Cooperation for the promotion of human biomonitoring | Umweltbundesamt

Background, objectives and tasks of cooperation

The Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) and the German Chemical Industry Association (VCI) initiated the collaboration in 2010 to promote human biomonitoring (HBM). The main objective of the cooperation is to improve the knowledge about substances to which the population might be increasingly exposed or which may have an effect on health. Therefore, chemical-analytical methods are being developed which can reveal a potential exposure of the general population to these substances. The primary goal of the cooperation is to develop sensitive methods that are able to detect the generally low concentrations which occur in the not occupationally exposed general public (known as background concentration).

One of the main objectives of the cooperation between the BMU and the VCI is to select up to 50 substances within ten years (substance prioritization) that meet the criteria of a) consumer relevance, b) and/or special relevance to health, and c) lack of a specific and sufficiently sensitive HBM method. The prioritization is followed by the development of specific analytical methods and their application in suitable population surveys. The VCI is responsible for method development, and the German Environment Agency (UBA) supports the Federal Environment Ministry (BMUV) in the application of the methods in suitable studies. UBA provides administration and management of the cooperation.

The cooperation originally was formed for ten years. The selection of substances was finished in early 2020. The development of the analytical methods is a complex and lengthy process. Therefore, the cooperation has been extended to 2025.

Committees and members

Within the framework of the BMUV/VCI cooperation, two bodies, the HBM Expert Group and a Steering Committee, have been established.The members of the HBM Expert Group have backgrounds in chemical-analytical science, expertise in toxicology, environmental medicine and/ or regulatory affairs and work for the Federal Environment Ministry (BMU), the Federal Institute for Risk Assessment (BfR), the Federal Institute for Occupational Health and Safety (BAuA) and the German Environment Agency (UBA), in science (universities, private and state institutes) and in the chemical industry.

Membership is based on recommendation and approval by both cooperation partners; membership is – apart from the governmental representatives - personal rather than institutional.
The members of the Steering Committee are representatives from the BMUV, UBA and VCI (or its membership organizations).

Selection of substances and method development

Until 2019, the HBM Expert Group convened at the beginning and in the autumn of every year, firstly to select the substances for which methods are to be developed, and secondly to discuss individual critical steps in method developments. Since 2020, the Expert Group meets only once a year for exchange and discussion on progress made in the development of methods.

First discussions on the selection of substances commenced before the official start of the cooperation and were based on lists compiled by different international organisations, e.g. the list of CMR substances (carcinogenic, mutagenic, reprotoxic), the Candidate List to ⁠REACH⁠ Annex XIV, or the list of endocrine disruptors, and also considered substances of concern under discussion at the time. The BMUV commissioned the BfR in 2010 to draw up a list of approximately 120 substances which might be relevant for the cooperation. This list was based on BfR’s assessment work in the frame of consumer health protection and on basis of worldwide on different levels discussed consumer relevant substances (e.g. Candidate List of ⁠REACH⁠, cosmetic ingredients). The basic criteria for selection of substances from the available lists were:

• Good to very good bioavailability of the substances
• Toxicological relevance
• Exclusion of substances for which an HBM method exists, either for the compound itself or for its active components or metabolites (related research in “The MAK Collection for Occupational Health and Safety” and laboratory list of the IPASUM (Institute and Outpatient Clinic of Occupational, Social, and Environmental Medicine), Erlangen). If the methods found seemed not appropriate for this cooperation (e.g. not sensitive enough) an intense study of the provided methods was performed.
• Exclusion of substances with low likelihood of exposure (no consumer relevance) (e.g. research in the SPIN database)

The finally compiled list built the bases for further discussions on appropriate substances within the HBM Expert Group. Subsequent meetings have focused on a regular review of international lists of chemicals (e.g. current registration data according to REACH) in order to address changes in the authorization and evaluation of chemicals. Current discussions and expert reports on substances and substance groups were also considered. In addition, recommendations of the participating institutions to take up new substances were discussed, and toxicological fact sheets were used to determine the substance’s appropriateness for the cooperative project.

The discussions on substance selection in the HBM Expert Group included aspects of substance toxicity (health relevance), the potential of consumer exposure to the substances, and the availability of a specific HBM method for tracing the substance itself or its metabolites (as exposure or effect biomarkers) in human urine or blood samples. In the case that an HBM method existed in the occupational safety field (MAK Collection), the expert group discussed the biomarkers used, possible detection and determination limits and/or the need for an additional metabolism study. The decision-making process increasingly weighed whether the available information from human, animal and cell culture tests enable the HBM Commission to derive an assessment (HBM) value.

As a result of the discussions, the HBM Expert Group generated a list of proposed substances, which featured up to ten chemicals every year for which sufficient data was available to assess them as suitable for the cooperation project.

The list of proposed substances from the HBM Expert Group was submitted to the Steering Committee for its annual spring meeting. The Steering Committee selected up to 5 substances per year for which the cooperation partners were to develop HBM methods. Consideration was also given to whether the VCI is able to find industry sponsors for the substance whose expertise is required for the effective development of analytical methods. This substance selection has been completed since spring 2020.

