Cooperation for the promotion of human biomonitoring
The German Environment Agency supports the cooperation on human biomonitoring between the Federal Ministry for the Environment and the German chemical industrial association (VCI). The cooperation is significant for the development of new analytical methods to enable the detection of chemicals in urine or blood samples to which the population may have increased exposure or which are of special rel
The German Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) and the German Chemical Industry Association (VCI) initiated collaboration in 2010 to provide funding for human biomonitoring (HBM). The main objectives of the cooperation are to improve the knowledge about newer chemicals to which the population might be increasingly exposed or which might have an effect on health, and to develop methods which can detect the smallest concentrations of these substances. The aim is not primarily to determine the occurrence of these substances in population groups with higher workplace exposure – which can be quite significant – but rather to develop methods which can also detect very low concentrations in the urine or blood of the unexposed general public (known as background concentration). Plans for cooperation were originally made for 10 years. After a three-year pilot phase, the two partners gave a positive evaluation in 2013, which set the course for further cooperation as planned.
One of the main objectives of the cooperation between the BMUB and the VCI is to select up to 50 substances within ten years (substance prioritisation) which meet the criteria of consumer relevance, special relevance to health, or the fact that there is no specific HBM method available. This is where work begins on the development of specific methods of analysis and their application in suitable screening tests. The VCI is responsible for the development of methods, and the German Environment Agency (UBA) supports the Federal Environment Ministry (BMUB) in the application of the methods in the tests. UBA provides administration and management of the cooperation.
Committees and members
The BMUB and the VCI cooperate in two committees: the HBM Expert Group and the Steering Committee.
The members of the HBM expert group have backgrounds in chemical-analytical science, expertise in toxicology and/or environmental medicine and work for the Federal Environment Ministry (BMUB), the higher federal authorities "Federal Institute for Risk Assessment (BfR)", "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 contingent upon recommendation and approval by both cooperation partners; membership is personal rather than institutional. The members of the Steering Committee are representatives from the BMUB, UBA and VCI (or its membership organisations).
Selection of substances and method development
The HBM Expert Group convenes at the beginning and in autumn of every year to select the substances for which methods are to be developed and to discuss the individual critical steps of this development.
The BMUB commissioned the BfR in 2010 to draw up a list of some 120 substances which might be relevant for the cooperation. The list was based on lists compiled by different international organisations (e.g. the list of CMR (carcinogenic, mutagenic, reprotoxic) substances, 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 basic criteria for selection of substances from the available lists were:
Good to very good bioavailability of the substances / mutagenic carcinogens
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)
Researching the uses and likelihood of consumer exposure, e.g. in the SPIN database
Exclusion of substances with low likelihood of exposure (no consumer relevance)
The HBM expert group’s first discussion on appropriate substances was based on the list which was drawn up. Subsequent meetings have focused on a regular review of international chemical lists. Recommendations of the participating institutions to take up new substances are heard, and toxicological fact sheets are used to determine the substance’s appropriateness for the cooperative project.
Regular items on the agenda of the HBM Expert Group discussion include: aspects of substance toxicity (health relevance), 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 cases where an HBM method used in the occupational safety field exists (MAK Collection), the expert group discusses the biomarkers used, possible detection and determination limits and/or the need for an additional metabolism study. The decision-making process increasingly weighs whether the available information from human, animal and cell culture tests enable the HBM Commission to derive an assessment (HBM) value.
The results of the HBM Expert Group’s discussion generate a list of proposed substances, which features about ten chemicals every year and for which there was sufficient data available to classify them as eligible for the cooperation project.
The list of proposed substances from the HBM Expert Group is submitted to the Steering Committee for its annual spring meeting. The Steering Committee selects up to 5 substances per year for which the cooperative partners are to develop HBM methods. Consideration is given to whether the VCI is able to find industrial sponsors for the substance whose expertise is required for the effective development of analysis methods.
26 substances have been selected since the start of the BMUB and the VCI cooperation on the development of human biomonitoring (HBM) methods; they include phthalates and phthalate substitutes (plasticisers), flame retardants, cosmetics additives (UV filters, fragrances) and allergenic substances (food or cosmetics preservatives). The development of a method for three additional substances (cyclosiloxanes) was discontinued due to difficulties of analysis (high background concentrations).
