reasons for inviting certain worker to participate. Workers should also be aware of their personal benefits of knowing their internal exposure. Moreover, it is in the responsibility of the competent OHP to check the quality and validity of received result according to a checklist (Fig. 2).

### Step 1. Define the overall goal of the occupational biomonitoring program.

Occupational biomonitoring programs should have a defined overall goal and approach for sample collection, analytical methods, and statistical analysis as well as for managing and communicating the results. The biomonitoring program should additionally describe actions to follow in response to the findings obtained through biomonitoring. Such a program will likely perform better if it is not imposed but where workers have participated in developing the biomonitoring program.

The OHP in charge of the biomonitoring program will need to understand and follow regulations regarding workers' right to information, consultation, and participation as well as communicate the aims of the biomonitoring program before enrolling the workers. Some countries require the workers to sign a written informed consent, while others do not because a biomonitoring program is part of a legal obligation or medical examinations.

### Step 2. Assess current occupational exposure knowledge.

Occupational biomonitoring programs should build on (1) current occupational exposure knowledge including possible exposure scenarios (workplace conditions, RMM in place and task descriptions, probability and magnitude of exposures, main exposure routes, exposure duration

<figure><img src="image_2.png" /><figcaption>Fig. 1. Outline of the stepwise approach to set up an occupational biomonitoring program as described in the OECD biomonitoring approach.</figcaption></figure>
and frequency), (2) available occupational hygiene data (exposure information either quantitative or qualitative such as chemical agent information obtained from safety data sheets, sampling and analytical methods for the samples taken being either air, surface, and emission measurements, chemical exposure results, sampling device information including calibration records, engineering control information including maintenance and other supporting records, work area information, process/operation information, exposure modifier information, personal protective equipment used including fit testing and performance records, report tracking), and finally, (3) assess worker compliance with already implemented occupational RMM. Work histories should be collected to help interpret the biomonitoring results. The latter can be conducted, e.g., through direct observations of workers conducting their tasks and discussions with workers. SEGs are created using the exposure profiles and duration of the tasks performed in the working shifts throughout the year (Rappaport et al. 1995) and requires occupational hygiene skills. The following information is usually required: job classification, an inventory of tasks within a job, task specific exposure profiles, operational conditions and RMM in place, exposure duration within the shift and throughout time, and other variables that can influence exposure (exposure determinants). SEGs help organize exposure reduction strategies in the risk management reductions currently in place and recognize the need of additional RMM.

### Step 3. Selection of appropriate biomarker.

Developing the biomonitoring program includes decisions on the selection of an appropriate biomarker and a laboratory to analyze it. One criterion for the selection of a biomarker is that an established OBL exists for the selected biomarker (or can be derived). The OBL is linked to the sampling time (biomarker elimination kinetics known) and an indication should be given of the method (chemical or biological analytical analysis) that can be used to verify compliance with the OBL (see Fig. 2). The biomonitoring results are evaluated against the established OBL (concentration of the biomarker in the biological matrix versus the OBL). The biomarker concentrations reflect a defined exposure interval that can be interpreted for possible occupational exposures. Laboratories chosen for the analysis (see step 5 for how to choose a chemical analytical laboratory) should be contacted before the sampling begins to follow prescribed validated chemical analytical methods including shipping and storing instructions. Finally, validated protocols for collection, storage and shipping of samples ensure their integrity.

### Step 4. Defining the sampling strategy.

An appropriate sampling strategy (consider the collection time of the sample according to the toxicokinetics of the selected biomarkers, biological media, sensitivity of the sampling and chemical analytical methods) ensures that a sufficient number of samples (consider exposure variability and possible errors (sensitivity, specificity, and reliability)) are collected from a set of workers with a specific type of job or certain tasks. Inter- and intra-worker variabilities in biomonitoring includes the variability in exposure routes in addition to respiration rate (physically demanding work activities increase the respiration rates and will thus increase the internal exposure), thus will be greater compared to external exposure measurement methods. This is an important asset with biomonitoring to measure actual internal exposure. The sample number should have sufficient statistical power to decide whether the biomonitoring result is compliant or exceeds the established OBL. The selection of workers to include into the program should mirror the occupational biomonitoring program objective and is based on current knowledge (Step 1 & Step 2). The chosen biomarker(s) should be collected in an appropriate biological matrix at appropriate times (Step 3). The timing of the sample collection should be based on the anticipated exposure time (e.g., spot urine samples collected post-shift) and toxicokinetics (e. g. aligned with elimination half-life time of the investigated analytes). The sample storage and transport conditions to the laboratories are also specified (Step 3). The occupational biomonitoring program should specify the number of samples collected per worker or if the workers' exposures should be assessed during a specified