After the annual selection of up to five substances by the Steering Committee, the VCI commissions a laboratory (often a member of the HBM Expert Group) to develop a suitable method. The June 2013 issue of BMU-Umwelt features an article with details of the challenges involved in developing these methods (only available in German).

Selected substances

In 10 years of joint project work on human biomonitoring (2010-2020), the BMUV and VCI selected fifty substances for which the first human biomonitoring analysis methods are developed. These substances include phthalates and phthalate substitutes (plasticizers), flame retardants (for furniture or clothes), solvents (in cleaning products or wall colours), cosmetic additives (UV filters, fragrances, preservatives), plastics additives (UV-stabilizers), biocides and allergenic substances (preservatives for food, cosmetics or household products).

Detailed information on the selected substances, their uses, and their chemical names are shown in the Table “Selected Substances” below.

The webpages of the Human Biomonitoring Commission have information on helath significance, toxicological effects and any assessment (HBM) values already derived by the Commission.

More than half of the analytical methods have already been developed

Within the framework of the BMU/VCI cooperation urine and, in some cases, blood analysis methods for more than half of the selected substances have now been developed. These methods enable the analytical determination of substances for which there had been no method of detection (in these low concentrations) worldwide.

These include methods for the analysis of metabolites of the phthalate DPHP and the phthalate substitutes DINCH, DEHTP, TOTM, DnBA, DINA and DEHA. These plasticizers are increasingly used to replace, e.g., the now banned DEHP in different fields of application, for example in toys, food packaging or medical tubes. A method has also been developed for the analysis of MDI, an ingredient in single-component foam for the fixing and insulation of window and door frames. A method for the detection of 2-MBT (2-mercaptobenzothiazole) has been developed, which is used as a vulcanization accelerator in the production of household rubber products and tires. Methods are also available for lysmeral, 7-hydroxycitronellal and geraniol, fragrances frequently used in cosmetics and cleaning products and detergents. May cosmetics (like cream and sun blocker) contain UV-filters and preservatives, for some of which analytical methods have been developed (4-MBC, Octocrylene, CMI/MI (3:1), EHS, homosalate, Uvinul A Plus (DHHB), UV (Tinuvin) 328). New analytical methods are now also available for the preservative BHT, which is also used as a food additive, as well as for the feed additive ethoxyquin and the plastic additive 2,4-DTBP, which can be released from pipes for drinking water. Appropriate analytical methods to measure the background level for the flame retardants HBCDD and TDCPP are also available.

More information on the methods already developed can be found in the Table “Developed analysis methods”.

The method development for three substances (cyclosiloxanes D4, D5, D6) was discontinued due to analytical difficulties. Additionally, it was not possible to develop a method for the substance Keromet MD as it rapidly degrades to unspecific metabolites very fast once it has entered the human body. The method development for octyl methoxycinnamate was finished. However, no sufficient amounts of specific metabolites for the determination of the background exposure in the general population could be determined. Hence, the method is not suitable for application in population studies.

Once a method has been developed by an internationally renowned laboratory commissioned by the VCI, the method and the established exposure biomarkers are publislhed in peer reviewed journals and often also presented at conferences. Thus, the method becomes publicly available and can be used in laboratories worldwide (see publications at the end of the article).

The new analytical methods fulfill the high validity and quality standards of the working group “Analyses in biological Materials” of the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (known as the MAK Commission of the German Research Foundation (DFG). These standards include:

• Identification of one or more specific biomarkers (mainly metabolites)
• Development and validation of an analytical method for the determination and quantification of the biomarker(s) in urine or blood.

In addition, the method will be applied to approximately 40 non-occupationally exposed volunteers to confirm the suitability of the method to determine the background exposure.

Application of the new methods

The first application of the methods in population surveys is carried out by the German Environment Agency. Either human samples of the Environmental Specimen Bank or samples taken for the German Environmental Survey (GerES), a population representative survey, are analysed.

In the German Environmental Survey for Children and Adolescents, GerES 2014-2017 (GerES V), the methods for the determination of DINCH, DPHP, DEHTP, TOTM, the solvents NMP and NEP, the fragrance lysmeral and the methods for 2-MBT, 4-MBC, BHT as well as C(M)IT/MIT (3:1) have been applied. In the collective of the Environmental Specimen Bank the methods for the analysis of DINCH, DPHP, DEHTP, NMP und NEP, HBCDD, 2-MBT, 4-MBC, BHT, ethoxyquinand C(M)IT/MIT (3:1) as well as methods for the fragrances 7-hydroxycitronellal, geraniol and lysmeral have been applied. The spectrum of BMUV/VCI substances measured in the Environmental Specimen Bank samples is continuously extended. Some methods will also be applied in the German Environmental Survey on Adults, GerES VI. The results of these studies will be presented in peer reviewed journals or on the respective web pages.

