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Human biomonitoring (HBM) data is a very useful metric for assessing human's exposures to chemicals in commerce. To assess the potential health risks associated with the presence of chemicals in blood, urine or other biological matrix requires HBM assessment values. While HBM assessment values based on human exposure-response data remain the most highly valuable and interpretable assessment values, enough data exists for such values for very few chemicals. As a consequence, efforts have been undertaken to derive HBM assessment values in which external dose based guidance values such as tolerable daily intakes have been translated into equivalent biomonitoring levels. The development of HBM values by the German HBM Commission and Biomonitoring Equivalents by Summit Toxicology has resulted in conceptually similar assessment values. The review of the development of these values provided here demonstrates examples and approaches that can be used to broaden the range of chemicals for which such assessment values can be derived. Efforts to date have resulted in the publication of HBM assessment values for more than 80 chemicals, and now provide tools that can be used for the evaluation of HBM data across chemicals and populations.

Haemoglobin adducts are highly valuable biomarkers of cumulative exposure to carcinogenic substances. We have developed and applied an analytical method for the simultaneous quantification of five haemoglobin adducts of important occupational and environmental carcinogens. The N-terminal adducts were determined with gas chromatography as pentafluorophenylthiohydantoine derivatives according to the modified Edman-procedure and subsequent acetonization of the glycidamide adduct N-(R,S)-2-hydroxy-2-carbamoylethylvaline (GAVal). The use of self-synthesized labelled internal standards in combination with tandem mass spectrometry using negative chemical ionisation guarantees both high accuracy and sensitivity of our determination. The limit of detection for N-2-hydroxyethylvaline (HEVal), N-(R,S)-2-hydroxypropylvaline (HPVal), N-2-carbamoylethylvaline (AAVal) and N-(R,S)-2-hydroxy-2-carbamoylethylvaline (GAVal) was 2 pmol/g globin, for N-2-cyanoethylvaline (CEVal) it was determined as 0.5 pmol/g globin, which was sufficient to determine the background levels of these adducts in the non-smoking general population. The between-day-precision for all analytes using a human blood sample as quality control material ranged from 4.7 to 12.3%. We investigated blood samples of a small group (n = 104) of non-smoking persons of the general population for the background levels of these haemoglobin adducts. The median values for HEVal, HPVal, CEVal, AAVal and GAVal in a group of 92 non-smoking persons were 18.1, 4.1

The creatinine correction approach has been used to estimate daily intake for contaminants whose primary route of elimination is through urine. This method is challenged using the phthalate di-2-ethylhexyl phthalate (DEHP) as an example. An alternate prediction approach based on human experimental metabolism and urinary excretion data on DEHP was developed. This alternate model was developed from urine measurements of four metabolites of DEHP from two individuals partaking in different experiments, for up to 44 h after known exposures. Particular attention was paid to the changing ratios of the metabolites over time: they took a certain form when exposure was in the "near" (the past few hours) versus the "distant" (24 h or more) past. The creatinine correction approach was applied to measurements of the same four metabolites from 18 individuals in the National Health And Nutrition Evaluation Survey (NHANES) 2003/2004. The alternate model was also applied to these individuals, and the results were compared. Predictions using the two methods were similar or the creatinine correction predicted higher concentrations when the ratio suggested that the DEHP exposure was "near" in time, but the alternate approach predicted intakes that were an order of magnitude higher when the ratios suggested that the intake was "distant". As much as 25% of all NHANES measurements contain metabolites whose key ratio suggest that exposure was "distant". Uncertainties notwithstanding, the analysis in this article suggests that the creatinine correction approach should be used cautiously for DEHP and possibly other contaminants with similar exposure characteristics: rapid metabolism with metabolite urine elimination half-lives on the order of hours, and exposure patterns that may not be continuous and ongoing.

