Derivation of occupational biomonitoring levels (OBLs) is needed to effectively utilize biomonitoring for assessing exposures to chemical substances, and consequently, implement risk reduction measures to reduce health risks among workers. OBLs are the appropriate option for chemical substances that can be absorbed through the skin. This methodology for derivation of OBLs has been developed in collaboration with scientific and regulatory experts from more than 40 institutes in 15 countries within the Organization for Economic Cooperation and Development (OECD) framework. This manuscript provides a summary of the guidance on derivation of OBLs destined for scientists, risk assessors, and regulators who are tasked with establishing OBLs for regulatory purposes and implementing occupational biomonitoring programs. The derivation methodology follows a tiered approach based on the strength of evidence and quality of the data that we have labeled level of confidence. The tiered approach serves as a practical framework in occupational health risk assessment and management. We distinguish between four OBL levels depending on the strength of scientific evidence and confidence level: health-based derivation of OBL based on robust epidemiological data showing causal exposure-health effect relationship and Provisional OBL (POBL) based on robust toxicological animal data showing dose-response relationship as well as two assessment values which are not health based: reference levels in the general population (Reference OBL or (ROBL)), and Technical achievable OBL or (TOBL). Four case studies illustrating the derivation methods for OBLs and POBLs are also provided. Using this state-of-the-art approach (OECD guidance document no. 370) will lead to a harmonized derivation of OBLs and subsequently to evidence-based risk management measures.

In den letzten Jahren wurden Molaren-Inzisiven-Hypomineralisationen (MIH) mit einer relativ hohen Inzidenz bei Kindern und Jugendlichen in Deutschland beobachtet. Als ursächlich für die Entwicklung einer MIH stehen chemische Verbindungen, die das endokrine System beeinflussen können und die unter den Begriffen Xenoöstrogene oder endokrine disruptive Chemikalien (EDC) zusammengefasst werden, besonders unter Verdacht. Diese Hypothese muss jedoch noch durch epidemiologische Verlaufsstudien überprüft werden.

Abstract The uptake of hazardous substances at the workplace through the skin can be one major route of exposure and therefore add to the occupational health risk for employees. More than one third of all substances with a limit value in workplace air in Germany have been designated with ‘H’ by the MAK Commission of the Deutsche Forschungsgemeinschaft (DFG), indicating that the percutaneous absorption under workplace conditions can make a significant contribution to the systemic exposure of an employee. The recommendations of the MAK Commission are one major source for regulatory decisions taken by the German Ministry of Labor and Social Affairs for sustaining health and safety in the work area. This presentation summarizes the general approach of the MAK Commission’s working group on percutaneous absorption, the selection and ranking of data (workplace studies, animal studies, in vitro studies, mathematical models or algorithms) as well as the quantitative criteria for an assignment with ‘H’. For the final assessment, the estimated absorbed amount of a substance is compared with the systemically tolerable amount extrapolated from the no observed adverse effect level (NOAEL). A designation with ‘H’ is recommended if the percutaneous uptake accounts for approximately 25 % or more of the tolerable quantity. Only in the case of genotoxic substances without limit values is the ability of a substance to cross the skin barrier sufficient in itself to recommend designation with an ‘H’. The assessment process as well as its merits and challenges are illustrated by some examples.

Technical products containing N-Phenyl-beta-naphthylamine (PBNA) are contaminated with beta-naphthylamine (BNA), a known carcinogen. Both amines penetrate the skin to different degrees, but little is known about their dermal-depot formation. This study investigated the dermal penetration of PBNA and its degradation product BNA using a viable human-skin model. PBNA (259 mu g) or BNA (0.52 mu g) in n-hexane and industrial grease were applied to freshly excised human skin (n = 6, 0.64 cm(2)) for 2-72 h. After temporary/continuous and single/repeated exposure, samples were taken (stratum corneum, epidermis/dermis, receptor fluid) and analyzed for their amine content by GC-MS. Continuous exposure led to a PBNA dermal depot of similar to 47 mu g/cm(2) over 72 h. Temporary applications also resulted in lower but consistent PBNA dermal depots. A single 2-h application resulted in a dermal depot of similar to 16 mu g/cm(2) after 72 h, while this was similar to 25 mu g/0.64 cm(2) with repeated applications. BNA behaved differently; with repeated 2-h applications, intradermally retained BNA initially increased 3-6 fold, then dropped to similar to 200-250 ng/cm(2). This incomplete decline upon repeated short-term exposure to PBNA suggests that a BNA dermal depot is formed either due to contamination of PBNA with BNA or to enzymatic conversion of PBNA to BNA. Additionally, PBNA dermal depots were saturable under the given conditions. These findings highlight the importance of understanding the dermal-exposure dynamics of potential carcinogenic compounds in industrial settings.