With these results, for example, an estimation of the average corporal burden of the population of these substances is possible. This supports the assessment of the effectiveness of existing European and German legal regulations for the use of these substances – or may contribute to further regulations.

Progress made in the BMU/VCI project was part of the reason why Germany has been asked to coordinate an EU-wide programme on human-biomonitoring with the acronym HBM4EU. Under this initiative, the European Commission supplies a co-fund of 50 million euros between 2017 and 2021 to bring together and advance human-biomonitoring activities in the EU member states and a couple of associated countries. The German Environment Agency (UBA) is leading and successfully managing this complex project and is also incorporating the results of the BMU/VCI cooperation into this work.

Literature

2-MBT

Gries, W., Küpper, K., Leng, G., 2015. Rapid and sensitive LC-MS-MS determination of 2-mercaptobenzothiazole, a rubber additive, in human urine. Anal Bioanal Chem 407, 12, 3417-3423, https://doi.org/10.1007/s00216-015-8533-5.

Leng, G., Gries, W., 2017. New specific and sensitive biomonitoring methods for chemicals of emerging health relevance. Int J Hyg Environ Health 220, 2 Pt A, 113-122, https://doi.org/10.1016/j.ijheh.2016.09.014.

Murawski, A., Schmied-Tobies, M.I.H., Schwedler, G., Rucic, E., Gries, W., Schmidtkunz, C., Küpper, K., Leng, G., Conrad, A., Kolossa-Gehring, M., 2020. 2-Mercaptobenzothiazole in urine of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V). Int J Hyg Environ Health 228, 113540, https://doi.org/10.1016/j.ijheh.2020.113540.

4-MBC

Leng, G., Gries, W., 2017. New specific and sensitive biomonitoring methods for chemicals of emerging health relevance. Int J Hyg Environ Health 220, 2 Pt A, 113-122, https://doi.org/10.1016/j.ijheh.2016.09.014.

Murawski, A., Schmied-Tobies, M.I.H., Rucic, E., Schmidtkunz, C., Küpper, K., Leng, G., Eckert, E., Kuhlmann, L., Göen, T., Daniels, A., Schwedler, G., Kolossa-Gehring, M., 2021. Metabolites of 4-methylbenzylidene camphor (4-MBC), butylated hydroxytoluene (BHT), and tris(2-ethylhexyl) trimellitate (TOTM) in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey GerES V (2014-2017). Environ Res 192, 110345, https://doi.org/10.1016/j.envres.2020.110345.

7-Hydroxycitronellal

Pluym, N., Petreanu, W., Weber, T., Scherer, G., Scherer, M., Kolossa-Gehring, M., 2020. Biomonitoring data on young adults from the Environmental Specimen Bank suggest a decrease in the exposure to the fragrance chemical 7-hydroxycitronellal in Germany from 2000 to 2018. Int J Hyg Environ Health 227, 113508, https://doi.org/10.1016/j.ijheh.2020.113508.

Stoeckelhuber, M., Krnac, D., Pluym, N., Scherer, M., Leibold, E., Scherer, G., 2017. A validated UPLC-MS/MS method for biomonitoring the exposure to the fragrance 7-hydroxycitronellal. J Chromatogr B Analyt Technol Biomed Life Sci 1068-1069, 261-267, https://doi.org/10.1016/j.jchromb.2017.10.040.

Stoeckelhuber, M., Krnac, D., Pluym, N., Scherer, M., Peschel, O., Leibold, E., Scherer, G., 2018. Human metabolism and excretion kinetics of the fragrance 7-hydroxycitronellal after a single oral or dermal dosage. Int J Hyg Environ Health 221, 2, 239-245, https://doi.org/10.1016/j.ijheh.2017.10.015.

Alkylphenols

Leng, G., Gries, W., 2017. New specific and sensitive biomonitoring methods for chemicals of emerging health relevance. Int J Hyg Environ Health 220, 2 Pt A, 113-122, https://doi.org/10.1016/j.ijheh.2016.09.014.

Ringbeck, B., Belov, V.N., Schmidtkunz, C., Küpper, K., Gries, W., Weiss, T., Brüning, T., Hayen, H., Bury, D., Leng, G., Koch, H.M., 2021. Human Metabolism and Urinary Excretion Kinetics of Nonylphenol in Three Volunteers after a Single Oral Dose. Chem Res Toxicol 34, 11, 2392-2403, https://doi.org/10.1021/acs.chemrestox.1c00301.

Ringbeck, B., Bury, D., Hayen, H., Weiss, T., Brüning, T., Koch, H.M., 2021. Determination of specific urinary nonylphenol metabolites by online-SPE-LC-MS/MS as novel human exposure biomarkers. J Chromatogr B Analyt Technol Biomed Life Sci 1177, 122794, https://doi.org/10.1016/j.jchromb.2021.122794.