The BMUB/VCI cooperation has developed the first ever analytical methods for the determination of non-measurable substance quantities (at least at such low concentrations) in urine and blood samples.
These include a method for the analysis of metabolites of the relatively new phthalate DPHP and the phthalate substitute DINCH. Both of these plasticisers are increasingly used to replace the now banned DEHP (Di-(2-ethylhexyl)phthalate) in different fields of application. 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. Methods to measure the following have been developed for: 2-MBT (2-mercaptobenzothiazole), which is used as a vulcanisation accelerator in the production of household rubber products and tyres; Lysmeral, an additive frequently used in cosmetics and cleaning products and detergents.
Once a method has been developed by an internationally renowned laboratory commissioned by the VCI, the method is presented in peer reviewed journals and is often also presented at specialist conferences, whereby the method becomes publicly available. The Working Group "Analyses in Biological Material" (AibM) of the Deutsche Forschungsgemeinschaft carries out an independent verification of the method for quality assurance. Since the laboratories work on a voluntary basis for this procedure, the process can in fact take several years.
The AibM has completed validation for DINCH, thus making the method available for application as standard worldwide.
Application of the new methods/publications
The first application of the methods in population surveys occurs through the German Environment Agency in the analysis of human samples in the Environmental Specimen Bank or samples taken for the German Environmental Survey (GerES).
Bury D, Belov V, Qi Y, Hayen H, Volmer DA, Brüning T, Koch HM. Determination of urinary metabolites of the emerging UV filter Octocrylene by online-SPE-LC-MS/MS. Anal Chem 90(1):944-951 (2018). http://dx.doi.org/10.1021/acs.analchem.7b03996
Höllerer C, Becker G, Göen T, Eckert E. Regioselective ester cleavage of di-(2-ethylhexyl) trimellitates by porcine liver esterase. Toxicology In Vitro, March 2018; 47:178-185. https://doi.org/10.1016/j.tiv.2017.11.015
Höllerer C, Müller J, Göen T, Eckert E. Isomeric separation and quantitation of di-(2-ethylhexyl) trimellitates and mono-(2-ethylhexyl) trimellitates in blood by LC–MS/MS. Journal Of Chromatography B 1 September 2017; Volumes 1061-1062:153-162. https://doi.org/10.1016/j.jchromb.2017.07.014
Lessmann F, Schütze A, Weiss T, Brüning T, Koch HM. Determination of metabolites of di(2-ethylhexyl) terephthalate (DEHTP) in human urine by HPLC-MS/MS with on-line clean-up, Journal of Chromatography B, 2016, Volume 1011:196-203. http://dx.doi.org/10.1016/j.jchromb.2015.12.042
Schettgen T, Bertram J, Kraus T. Quantification of N-methylmalonamic acid in urine as metabolite of the biocides methylisothiazolinone and chloromethylisothiazolinone using gas chromatography-tandem mass spectrometry. Journal Of Chromatography B, Volumes 1044–1045, 15 February 2017, Pages 185-193. https://doi.org/10.1016/j.jchromb.2017.01.019
Schettgen T, Kraus T. Urinary excretion kinetics of the metabolite N-methylmalonamic acid (NMMA) after oral dosage of chloromethylisothiazolinone and methylisothiazolinone in human volunteers. Archives of Toxicology. December 2017, Volume 91, Issue 12, pp 3835–3841. http://dx.doi.org/10.1007/s00204-017-2051-5
Stoeckelhuber M, Krnac D, Pluym N, Scherer M, Leibold E, Scherer G. A validated UPLC–MS/MS method for biomonitoring the exposure to the fragrance 7-hydroxycitronellal. Journal Of Chromatography B 15 November 2017;Volumes 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. Human metabolism and excretion kinetics of the fragrance 7-hydroxycitronellal after a single oral or dermal dosage. International Journal Of Hygiene And Environmental Health 221, 2018, 239-245 https://doi.org/10.1016/j.ijheh.2017.10.015
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