UV-P (2-(2H-Benzotriazol-2-yl)-p-cresol) is used as an ultraviolet (UV) light absorber in coating products, paints, adhesives, and sealants. Due to its widespread industrial and consumer uses, human exposure to UV-P is conceivable. In the study presented herein, initial data on its human in vivo metabolism were obtained for three study participants after single oral administration of 0.3 mg of UV-P/kg body weight. Urine and blood samples of two volunteers were collected up to 48 h after exposure. The third study participant donated urine and blood samples up to 72 h. Maximum levels of UV-P in blood of 184 ± 36 µg/l (85 ± 3

Background: 2-Ethylhexyl salicylate (EHS) is used as a UV filter in personal care products, especially sunscreens. The elimination of EHS and its metabolite 2-ethyl-5-hydroxyhexyl salicylate (5OH-EHS) after dermal exposure has been previously investigated and showed that both are excreted in high amounts. However, the low stability of the reference substance for EHS highly affected the analysis of this parameter. Since EHS was assumed to be excreted primarily as a conjugate to glucuronic acid in vivo, we compared the stability of unconjugated EHS to that of glucuronidated EHS (EHS-GlcA) in urine at 8 degrees C and -20 degrees C. Results: The relative recovery of unconjugated EHS decreases significantly when stored at both 8 degrees C and -20 degrees C. Stored as EHS-GlcA, the relative recovery remains steady over the course of the experiment. In addition to the stability experiment, the fraction of unconjugated EHS in human urine samples directly after dermal exposure to EHS was assessed, and only a low effective portion of unconjugated EHS was found. The same samples were reassessed after several months of storage at -20 degrees C and showed relative recoveries within the acceptance criteria, which also endorses the low initial level of unconjugated EHS. The hydroxylated EHS metabolites, 5OHEHS, 4OH-EHS and 2OH-EHS, were also included in the experiment and showed slightly decreasing relative recoveries at 8 degrees C, but stable relative recoveries at -20 degrees C. Significance: Despite unconjugated EHS being excreted only in a low portion in vivo, its low stability in urine may affect the effectiveness of EHS biomonitoring, because only the use of EHS glucuronide guarantees a stable and reliable calibration in urine. However, the hydroxylated EHS metabolites have proven to be suitable standards for calibration as well as parameters for biomonitoring when stored at -20 degrees C.

Little is known about exposure determinants of acrylamide (AA), a genotoxic food-processing contaminant, in Europe. We assessed determinants of AA exposure, measured by urinary mercapturic acids of AA (AAMA) and glycidamide (GAMA), its main metabolite, in 3157 children/adolescents and 1297 adults in the European Human Biomonitoring Initiative. Harmonized individual-level questionnaires data and quality assured measurements of AAMA and GAMA (urine collection: 2014–2021), the short-term validated biomarkers of AA exposure, were obtained from four studies (Italy, France, Germany, and Norway) in children/adolescents (age range: 3–18 years) and six studies (Portugal, Spain, France, Germany, Luxembourg, and Iceland) in adults (age range: 20–45 years). Multivariable-adjusted pooled quantile regressions were employed to assess median differences (β coefficients) with 95% confidence intervals (95% CI) in AAMA and GAMA (µg/g creatinine) in relation to exposure determinants. Southern European studies had higher AAMA than Northern studies. In children/adolescents, we observed significant lower AA associated with high socioeconomic status (AAMA:β = − 9.1 µg/g creatinine, 95% CI − 15.8, − 2.4; GAMA: β = − 3.4 µg/g creatinine, 95% CI − 4.7, − 2.2), living in rural areas (AAMA:β = − 4.7 µg/g creatinine, 95% CI − 8.6, − 0.8; GAMA:β = − 1.1 µg/g creatinine, 95% CI − 1.9, − 0.4) and increasing age (AAMA:β = − 1.9 µg/g creatinine, 95% CI − 2.4, − 1.4; GAMA:β = − 0.7 µg/g creatinine, 95% CI − 0.8, − 0.6). In adults, higher AAMA was also associated with high consumption of fried potatoes whereas lower AAMA was associated with higher body-mass-index. Based on this large-scale study, several potential determinants of AA exposure were identified in children/adolescents and adults in European countries.