Ringbeck, B., Weber, T., Bury, D., Kasper-Sonnenberg, M., Pälmke, C., Brüning, T., Koch, H.M., Kolossa-Gehring, M., 2022. Nonylphenol (NP) exposure in Germany between 1991 and 2021: Urinary biomarker analyses in the German Environmental Specimen Bank (ESB). Int J Hyg Environ Health 245, 114010, https://doi.org/10.1016/j.ijheh.2022.114010.

BHT

Leng, G., Gries, W., 2017. New specific and sensitive biomonitoring methods for chemicals of emerging health relevance. Int J Hyg Environ Health 220, 2 Pt A, 113-122, https://doi.org/10.1016/j.ijheh.2016.09.014.

Murawski, A., Schmied-Tobies, M.I.H., Rucic, E., Schmidtkunz, C., Küpper, K., Leng, G., Eckert, E., Kuhlmann, L., Göen, T., Daniels, A., Schwedler, G., Kolossa-Gehring, M., 2021. Metabolites of 4-methylbenzylidene camphor (4-MBC), butylated hydroxytoluene (BHT), and tris(2-ethylhexyl) trimellitate (TOTM) in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey GerES V (2014-2017). Environ Res 192, 110345, https://doi.org/10.1016/j.envres.2020.110345.

Schmidtkunz, C., Küpper, K., Weber, T., Leng, G., Kolossa-Gehring, M., 2020. A biomonitoring study assessing the exposure of young German adults to butylated hydroxytoluene (BHT). Int J Hyg Environ Health 228, 113541, https://doi.org/10.1016/j.ijheh.2020.113541.

CIT/MIT

Murawski, A., Schmied-Tobies, M.I.H., Rucic, E., Schettgen, T., Bertram, J., Conrad, A., Kolossa-Gehring, M., 2020. The methylisothiazolinone and methylchloroisothiazolinone metabolite N-methylmalonamic acid (NMMA) in urine of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V). Int J Hyg Environ Health 227, 113511, https://doi.org/10.1016/j.ijheh.2020.113511.

Schettgen, T., Bertram, J., Kraus, T., 2017. Quantification of N-methylmalonamic acid in urine as metabolite of the biocides methylisothiazolinone and chloromethylisothiazolinone using gas chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 1044-1045, 185-193, https://doi.org/10.1016/j.jchromb.2017.01.019.

Schettgen, T., Bertram, J., Kraus, T., 2021. New data on the metabolism of chloromethylisothiazolinone and methylisothiazolinone in human volunteers after oral dosage: excretion kinetics of a urinary mercapturic acid metabolite ("M-12"). Arch Toxicol 95, 8, 2659-2665, https://doi.org/10.1007/s00204-021-03100-5.

Schettgen, T., Bertram, J., Weber, T., Kraus, T., Kolossa-Gehring, M., 2021. Quantification of a mercapturate metabolite of the biocides methylisothiazolinone and chloromethylisothiazolinone ("M-12") in human urine using online-SPE-LC/MS/MS. Anal Methods 13, 15, 1847-1856, https://doi.org/10.1039/d1ay00183c.

Schettgen, T., Kraus, T., 2017. Urinary excretion kinetics of the metabolite N-methylmalonamic acid (NMMA) after oral dosage of chloromethylisothiazolinone and methylisothiazolinone in human volunteers. Arch Toxicol 91, 12, 3835-3841, https://doi.org/10.1007/s00204-017-2051-5.

Schettgen, T., Rüther, M., Weber, T., Kraus, T., Kolossa-Gehring, M., 2020. N-methylmalonamic acid (NMMA) as metabolite of methylisothiazolinone and methylchloroisothiazolinone in 24-h urine samples of the German Environmental Specimen Bank from 2000 to 2017 - exposure and time trends. Chemosphere 246, 125743, https://doi.org/10.1016/j.chemosphere.2019.125743.

Climbazole

Schmidtkunz, C., Küpper, K., Gries, W., Leng, G., 2021. A validated LC-MS/MS method for the quantification of climbazole metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci 1173, 122677, https://doi.org/10.1016/j.jchromb.2021.122677.

DEHA

Nehring, A., Bury, D., Kling, H.W., Weiss, T., Brüning, T., Koch, H.M., 2019. Determination of human urinary metabolites of the plasticizer di(2-ethylhexyl) adipate (DEHA) by online-SPE-HPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 1124, 239-246, https://doi.org/10.1016/j.jchromb.2019.06.019.

Nehring, A., Bury, D., Ringbeck, B., Kling, H.W., Otter, R., Weiss, T., Brüning, T., Koch, H.M., 2020. Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose. Toxicol Lett 321, 95-102, https://doi.org/10.1016/j.toxlet.2019.12.006.

DEHTP

Lessmann, F., Kolossa-Gehring, M., Apel, P., Rüther, M., Pälmke, C., Harth, V., Brüning, T., Koch, H.M., 2019. German Environmental Specimen Bank: 24-hour urine samples from 1999 to 2017 reveal rapid increase in exposure to the para-phthalate plasticizer di(2-ethylhexyl) terephthalate (DEHTP). Environ Int 132, 105102, https://doi.org/10.1016/j.envint.2019.105102.