The fetus is considered to be the most sensitive stage of life to the potential developmental and reproductive toxicity of the phthalates. But, data on human fetal exposure to phthalates is still scarce. In this pilot study we collected 11 pairs of amniotic fluid (AF) and corresponding maternal urine (MU) samples during Caesarean section and analysed them for several phthalate metabolites by LC-MS/MS. In all AF samples, metabolites of di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), butylbenzyl phthalate (BBzP), di(2-ethylhexyl) phthalate (DEHP) were detectable. For the first time, we were able to detect also oxidative phthalate metabolites in AF, with two carboxy metabolites of DEHP showing the highest abundance. In the MU samples, the concentrations of the phthalate metabolites were generally much higher than in the AF samples. There was a statistically significant linear correlation for the DiBP monoester (MiBP) (r=0.93; p

The Integrated Exposure Assessment Survey (INES) was started in the year 2005. Altogether 50 healthy adults living in Bavaria, Germany, were included into the study. Monitoring was conducted in accordance with relevant routes of human exposure (inhalation, ingestion) and integrated different pathways (indoor air, food, house dust). This approach consisted of a combination of external measurements of contaminants with the determination of these substances, or their metabolites in body fluids. The target substances were phthalates, perfluorinated compounds (PFC), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), and polybrominated diphenylethers (PBDEs). This paper gives a brief description of the objectives and the concept of INES as well as methods of sampling and analyses of target compounds. Some preliminary results of biomonitoring data for PFC and phthalates as well as of the dietary intake of DEHP will be discussed.

In der Pilotstudie des Kinder-Umwelt-Surveys (KUS) wurden die Urine von 2- bis 17-jahrigen Kindern aus vier Orten in Deutschland auf ihre Gehalte an Organophosphat- und Pyrethroidmetaboliten untersucht (N = 396 bzw. 363). Die 95. Perzentile der Gehalte der Pyrethroidmetabolite betrugen Cis-Cl2CA 0,74 μg/l, trans-Cl2CA 1,7 μg/l, Br2CA 0,52 μg/l, F-PBA

© 2014 Elsevier Inc. All rights reserved., In 2011 and 2012,the COPHES/DEMOCOPHES twin projects performedt he first ever harmonized human biomonitoring survey in 17 European countries.In more than 1800 mother–child pairs,individual lifestyle data were collected and cadmium,cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples.While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures,the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle.In general,13 countries having implemented DEMOCOPHES provided high quality data from external sources that were relevant for interpretation purposes.However,some data were not available for reporting or were not in line with predefined specifications. Therefore,only part of the external information could be included in the statistical analyses. Nonetheless,there was a highly significant correlation between national levels of fish consumption and mercury in hair,the strength of antismoking legislation was significantly related to urinary cotinine levels,and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality.These results again show the potential of biomonitoring data to provide added value for(the evaluation of)evidence-informed policy making., The European Commission,Belgium,DG for Research and Innovation(RTD),who is funding COPHES in the 7th Framework Programme(No.244237).DEMOCOPHES(LIFE09ENV/BE/000410)received 50% funding through the LIFE+ financial instrument of the European Union(DGENV),as well as 50% through funding received from the DEMOCOPHES partners.

Perfluorinated compounds (PFCs) are a large group of chemicals produced for several decades and widely used for many industrial and consumer applications. Because of their global occurrence in different environmental media, their persistence, and their potential to bioaccumulate in organisms they are of toxicological and public concern.In the present study, the internal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in 356 human plasma samples collected from an adult population in Germany in 2005 is quantified.We were able to detect the target analytes in all plasma samples and observed a significant correlation between the PFOS and PFOA concentrations. In female participants, the levels of PFOS and PFOA ranged between 2.5-30.7 (median: 10.9 microg/l) and 1.5-16.2 microg/l (median: 4.8 microg/l), respectively. In males we observed concentrations from 2.1 to 55.0 microg/l (median: 13.7 microg/l) for PFOS and from 0.5 to 19.1 microg/l (median: 5.7 microg/l) for PFOA. A significant correlation between both PFOS and PFOA concentrations and gender was observed. We also found increased levels of the PFCs with increasing age of the participants, but this association reached statistical significance among females only.Our data agree well with results of other recent studies in Europe and suggest that the current exposure of the adult German population is lower than the exposure of the US and Canadian population. The sources of human exposure are currently not well understood. Toxicological implications are restricted to animal studies and occupational investigations not adequate for quantitative risk assessment in humans. Overall, more scientific research is necessary to characterize the body burden of PFCs (especially for relevant subsets of the population) and the main sources and routes, which are responsible for human exposure and possible health implications of these compounds.