Biomonitoring ist integraler Bestandteil der arbeitsmedizinischen Vorsorge bei potenziellen Gefahrstoffexpositionen. Die Ergebnisse können zu wichtigen Schlussfolgerungen hinsichtlich des Gesundheitsrisikos der einzelnen Beschäftigten oder der Gefährdungsbeurteilung führen. Der Vermeidung von Fehlern und Mängeln beziehungsweise der Sicherung der Qualität kommt daher im gesamten Workflow des Biomonitorings eine fundamentale Bedeutung zu.

The study aims to reveal the exposure to perfluoroalkyl substances (PFAS) in workers in different industry sectors with exposures to hexavalent chromium (Cr(VI)). The PFAS exposure of in total 172 individuals from 4 countries was assessed by the determination of 8 perfluoroalkyl carboxylic acids and 4 perfluoroalkyl sulfonic acids in plasma samples. The participants were 52 chrome plating workers, 43 welders, 3 surface treating workers and 74 workers without any occupational Cr exposure as controls. Significant differences between workers with Cr exposure and controls were found for the perfluoroalkyl sulfonic acids, particularly for perfluorooctane sulfonic acid (PFOS). The median and maximum levels were, respectively, 4.83 and 789 μg/l for chrome plating workers, 4.97 and 1513 μg/l for welders, and 3.65 and 13.9 μg/l for controls. The considerably high PFOS exposure in Cr platers and welders can be explained by the former application of PFOS as mist suppressants in electroplating baths, which resulted in an exposure of the directly involved operators, but also of welders performing maintenance and repair service at these workplaces.

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Abstract Introduction Biomonitoring is the most powerful approach to assess individual exposure and health risk of workers from chemical substances. However, availability and implementation of published biomonitoring methods often pose notable challenges. In 1955 the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) was founded by the Deutsche Forschungsgemeinschaft. Within the Commission, the working group “Analyses of Hazardous Substances in Biological Materials” (AiBM) develops, verifies, and publishes procedures for the determination of biomonitoring parameters. Methods AiBM applies a multi-stage process to develop and evaluate biomonitoring methods. Within this process it is essential that every method is verified by a second laboratory to ensure the reproducibility of the analytical procedure and the reliability data. Submitted methods and examination reports are discussed within the working group. Positively evaluated methods are adopted for publication. Others are returned to the developer for revision. Methods with fundamental drawbacks are rejected. Adopted methods were published first in a book series and, since 2016, in the quarterly online journal “The MAK Collection for Occupational Health and Safety”. Results and Discussion Since 1985, AibM has published nearly 200 analytical methods in English. Such methods include inorganic parameters (e.g. Pb, Hg, As) as well as organic parameters (e.g. solvents, plasticizers, pesticides) and are available online free of charge (https://onlinelibrary.wiley.com/doi/book/10.1002/3527600418 and https://series.publisso.de/de/pgseries/overview/mak/dam). Conclusion These detailed, ready-to-use protocols for human biomonitoring enable the monitoring of occupational exposure and often the determination of the background exposure in the general population as well.

2-Phenoxyethanol (PhE) is an amphiphilic organic compound frequently used as a broad-spectrum preservative in cosmetic products and other consumer goods. PhE is also used as a biocidal component in occupational settings. A previous volunteer study by our working group following oral exposure to PhE showed that PhE is almost completely taken up into the human body followed by an extensive metabolization and fast urinary elimination. However, with respect to the importance of transdermal uptake, we now conducted another volunteer study applying dermal PhE exposure: five volunteers were dermally exposed with 0.4 mg/kg body weight of PhE each on a specified 800 cm2 skin area using non-occlusive conditions. Subsequently, blood and urine samples were collected up to 48 h post-exposure. The present study illustrates the fast transdermal uptake of PhE. Following systemic resorption, PhE was extensively metabolized and rapidly eliminated in urine mainly in form of the metabolites PhAA (phenoxyacetic acid) and 4-OH-PhAA (4-hydroxyphenoxyacetic acid) accounting together for over 99