Lessmann, F., Schütze, A., Weiss, T., Brüning, T., Koch, H.M., 2016. Determination of metabolites of di(2-ethylhexyl) terephthalate (DEHTP) in human urine by HPLC-MS/MS with on-line clean-up. J Chromatogr B Analyt Technol Biomed Life Sci 1011, 196-203, https://doi.org/10.1016/j.jchromb.2015.12.042.

Lessmann, F., Schütze, A., Weiss, T., Langsch, A., Otter, R., Brüning, T., Koch, H.M., 2016. Metabolism and urinary excretion kinetics of di(2-ethylhexyl) terephthalate (DEHTP) in three male volunteers after oral dosage. Arch Toxicol 90, 7, 1659-1667, https://doi.org/10.1007/s00204-016-1715-x.

Schwedler, G., Rucic, E., Koch, H.M., Lessmann, F., Brüning, T., Conrad, A., Schmied-Tobies, M.I.H., Kolossa-Gehring, M., 2020. Metabolites of the substitute plasticiser Di-(2-ethylhexyl) terephthalate (DEHTP) in urine of children and adolescents investigated in the German Environmental Survey GerES V, 2014-2017. Int J Hyg Environ Health 230, 113589, https://doi.org/10.1016/j.ijheh.2020.113589.

DINA

Gotthardt, A., Bury, D., Kling, H.W., Otter, R., Weiss, T., Brüning, T., Koch, H.M., 2021. Quantitative investigation of the urinary excretion of three specific monoester metabolites of the plasticizer diisononyl adipate (DINA). EXCLI J 20, 412-425, https://doi.org/10.17179/excli2021-3360.

DINCH

Kasper-Sonnenberg, M., Koch, H.M., Apel, P., Rüther, M., Pälmke, C., Brüning, T., Kolossa-Gehring, M., 2019. Time trend of exposure to the phthalate plasticizer substitute DINCH in Germany from 1999 to 2017: Biomonitoring data on young adults from the Environmental Specimen Bank (ESB). Int J Hyg Environ Health 222, 8, 1084-1092, https://doi.org/10.1016/j.ijheh.2019.07.011.

Koch, H.M., Schütze, A., Pälmke, C., Angerer, J., Brüning, T., 2013. Metabolism of the plasticizer and phthalate substitute diisononyl-cyclohexane-1,2-dicarboxylate (DINCH((R))) in humans after single oral doses. Arch Toxicol 87, 5, 799-806, https://doi.org/10.1007/s00204-012-0990-4.

Schütze, A., Kolossa-Gehring, M., Apel, P., Brüning, T., Koch, H.M., 2014. Entering markets and bodies: increasing levels of the novel plasticizer Hexamoll(R) DINCH(R) in 24 h urine samples from the German Environmental Specimen Bank. Int J Hyg Environ Health 217, 2-3, 421-426, https://doi.org/10.1016/j.ijheh.2013.08.004.

Schütze, A., Lorber, M., Gawrych, K., Kolossa-Gehring, M., Apel, P., Brüning, T., Koch, H.M., 2015. Development of a multi-compartment pharmacokinetic model to characterize the exposure to Hexamoll(R) DINCH(R). Chemosphere 128, 216-224, https://doi.org/10.1016/j.chemosphere.2015.01.056.

Schütze, A., Otter, R., Modick, H., Langsch, A., Brüning, T., Koch, H.M., 2017. Additional oxidized and alkyl chain breakdown metabolites of the plasticizer DINCH in urine after oral dosage to human volunteers. Arch Toxicol 91, 1, 179-188, https://doi.org/10.1007/s00204-016-1688-9.

Schütze, A., Pälmke, C., Angerer, J., Weiss, T., Brüning, T., Koch, H.M., 2012. Quantification of biomarkers of environmental exposure to di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) in urine via HPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 895-896, 123-130, https://doi.org/10.1016/j.jchromb.2012.03.030.

Schwedler, G., Conrad, A., Rucic, E., Koch, H.M., Leng, G., Schulz, C., Schmied-Tobies, M.I.H., Kolossa-Gehring, M., 2020. Hexamoll(R) DINCH and DPHP metabolites in urine of children and adolescents in Germany. Human biomonitoring results of the German Environmental Survey GerES V, 2014-2017. Int J Hyg Environ Health 229, 113397, https://doi.org/10.1016/j.ijheh.2019.09.004.

DnBA

Ringbeck, B., Bury, D., Gotthardt, A., Hayen, H., Otter, R., Weiss, T., Brüning, T., Koch, H.M., 2021. Human metabolism and urinary excretion kinetics of di-n-butyl adipate (DnBA) after oral and dermal administration in three volunteers. Toxicol Lett 343, 11-20, https://doi.org/10.1016/j.toxlet.2021.02.012.