task and/or day e.g., associated with high exposures (worst-case scenario). Sampling intervals within the sampling series can be based on the apparent elimination half-life of the biomarker, and consequently, the sample collection time is determined by the peak elimination (maximum concentration of the exposure biomarker in the biological matrix) of the biomarkers for substances with relative short half-lives and at steady state for substances with long half-lives. The timing of the biomonitoring sample is less critical for chemicals with long half-lives (in years) because exposures can be quantified decades after they occurred. After exposure to chemicals with short half-lives (hours or a few days), it is necessary to collect the biomonitoring sample at peak elimination. Biomonitoring can also be used after accidental exposures to chemicals to back-calculate the internal exposures given the chemical's half-life (e. g., (Scheepers & Smolders, 2014). Air and biomonitoring are complementary and worthwhile if the route of exposure is unknown.

### Step 5. Choosing a chemical analytical laboratory.

The selected chemical analytical laboratory needs to operate in compliance with laboratory quality standard (e. g. ISO standards and GLP) and should be able to: (1) analyze accurately the intended biomarker (e.g., certification of the method, participation in external quality assessment schemes, and high accuracy in analyzing certified reference materials), see Fig. 2; (2) use a validated chemical analytical method for the intended biomarker (Bader et al., 2012); (3) follow a Standard Operating Procedure (SOP); and (4) communicate to the OHP the requirements before sample collection (e.g., specific sampling requirements, storage and shipment of samples, and required sampling materials). Preferably, the laboratory can provide counselling on all aspects of biomonitoring from sampling up to the interpretation of results regarding the OBL compliance.

<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Checklist for items included in the laboratory report. Note that biomarker concentrations need correct units and that the analytical methods require information on performance indicators (sensitivity, specificity, and reproducibility annotated).</figcaption></figure>
### Step 6. Ensuring sample quality during sample collection

Contamination or the loss of the samples' integrity should be avoided by implementing necessary precautionary measures in collecting and handling the biological samples. Quality should be implemented into all seven steps. The OHP in charge needs to inform the participating workers of possible contamination risk when they provide urine samples such as wash their hands before the urine collection and change of work clothes. This is especially important when the exposure biomarker is the chemical used (e.g., metals). In addition, blood samples need to be collected by licensed professionals in agreement with the sampling protocol (e.g., selection of blood collection tubes according to the selected biomarker). Exposure information should be recorded on the sampling sheet on the day the samples are collected (e.g., detailed task descriptions, chemicals used, process/operation information, exposure modifier information, observed exposure routes, workplace conditions including engineering control information, exposure duration and frequency, personal protective equipment, accidents/spills, observations made regarding the workplace air, surface, and emission sources.

The laboratory report with the biomarker concentrations in the biological samples should follow data protection rules and should only be given to the OHP who sent the samples, or to another person authorized to handle individual confidential data. The reproducibility of the laboratory results is pivotal and should be implemented in the quality control and quality assurance (e.g., make sure to send duplicate samples to compare the results). Fig. 2 lists the items that should be part of a laboratory report.

### Step 7. Communicating and disseminating results to individuals and on group level.

#### - Communicating results to individual workers

The OHP should communicate and explain the biomonitoring results to the workers participating in the biomonitoring program. Workers need to know if their results were OBL compliant or not. The primary purpose of occupational biomonitoring is to assess workers' exposures to the chemicals that they use taking into account all routes of exposure, use of personal protective equipment (such as respirators and gloves), and the way that tasks are undertaken. The OHP needs to discuss biomonitoring results with the worker whether their exposures are being adequately controlled and how their own behavior can impact their exposure. When results indicate that RMMs need to be improved, then corrections are expected from management, but where results indicate that human behavior is a factor, then the OHP can help the worker improve their own ways of reducing chemical exposures. Additional help such as work histories that give detailed descriptions on jobs and tasks held during a worker's working life, are useful when the biomarker elimination half-life is long (accumulate in the body) or prior jobs have lasting internal exposures.