2-Phenoxyethanol (PhE) is an aromatic glycol ether and is used in a variety of functions and applications, e.g., as preservative in pharmaceuticals, cosmetic and personal care products, as biocide in disinfectants (e.g. human hygiene), or as a solvent in formulations (e.g. coatings, functional fluids). Despite its widespread use, little is yet known on its biotransformation and toxicokinetics in humans. Therefore, a pilot study was conducted with oral administration of PhE (5 mg/kg body weight) to five volunteers. Blood and urine samples were collected and analyzed for PhE and three of its presumed metabolites up to 48 h post-exposure. Additionally, one volunteer was dermally exposed to PhE and monitored until 72 h post-exposure. PhE was rapidly resorbed following both oral and dermal application with t max-levels in blood of about 1 h and 3 h, respectively. Metabolism of PhE was observed to be rather extensive with phenoxyacetic acid (PhAA) and 4-hydroxyphenoxyacetic acid (4-OH-PhAA) as the main metabolites found in blood and urine following oral and dermal exposure. PhE was excreted rapidly and efficiently via urine mostly in metabolized form: following oral exposure, on average 77% and 12% of the applied dose was excreted within 48 h as PhAA and 4-OH-PhAA, respectively. A similar metabolism pattern was observed following the single dermal exposure experiment. The obtained data on biotransformation and toxicokinetics of PhE in humans provide valuable information on this important chemical and will be highly useful for pharmacokinetic modelling and evaluation of human PhE exposure.

Abstract Introduction 2-Phenoxyethanol (PhE) is a biocide which is used as a preservative in cosmetics but also in metal-working fluids. Occupational prevention measures mainly target the inhalative exposure route, but dermal exposure is equally important. However, little is known on human toxicokinetics of PhE following dermal exposure. Methods A human-experimental study was conducted with five volunteers that were dermally exposed to 412 ± 14 µg PhE/kg bw in a single dose. Blood and urine samples were collected at regular intervals up to 48 hours post-exposure. All samples were analyzed for PhE and for three PhE metabolites. The study was approved by the local ethics committee of the Friedrich-Alexander-University Erlangen-Nürnberg, Germany (No. 296_19B). Results PhE was quickly absorbed with t(max) in blood of about 1.0 h. The main metabolite in both blood and urine was found to be 2-phenoxyacetic acid (PhAA) with 4OH-PhAA and 4OH-PhE identified as minor metabolites. Recovery in urine after 48 h was 44.2 ± 9.9 % PhE. Excretion half-lives of PhE (metabolites) were in the range of 1.7 – 3.9 h. Discussion PhE showed high bioavailability following dermal exposure and is rapidly resorbed and excreted within 48 h with PhAA as the main metabolite in blood and urine. Although, some inter-individual variances of PhE biotransformation were observed, PhAA could be confirmed as a reliable biomarker of exposure to PhE. Conclusion Dermal exposure to 2-phenoxyethanol results in an immediate systemic uptake of PhE, thus pointing to a potential occupational safety issue. The determination of PhAA in urine allows for a reliable biomonitoring of 2-phenoxyethanol.

The chemical UV filter 2-ethylhexyl salicylate (EHS) is used in various personal-care products. The dermal and oral metabolism of EHS have already been targeted by different studies. However, toxicokinetic data after a single dermal exposure to EHS was missing. In our study, three volunteers were dermally exposed to a commercial EHS-containing sunscreen for 9 h with an application dose of 2 mg sunscreen per cm2 body surface area. The exposure was performed indoors, and sunscreen was applied on about 75

As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per-and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzo-phenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from house-holds with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Sigma (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures.

Abstract The application of biocidal products by foam is considered an alternative to droplet spraying when disinfecting surfaces or fighting infestations. Inhalation exposure to aerosols containing the biocidal substances cannot be ruled out during foaming. In contrast to droplet spraying, very little is known about aerosol source strength during foaming. In this study, the formation of inhalable aerosols was quantified according to the aerosol release fractions of the active substance. The aerosol release fraction is defined as the mass of active substance transferred into inhalable airborne particles during foaming, normalised to the total amount of active substance released through the foam nozzle. Aerosol release fractions were measured in control chamber experiments where common foaming technologies were operated according to their typical conditions of use. These investigations include foams generated mechanically by actively mixing air with a foaming liquid as well as systems that use a blowing agent for foam formation. The values of the aerosol release fraction ranged from 3.4 × 10−6 to 5.7 × 10−3 (average values). For foaming processes based on mixing air and the foaming liquid, the release fractions could be correlated to the process and foam parameters such as foam exit velocity, nozzle dimensions, and foam expansion ratio.