Ringbeck, B., Bury, D., Hayen, H., Weiss, T., Brüning, T., Koch, H.M., 2020. Determination of di-n-butyl adipate (DnBA) metabolites as possible biomarkers of exposure in human urine by online-SPE-LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 1141, 122029, https://doi.org/10.1016/j.jchromb.2020.122029.

DPHP

Gries, W., Ellrich, D., Küpper, K., Ladermann, B., Leng, G., 2012. Analytical method for the sensitive determination of major di-(2-propylheptyl)-phthalate metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci 908, 128-136, https://doi.org/10.1016/j.jchromb.2012.09.019.

Leng, G., Gries, W., 2017. New specific and sensitive biomonitoring methods for chemicals of emerging health relevance. Int J Hyg Environ Health 220, 2 Pt A, 113-122, https://doi.org/10.1016/j.ijheh.2016.09.014.

Leng, G., Koch, H.M., Gries, W., Schütze, A., Langsch, A., Brüning, T., Otter, R., 2014. Urinary metabolite excretion after oral dosage of bis(2-propylheptyl) phthalate (DPHP) to five male volunteers--characterization of suitable biomarkers for human biomonitoring. Toxicol Lett 231, 2, 282-288, https://doi.org/10.1016/j.toxlet.2014.06.035.

Schmidtkunz, C., Gries, W., Weber, T., Leng, G., Kolossa-Gehring, M., 2019. Internal exposure of young German adults to di(2-propylheptyl) phthalate (DPHP): Trends in 24-h urine samples from the German Environmental Specimen Bank 1999-2017. Int J Hyg Environ Health 222, 3, 419-424, https://doi.org/10.1016/j.ijheh.2018.12.008.

Schütze, A., Gries, W., Kolossa-Gehring, M., Apel, P., Schröter-Kermani, C., Fiddicke, U., Leng, G., Brüning, T., Koch, H.M., 2015. Bis-(2-propylheptyl)phthalate (DPHP) metabolites emerging in 24h urine samples from the German Environmental Specimen Bank (1999-2012). Int J Hyg Environ Health 218, 6, 559-563, https://doi.org/10.1016/j.ijheh.2015.05.007.

Schwedler, G., Conrad, A., Rucic, E., Koch, H.M., Leng, G., Schulz, C., Schmied-Tobies, M.I.H., Kolossa-Gehring, M., 2020. Hexamoll(R) DINCH and DPHP metabolites in urine of children and adolescents in Germany. Human biomonitoring results of the German Environmental Survey GerES V, 2014-2017. Int J Hyg Environ Health 229, 113397, https://doi.org/10.1016/j.ijheh.2019.09.004.

EHS

Bury, D., Brüning, T., Koch, H.M., 2019. Determination of metabolites of the UV filter 2-ethylhexyl salicylate in human urine by online-SPE-LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 1110-1111, 59-66, https://doi.org/10.1016/j.jchromb.2019.02.014.

Bury, D., Griem, P., Wildemann, T., Brüning, T., Koch, H.M., 2019. Urinary metabolites of the UV filter 2-Ethylhexyl salicylate as biomarkers of exposure in humans. Toxicol Lett 309, 35-41, https://doi.org/10.1016/j.toxlet.2019.04.001.

Ethoxyquin

Stoeckelhuber, M., Scherer, M., Bracher, F., Peschel, O., Leibold, E., Scherer, G., Pluym, N., 2020. Development of a human biomonitoring method for assessing the exposure to ethoxyquin in the general population. Arch Toxicol 94, 12, 4209-4217, https://doi.org/10.1007/s00204-020-02871-7.

Geraniol

Jäger, T., Bäcker, S., Brodbeck, T., Bader, M., Scherer, G., Stöckelhuber, M., Göen, T., Hartwig, A., Geraniol–Determination of 8‑carboxy‑geraniol, Hildebrandt acid, geranic acid, and 3‑hydroxycitronellic acid in urine by UPLC‑MS/MS. https://doi.org/10.34865/bi10624e6_3or.

Jäger, T., Bäcker, S., Brodbeck, T., Leibold, E., Bader, M., 2020. Quantitative determination of urinary metabolites of geraniol by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Analytical Methods 12, 47, 5718-5728, https://doi.org/10.1039/D0AY01582B.

Pluym, N., Stockelhuber, M., Weber, T., Scherer, G., Scherer, M., Kolossa-Gehring, M., 2022. Time trend of the exposure to geraniol in 24-h urine samples derived from the German Environmental Specimen Bank from 2004 to 2018. Int J Hyg Environ Health 239, 113880, https://doi.org/10.1016/j.ijheh.2021.113880.

HBCDD

Leng, G., Gries, W., 2017. New specific and sensitive biomonitoring methods for chemicals of emerging health relevance. Int J Hyg Environ Health 220, 2 Pt A, 113-122, https://doi.org/10.1016/j.ijheh.2016.09.014.

Homosalate

Ebert, K.E., Belov, V.N., Weiss, T., Brüning, T., Hayen, H., Koch, H.M., Bury, D., 2021. Determination of urinary metabolites of the UV filter homosalate by online-SPE-LC-MS/MS. Anal Chim Acta 1176, 338754, https://doi.org/10.1016/j.aca.2021.338754.