#### - Communicating of OBL compliaces to the workplace management

Compliance with the OBL means that the implemented RMM for controlling occupational exposure among workers are effective for the substance in question. In case of non-compliance, actions should be targeted to improving working conditions and risk management reductions. Biomonitoring data can be used to assess the effectiveness of exposure controls, develop risk communications, and identify failures of prevention and control. Biomonitoring programs can be an early warning system for elevated internal chemical exposures.

## 3. Biomonitoring programs for compliance

### 3.1. Inclusion of workers in the biomonitoring program for OBL compliance purpose

The *best approach* is to include as many workers as possible in the biomonitoring program because it gives information on individual worker exposures. The *second-best approach* is to at least, include all workers who are at risk of a higher chemical exposures. If the assessment of the entire group of exposed workers is not feasible, the assessment

shall focus on the workers with a higher risk of chemical exposures and workers are randomly selected within the SEG. Occupational biomonitoring is implemented in different laws and regulations depending on region and country. The laws dictate who should be included in occupational biomonitoring (voluntary basis or compulsory, as it is for blood lead concentrations in many countries) and who (occupational hygienists, occupational nurses, occupational medical doctors, or other professions) are eligible to set-up and run such programs. Although, this would benefit from harmonization, it is outside the scope of the current manuscript. The compliance with the OBL can be checked by collecting a series of consecutive samples from an individual worker. For routine working conditions, the most conservative option is to assess that all valid biomonitoring measurements of a sampling series were below the OBL. An optional approach is to calculate the mean of the measured sampling series for an individual worker, add the coefficient of variation (CV), and then check that (1) the mean is below the OBL and (2) the coefficient of variation (CV) is less than 30 % or, alternatively, that the mean value is less than 0.5 x OBL value. In both cases (CV<30 % and mean value < 0.5 OBL), it is necessary to specify a priori how far a single value is allowed to be above the OBL. No single values should exceed a threshold for acute toxic effects. The *third-best option* is to use the SEG approach as an early warning approach for the OHPs in cases where the workforce is too large to include all workers. The SEGs help assess risk management reductions currently in place and recognize the need of additional risk management reductions on a group level. It can show, with a certain statistical probability, whether a worker is likely over-exposed, but will not answer the question of whether a specific worker is at risk (e.g., skin contact can vary significantly among workers). If the biomonitoring values from one SEG member deviate strongly from the rest of the SEG results or the biomonitoring results in the SEG deviate strongly from a log normal distribution, then the constitution of the respective SEGs should be scrutinized. The validity of a SEG should undergo an annual reassessment, provided there are no significant changes in the workplace or tasks. The number of required samples per SEG has been elaborated and given in supplementary Table 1. A detailed technical biomonitoring compliance guide will need to be elaborated on national levels respecting the national legislations occupational chemical exposures.

### 3.2. Reliability of the biomonitoring results

Reliability of the biomonitoring results are ensured by the design and the consequent evaluation of the sampling strategy. Common factors that influence reliability of biomonitoring results are that the day of the sample collection was not representative of a usual exposure situation; the sampling time was not appropriately chosen according to exposure interval; an external contamination occurred; the storage and transportation conditions were inappropriate due to unknown changes in schedules; and urinary creatinine levels were out of normal range (0.3-3 g/L). Creatinine values are sometimes used because the exposure biomarker value needs to be corrected for the urine volume, and values greater that the normal value can indicate heavy physical work or hot environment, which needs to be addressed. If high creatinine values persist in the consequent samples obtained, the worker should be referred to the physician with the accompanied efforts in characterizing the worker's occupational exposures. Fig. 3 depicts a flow chart that can be used to determine OBL compliance of the biomonitoring results.