Polycyclic aromatic hydrocarbons (PAHs) were included as priority substances for human biomonitoring (HBM) in the European Human Biomonitoring Initiative (HBM4EU), which intended to harmonise and advance HBM across Europe. For this project, a specific Quality Assurance and Quality Control (QA/QC) programme applying Inter-laboratory Comparison Investigations (ICIs) and External Quality Assurance Schemes (EQUASs) was developed to ensure the comparability and accuracy of participating analytical laboratories. This paper presents the results of four ICI/EQUAS rounds for the determination of 13 PAH metabolites in urine, i.e. 1-naphthol, 2-naphthol, 1,2-dihydroxynaphthalene, 2-, 3- and 9-hydroxyfluorene, 1-, 2-, 3-, 4- and 9-hydroxyphenanthrene, 1-hydroxypyrene and 3-hydroxybenzo(a)pyrene. However, 4 PAH metabolites could not be evaluated as the analytical capacity of participating laboratories was too low. Across all rounds and biomarkers, 86% of the participants achieved satisfactory results, although low limits of quantification were required to quantify the urinary metabolites at exposure levels of the general population. Using high-performance liquid or gas chromatography coupled with mass spectrometry (HPLC-MS; GC-MS) and isotope dilution for calibration as well as performing an enzymatic deconjugation step proved to be favourable for the accurate determination of PAHs in urine. Finally, the HBM4EU QA/QC programme identified an international network of laboratories providing comparable results in the analysis of urinary PAH biomarkers, although covering all parameters initially selected was still too challenging.

Many xenobiotics were identified as possible endocrine disruptors during the last decades. Structural analogy of these substances to natural hormones may lead to agonists or antagonists of hormone receptors. For a comprehensive human biomonitoring of such substances, we developed a simple, reliable, and highly sensitive method for the simultaneous monitoring of the parameters bisphenol A, triclosan, methylparaben, ethylparaben, propylparaben, butylparaben, benzophenone-1, benzophenone-3, 3,5,6-trichloropyridin-2-ol, p-nitrophenol, genistein, and daidzein in urine. Thereby, optimization of the enzymatic hydrolysis and the use of β-glucuronidase from E. coli K12 as well as sulfatase from Aerobacter aerogenes ensures the acquisition of intact analytes without cleavage of ester bonds among parabens. Validation of the method revealed limits of detection between 0.02 and 0.25 µg/L as well as limits of quantification between 0.08 and 0.83 µg/L. Thereby, the use of analyte-free surrogate matrix for calibration and control material influenced the sensitivity of the procedure positively. Furthermore, excellent precision in and between series was observed. Good absolute and relative recoveries additionally proved the robustness of the multimethod. Thus, the procedure can be applied for exploring the exposome to these prominent endocrine disruptors in the general population.

Background and purpose: Aluminum can be released into food by aluminum-containing food-contact materials (Al-FCM) during preparation or storage. There is considerable concern that extra aluminum intake may have negative effects on public health, especially with regard to its high background exposure and neurotoxic prop-erties of aluminum in high exposures. Human in-vivo data on the additional aluminum load from Al-FCM, however, are lacking. As such, the objective of this study was to explore whether the consumption of a diet highly exposed to such products leads to an increased systemic Al load in real-world conditions. Materials and methods: An exploratory, single-arm intervention study with a partially standardized diet was designed and carried out with 11 participants. The same 10-day sequence of dishes was repeated three times. Participants were exposed to Al-FCM from Days 11 to 20, whereas control-phase meals were prepared without Al-FCM during the first and last 10-day periods. Spot urine samples were collected each morning and evening and analyzed for their aluminum concentration; appropriate contamination countermeasures were taken.Principal results: Urinary aluminum excretion showed a strong dependency on the creatinine concentration in urine and required adjustment in further analyses. The creatinine-adjusted aluminum excretion during the exposure phase (median 1.98 & mu;g/g creatinine) was higher than in both control phases (1.78 & mu;g/g creatinine each). Two different mixed-effects regression models showed a significant effect in the exposure phase. Considering a discrete time effect, the creatinine-adjusted mean increase in the exposure phase was estimated to be 0.19 & mu;g/L (95% CI: 0.07-0.31; p = 0.0017).Major conclusions: This study demonstrated a measurable but fully reversible additional Al burden in humans from subacute Al-FCM exposure under real-world conditions. The estimated increase from Al-FCM corresponds to 8% of the baseline concentration. These data enable a more robust assessment of human health risks by Al-FCM.