Lysmeral, Lilial

Murawski, A., Fiedler, N., Schmied-Tobies, M.I.H., Rucic, E., Schwedler, G., Stoeckelhuber, M., Scherer, G., Pluym, N., Scherer, M., Kolossa-Gehring, M., 2020. Metabolites of the fragrance 2-(4-tert-butylbenzyl)propionaldehyde (lysmeral) in urine of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V). Int J Hyg Environ Health 229, 113594, https://doi.org/10.1016/j.ijheh.2020.113594.

Pluym, N., Krnac, D., Gilch, G., Scherer, M., Leibold, E., Scherer, G., 2016. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the human biomonitoring of non-occupational exposure to the fragrance 2-(4-tert-butylbenzyl)propionaldehyde (lysmeral). Anal Bioanal Chem 408, 21, 5873-5882, https://doi.org/10.1007/s00216-016-9702-x.

Scherer, M., Koch, H.M., Schütze, A., Pluym, N., Krnac, D., Gilch, G., Leibold, E., Scherer, G., 2017. Human metabolism and excretion kinetics of the fragrance lysmeral after a single oral dosage. Int J Hyg Environ Health 220, 2 Pt A, 123-129, https://doi.org/10.1016/j.ijheh.2016.09.005.

Scherer, M., Petreanu, W., Weber, T., Scherer, G., Pluym, N., Kolossa-Gehring, M., 2021. Human biomonitoring in urine samples from the Environmental Specimen Bank reveals a decreasing trend over time in the exposure to the fragrance chemical lysmeral from 2000 to 2018. Chemosphere 265, 128955, https://doi.org/10.1016/j.chemosphere.2020.128955.

MDI

Gries, W., Leng, G., 2013. Analytical determination of specific 4,4'-methylene diphenyl diisocyanate hemoglobin adducts in human blood. Anal Bioanal Chem 405, 23, 7205-7213, https://doi.org/10.1007/s00216-013-7171-z.

Leng, G., Gries, W., 2017. New specific and sensitive biomonitoring methods for chemicals of emerging health relevance. Int J Hyg Environ Health 220, 2 Pt A, 113-122, https://doi.org/10.1016/j.ijheh.2016.09.014.

NMP/NEP

Koch, H.M., Bader, M., Weiss, T., Koslitz, S., Schütze, A., Kafferlein, H.U., Brüning, T., 2014. Metabolism and elimination of N-ethyl-2-pyrrolidone (NEP) in human males after oral dosage. Arch Toxicol 88, 4, 893-899, https://doi.org/10.1007/s00204-013-1150-1.

Schmied-Tobies, M.I.H., Murawski, A., Rucic, E., Schwedler, G., Bury, D., Kasper-Sonnenberg, M., Koslitz, S., Koch, H.M., Brüning, T., Kolossa-Gehring, M., 2021. Alkyl pyrrolidone solvents N-methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP) in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey 2014-2017 (GerESV). Environ Int 146, 106221, https://doi.org/10.1016/j.envint.2020.106221.

Ulrich, N., Bury, D., Koch, H.M., Rüther, M., Weber, T., Kafferlein, H.U., Weiss, T., Brüning, T., Kolossa-Gehring, M., 2018. Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014. Int Arch Occup Environ Health 91, 8, 1073-1082, https://doi.org/10.1007/s00420-018-1347-y.

Octocrylene

Bury, D., Belov, V.N., Qi, Y., Hayen, H., Volmer, D.A., Brüning, T., Koch, H.M., 2018. Determination of Urinary Metabolites of the Emerging UV Filter Octocrylene by Online-SPE-LC-MS/MS. Anal Chem 90, 1, 944-951, https://doi.org/10.1021/acs.analchem.7b03996.

Bury, D., Modick-Biermann, H., Leibold, E., Brüning, T., Koch, H.M., 2019. Urinary metabolites of the UV filter octocrylene in humans as biomarkers of exposure. Arch Toxicol 93, 5, 1227-1238, https://doi.org/10.1007/s00204-019-02408-7.

Phenoxyethanol

Jäger, T., Eckert, E., Leibold, E., Bader, M., 2022. Reliable determination of the main metabolites of 2-phenoxyethanol in human blood and urine using LC-MS/MS analysis. Anal Methods, https://doi.org/10.1039/d2ay01407f.

TDCPP

Krystek, P., Beeltje, H., Noteboom, M., van den Hoeven, E.M., Houtzager, M.M.G., 2019. Analytical human biomonitoring method for the identification and quantification of the metabolite BDCPP originated from the organophosphate flame retardant TDCPP in urine. J Pharm Biomed Anal 170, 169-175, https://doi.org/10.1016/j.jpba.2019.03.036.