### 3.3. Non-compliance with the OBL

Some typical scenarios for non-compliance with the OBL are that workers comply with the risk management reductions, but they are insufficient; have a heavy physical load resulting in an elevated respiratory volume; have unusual long shifts (e.g., 12-h); have co-exposures that affect the toxicokinetics of the biomarker (not initially considered in the evaluation); or simply do not comply with general occupational
<figure><img src="image_4.png" /><figcaption>Fig. 3. Flow chart for determining compliance with OBL given a set of bio-
monitoring data (POBL Provisional Occupational Biological Limit value).</figcaption></figure>

hygiene requirements (e.g., eating and drinking in designated areas and
washing hands before eating) or the implemented exposure reduction
measures. If OBL exceedances persist over longer time periods, then non-
compliance with an OBL means that occupational health risks cannot be
excluded. Monitoring workers with specific exposure profiles or SEGs for
compliance of the OBL means that a sufficient subset of workers in the
same SEG needs to provide samples. Although, a single biomonitoring
measurement is not sufficient for the evaluation of OBL compliance, it
can be indicative of the presence of exposures, worst-case exposure
scenarios, and can stimulate follow-up measurements. A single bio-
monitoring value should never exceed a threshold for acute toxic effects.
If an OBL does not exist, then one must be derived based on available
toxicological, exposure, and epidemiological data. The OBL derivation
process has been outlined in the OECD occupational biomonitoring
guidance. There are multiple reasons for not complying with an OBL
leading to issues related to potential consequences. The knowledge
gained regarding exposure levels for the individuals (in terms of job
security, norm-filling, liability and other reasons) needs to be reflected
in the communication and anonymization of the results (see the
following chapter 4).

4. Ethical and legal aspects of biomonitoring

Since biomonitoring requires the use of human samples, ethical
principles and data protection legislation must be respected. The OECD
guidance includes a chapter on ethical requirements. Here, we provide a
short summary of key elements. Privacy requirements are stipulated in
local regulations and will differ according to the wider social, cultural,
and legal national context and the field in which they are applied.
Practices in occupational health research are adapted to different con-
ditions compared to those in routine surveillance programs. The
contribution of non-occupational exposures is normally far smaller
compared to occupational exposures. Biomonitoring considers the total
systemic exposures and will be more protective for an individual with
both occupational and non-occupational exposures irrespective of legal
responsibilities (e.g., employer, insurance). The guideline does not
include a discussion regarding attributing exposures to occupational and
non-occupational exposures. Biomonitoring can be part of compulsory
periodic health examinations for employees potentially exposed to
hazardous substances and are either offered requiring informed consent
from the worker or mandatory for the employee based on legal
requirements.

Data protection regulations specify the conditions under which
personal data may be processed and include special requirements for
sensitive personal health data. Note that data protection regulations do
not apply to anonymous data. However, occupational biomonitoring
data will often be coded and/or pseudonymized, and hence can fall

under data protection regulations.

Ethical guidelines for occupational health have been elaborated by
the International Commission on Occupational Health (ICOH), who
developed the International Code of Ethics for Occupational Health
Professionals. This covers basic principles, duties, and obligations of
OHPs, and conditions of executions of the functions of OHPs (ICOH,
2014). Other general ethical guidelines also exist (Convention for the
Protection of Human Rights and Dignity of the Human Being with regard
to the Application of Biology and Medicine: convention on Human
Rights and Biomedicine, 1999, Dumez et al., 2011, Casteleyn et al.,
2015). Here we added in Table 1 a set of questions are given to reduce
the risk that workers feel pressured into participating and that em-
ployers have personal information on workers.

These questions should be answered before setting up a bio-
monitoring program and answers for ethical assessment in occupational
biomonitoring. In occupational settings, the employer has a duty to
protect the workers from chemical hazards. This includes giving infor-
mation on the chemical risks to which the workers are exposed as well as
on the methods and tools for prevention. If biomonitoring is considered
a necessary part of the endeavor, be it obligatory for the worker or after
informed consent, the worker has a right to receive the result, but not the
duty. It is up to the OHP to interpret the results and to provide the
worker and the employer with adequate proposals for employment, at
individual and/or collective levels. The worker can also decline partic-
ipation in the biomonitoring program. Consequences of such refusal will
depend on the local health and safety legislation. All workers have in
principle equal rights for the protection of their health and the inva-
siveness of the biomonitoring sample collection methods should not lead
to a high burden for the worker. Less invasive sampling methods are
preferred. All workers should in principle have the same opportunity to
fully benefit from the biomonitoring program and have their data
assessed at individual and at collective level to provide the most
adequate information for further actions. If such actions are not possible
due to the sample collection approaches or the anonymization of the
results, the ethical justification of biomonitoring programs might be
critically diminished.