TOTM, TEHTM

Höllerer, C., Becker, G., Göen, T., Eckert, E., 2018. Human metabolism and kinetics of tri-(2-ethylhexyl) trimellitate (TEHTM) after oral administration. Arch Toxicol 92, 9, 2793-2807, https://doi.org/10.1007/s00204-018-2264-2.

Höllerer, C., Becker, G., Göen, T., Eckert, E., 2018. Regioselective ester cleavage of di-(2-ethylhexyl) trimellitates by porcine liver esterase. Toxicol In Vitro 47, 178-185, https://doi.org/10.1016/j.tiv.2017.11.015.

Höllerer, C., Göen, T., Eckert, E., 2018. Comprehensive monitoring of specific metabolites of tri-(2-ethylhexyl) trimellitate (TEHTM) in urine by column-switching liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 410, 18, 4343-4357, https://doi.org/10.1007/s00216-018-1086-7.

Höllerer, C., Müller, J., Göen, T., Eckert, E., 2017. Isomeric separation and quantitation of di-(2-ethylhexyl) trimellitates and mono-(2-ethylhexyl) trimellitates in blood by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 1061-1062, 153-162, https://doi.org/10.1016/j.jchromb.2017.07.014.

Kuhlmann, L., Göen, T., Eckert, E., 2021. Sensitive monitoring of the main metabolites of tri-(2-ethylhexyl) trimellitate (TOTM) in urine by coupling of on-line SPE, UHPLC and tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 1171, 122618, https://doi.org/10.1016/j.jchromb.2021.122618.

Murawski, A., Schmied-Tobies, M.I.H., Rucic, E., Schmidtkunz, C., Küpper, K., Leng, G., Eckert, E., Kuhlmann, L., Göen, T., Daniels, A., Schwedler, G., Kolossa-Gehring, M., 2021. Metabolites of 4-methylbenzylidene camphor (4-MBC), butylated hydroxytoluene (BHT), and tris(2-ethylhexyl) trimellitate (TOTM) in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey GerES V (2014-2017). Environ Res 192, 110345, https://doi.org/10.1016/j.envres.2020.110345.

UV 327

Fischer, C., Göen, T., 2021. Determination of UV-327 and its metabolites in human urine using dispersive liquid-liquid microextraction and gas chromatography-tandem mass spectrometry. Anal Methods 13, 35, 3978-3986, https://doi.org/10.1039/d1ay00932j.

Fischer, C., Göen, T., 2022. Development and Validation of a DLLME–GC–MS/MS Method for the Determination of Benzotriazole UV Stabilizer UV-327 and Its Metabolites in Human Blood. Journal of Analytical Toxicology, https://doi.org/10.1007/s00204-022-03401-3.

Fischer, C., Leibold, E., Göen, T., 2020. Identification of in vitro phase I metabolites of benzotriazole UV stabilizer UV-327 using HPLC coupled with mass spectrometry. Toxicol In Vitro 68, 104932, https://doi.org/10.1016/j.tiv.2020.104932.

Fischer, C., Leibold, E., Hiller, J., Göen, T., 2022. Human metabolism and excretion kinetics of benzotriazole UV stabilizer UV-327 after single oral administration. Arch Toxicol, https://doi.org/10.1007/s00204-022-03401-3.

UV 328 (Tinuvin 328)

Denghel, H., Göen, T., 2020. Determination of the UV absorber 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328) and its oxidative metabolites in human urine by dispersive liquid-liquid microextraction and GC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 1144, 122071, https://doi.org/10.1016/j.jchromb.2020.122071.

Denghel, H., Göen, T., 2021. Dispersive liquid-liquid microextraction (DLLME) and external real matrix calibration for the determination of the UV absorber 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328) and its metabolites in human blood. Talanta 223, Pt 1, 121699, https://doi.org/10.1016/j.talanta.2020.121699.

Denghel, H., Hiller, J., Leibold, E., Göen, T., 2021. Human metabolism and kinetics of the UV absorber 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328) after oral administration. Arch Toxicol 95, 8, 2677-2690, https://doi.org/10.1007/s00204-021-03093-1.

Denghel, H., Leibold, E., Göen, T., 2019. Oxidative phase I metabolism of the UV absorber 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328) in an in vitro model with human liver microsomes. Toxicol In Vitro 60, 313-322, https://doi.org/10.1016/j.tiv.2019.06.012.

Uvinul A Plus

Stoeckelhuber, M., Pluym, N., Bracher, F., Leibold, E., Scherer, G., Scherer, M., 2019. A validated UPLC-MS/MS method for the determination of urinary metabolites of Uvinul(R) A plus. Anal Bioanal Chem 411, 30, 8143-8152, https://doi.org/10.1007/s00216-019-02201-6.

Stoeckelhuber, M., Scherer, M., Peschel, O., Leibold, E., Bracher, F., Scherer, G., Pluym, N., 2020. Human metabolism and urinary excretion kinetics of the UV filter Uvinul A plus(R) after a single oral or dermal dosage. Int J Hyg Environ Health 227, 113509, https://doi.org/10.1016/j.ijheh.2020.113509.