5. Main recommendations for national and international authorities

**Use biomonitoring systematically.** Biomonitoring is important for protecting workers' health and controlling exposure to hazardous chemicals (Viegas et al., 2020). Therefore, it is recommended to implement occupational biomonitoring in national and international legislations to be able to protect workers' health. This will enable employers to routinely use biomonitoring in addition to traditional occupational hygiene methods to assess occupational exposures to hazardous substances. This is especially important for chemicals that easily cross the skin barrier and where hand-to-mouth contamination is plausible thus, resulting in systemic internal exposures. More examples are given in OECD guidance in chapter 1.2.

**Implement this harmonized biomonitoring approach into national and international regulations.** Finally, national and international regulations should implement this harmonized biomonitoring approach to ensure good worker protection.

6. Conclusion and outlook

Biomonitoring is an important approach in protecting workers'
health and for controlling exposures to hazardous chemicals when used
in accordance with current ethical standards. Exposure reduction is the
guiding principle of biomonitoring before any health effects are
apparent. Using the biomonitoring approach efficiently in occupational
exposure assessment needs to meet several requirements, including
being undertaken by those familiar with the work (the processes,
exposure control measures and worker's behavior) and closely
<caption>**Table 1**</caption>

Since biomonitoring requires the use of human samples, ethical principles and data protection legislation must be respected. A set of questions that should be answered before setting up a biomonitoring program and answers for ethical assessment in occupational biomonitoring are given below.

<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Question</th><th>Answer</th></tr></thead><tbody><tr><td>1) Who can implement a biomonitoring program in occupational health?</td><td>Employers must ensure the health protection and safe working environments for all employees and finances related costs (ILO, 1981). A competent OHP expert must implement the biomonitoring program. OHPs can only be considered experts in their field if they acquire and maintain the competences necessary for their duties as well as adhering to good practice and professional ethics. The OHPs have an advisory role, as the decisions and the ultimate responsibility lie with the employer. Basic requirements for acceptable OHP functioning are often specified by national law. Special attention should be given to ethical issues which may arise from competing objectives. Examples are the protection of employment and the protection of health, the right to information and confidentiality, and the conflicts between individual and collective interests of the workers within the company (ICOH, 2014).</td></tr><tr><td>2) What are the preconditions?</td><td>Informed consent is a central precondition of biomonitoring programs. However, the basis for a lawful processing might also be the specific legal obligations of the employer instead of worker's informed consent (see EU GDPR, art. 9 mentioned in chapter 9.3.3 Annex C: Specific regulations on data protection). When participation in biomonitoring programs is<ul><li>Voluntary: workers can decline participation without disadvantages in terms of employment law.</li><li>Mandatory: workers can decline participation, but this may lead to moving the worker to a job not associated with hazardous exposure risks; however, if no alternative is available, this may lead to the termination of employment. Financial consequences will differ according to national laws (e.g., social security and recognition of occupational diseases). Workers have a right-to-know or the option of the right-not-to-know about the collection and use of their personal data and the obligations are on the OHP and the employer. Information about the biomonitoring program should be given in a language and terminology all workers understand sufficiently. Information about the biomonitoring program should be given in a language and terminology all workers understand sufficiently.</li></ul>The OHPs are responsible for keeping the data secure and under strict confidentiality. The data must be kept in a suitable form to permit consultation at a later date. The individual biomonitoring results must be securely stored for an appropriate time as specified in the regulation. Note that national laws may require individual data to be kept even after the worker leaves the company and authorities may ask for individual data</td></tr><tr><td>3) What are the requirements regarding collection, storage, and access to the data?</td><td></td></tr></tbody></table>

<table><thead><tr><th>Question</th><th>Answer</th></tr></thead><tbody><tr><td>4) Who should receive the biomonitoring program results, and in which form?</td><td>under certain conditions. An individual worker has the right to access their own health and exposure records. The employers have no access to worker's individual data. The employers have access to aggregated or anonymized data provided by the OHP and used in exposure reduction strategies.<br>The OHP must inform (if wished) the workers of their individual biomonitoring results and clarify the results, explain possible causes of abnormal results and remediations as well as discuss, if necessary, further preventive measures (e.g., adapting the working conditions) and possible consequences of employment according to national regulations. Information provided to the employer can never contain any information on results of medical examinations nor individual biomonitoring results. The OHP presents the biomonitoring results (exposure data) and recommends risk management measures in a form that does not violate the confidentiality of personal data. Individual biomonitoring results may only be transmitted between OHPs under specific conditions of confidentiality. As mentioned earlier, the worker has the right to know, in advance, who will have access to the data within and outside the company.</td></tr><tr><td>5) Do workers have a right to decide whether to participate in biomonitoring programs?</td><td>All workers have in principle equal rights for the protection of their health. All workers with possible hazardous exposures should be offered to be part of a biomonitoring program in countries where biomonitoring is not mandatory or should be obliged to participate in the biomonitoring program in countries where biomonitoring is a mandatory part of the surveillance. Individual workers cannot demand to be included if they do not belong to the exposed group.</td></tr></tbody></table>

associated with it (on site or regularly “walking the floor”) (Jones, 2020). It is only by understanding the workplace and non-workplace sources of exposure that occupational health professionals can adequately interpret and act on biomonitoring results appropriately. The occupational health professionals need to be trained in conducting biomonitoring programs, which needs to be elaborated. Despite all the advantages of biomonitoring, it was recently identified as a largely underused exposure assessment tool in occupational health (Viegas et al., 2020). Biomonitoring involves the use of sensitive data and therefore implies some specific conditions. In addition, biomonitoring in an occupational context is different than biomonitoring in environmental settings and in a research context. The consequences of the same result may be very different according to the context and on such example, is the access to work. The main issue is that biomonitoring is currently regulated under health surveillance in many countries thus hampering biomonitoring as an exposure assessment tool on a routine basis. For example, the OHPs would benefit from using the biomonitoring approach when assessing chemicals having a skin notation and likely a skin absorption; however, OHPs are often only left with air monitoring options (OELs) due to the legal medical requirements. Consequently, the health-risk assessment is limited to inhaled chemicals, thus ignoring skin and oral exposures. This occupational biomonitoring approach offers up-to-date guidance for conducting biomonitoring in occupational exposure assessment and risk management. The approach aims to
simplify and harmonize exposure biomonitoring practices with a focus on harmonizing approaches for international comparison. It also provides practical advice on using, evaluating, and communicating biomonitoring results. The extensive OECD occupational biomonitoring guidance document (Occupational Biomonitoring Guidance Document (oecd.org)) as well as this harmonized occupational biomonitoring approach were both elaborated in the OECD framework and specifically, the Working Parties on Exposure and Hazard Assessment by scientific experts from 40 institutes and organizations representing 15 countries.

### CRediT authorship contribution statement

**Nancy B. Hopf:** Writing – original draft, Visualization, Validation, Methodology, Investigation, Data curation, Conceptualization. **Christophe Rousselle:** Writing – review & editing, Validation, Investigation. **Devika Poddalgoda:** Writing – review & editing, Methodology, Data curation, Conceptualization. **Farida Lamkarkach:** Writing – review & editing, Visualization, Methodology, Data curation, Conceptualization. **Jos Bessems:** Writing – review & editing, Validation, Methodology, Data curation, Conceptualization. **Kaspar Schmid:** Writing – review & editing, Investigation, Conceptualization. **Kate Jones:** Writing – review & editing, Visualization, Methodology, Investigation, Conceptualization. **Koki Takaki:** Writing – review & editing, Validation, Supervision. **Ludwine Casteleyn:** Writing – review & editing, Validation, Methodology, Data curation, Conceptualization. **Maryam Zare Jeddi:** Writing – review & editing, Visualization, Methodology, Data curation. **Michael Bader:** Writing – review & editing, Validation, Methodology, Data curation. **Michael Koller:** Writing – review & editing, Validation, Methodology, Data curation. **Patience Browne:** Writing – review & editing, Validation, Supervision. **Rex FitzGerald:** Writing – review & editing, Validation, Methodology, Investigation. **Susana Viegas:** Writing – review & editing, Validation, Methodology, Investigation, Data curation, Conceptualization. **Thomas Göen:** Writing – review & editing, Visualization, Validation, Methodology, Investigation, Data curation. **Tiina Santonen:** Writing – review & editing, Visualization, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Virpi Väänänen:** Writing – review & editing, Validation. **Radu - Corneliu Duca:** Writing – review & editing, Visualization, Validation, Methodology, Investigation, Data curation, Conceptualization. **Robert Pasanen-Kase:** Writing – review & editing, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

### Data availability

No data was used for the research described in the article.

## Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.envint.2024.108990.

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