BACKGROUND: Despite a decline of 70 to 90 % during the past 20 years, many presumed carcinogenic and teratogenic organochlorine compounds (OC) are still present in our biosphere and accumulate in our food-chain. They are prenatally transmitted from mother to fetus, and mother's milk due to its high lipid content is an elimination pathway of special importance in all mammals. It was the aim of the present study to investigate whether breast-feeding increases the body pollution of human infants with OC during the first six months of life. METHODS: The study was approved by the committee on Biomedical Research of the Heinrich Heine University Dusseldorf, Germany. With written informed consent of the parents, blood samples were taken from 10 breast-fed and bottle-fed infants at the age of six weeks and six months, respectively. Three higher chlorinated PCB (polychlorinated biphenyls) congeners (IUPAC nos. 138, 153, and 180), HCB, and DDE, the main metabolite of DDT in mammals, were analyzed with capillary gas chromatography with electron capture detection. Reliability was tested with gas chromatography-mass spectrometry. Furthermore, the sum of the three higher chlorinated biphenyls (SigmaPCB) was calculated. RESULTS: There were no differences between the study groups of breast-fed and bottle-fed infants with regard to sex distribution, gestational age, birth weight, age of the mothers, and smoking behavior of the parents. However, serum concentrations of all OC were significantly higher (p < 0.0001) in breast-fed than in bottle-fed infants as early as at six weeks of age, and their concentrations nearly doubled until the age of six months (median [microg/L]; A = six weeks; B = six months): PCB 138, A: 0.40 vs. 0.09; B: 0.72 vs. 0.07; PCB 153, A: 0.57 vs. 0.11; B: 0.99 vs. 0.09; PCB 180, A: 0.33 vs. 0.04; B: 0.58 vs. 0.02; Sigma PCB, A: 1.19 vs. 0.29; B: 2.28 vs. 0.18; HCB, A: 0.13 vs. 0.04; B: 0.43 vs. 0.07; DDE, A: 1.05 vs. 0.18 ; B: 1.90 vs. 0.19. DISCUSSION: Breast-feeding significantly increases the serum concentration of our infants with different OC within the first six months of life, which leads to a body burden with OC, in this amount last measured in the mid-1980 s in Germany. In face of these results, common recommendations for breast-feeding should be reconsidered, taken into account the availability of infants formula (industrial vs. Third World countries).

Background: Polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) are ubiquitous compounds with carcinogenic and teratogenic properties. They are chemically very stable and lipophilic and, therefore, accumulate in our food-chain. They are prenatally transmitted from mother to foetus, and mother's milk due to its high lipid content is an elimination pathway of special importance. Therefore, breast-feeding has been held responsible for elevated concentrations of these organochlorine compounds as well as for harmful effects in children later in life. Methods: Blood samples (2.5 ml) were taken from each 10 breast-fed and bottle-fed infants at 6 weeks of age. Blood specimens were immediately centrifuged, and serum was stored in glass tubes at −20 °C until analysis. Three higher chlorinated PCB congeners (IUPAC nos. 138, 153 and 180), HCB, and the organic metabolite of DDT, p,p≪-DDE, were analysed with capillary gas chromatography with electron capture detection. Reliability was tested with gas chromatography-mass spectrometry. Results: There were no differences between the study groups of breast-fed and bottle-fed infants with regard to sex distribution, gestational age, birth-weight, age of the mothers, and smoking behaviour of the parents. In contrast, serum concentrations of all organochlorine compounds were significantly higher (P

Polychlorinated biphenyls (PCB) were manufactured between 1929 and 1989. Due to their great chemical persistence, these substances have been used for many different purposes. These chemical properties, however, caused PCBto accumulate in the food chain and resulted in background exposure of the general population. PCB has also been used as plasticizer for sealants in prefabricated buildings, thus causing problems to the present date. At the end of the 90ies in a school in Nuremberg, Germany, elevated PCB concentrations were measured in indoor air. Some of these results were higher than 3,000 ng/m 3 which means decontamination according to the German "PCB directive". Press coverage made these results a matter of public debate, so that teachers, school children and parents were highly worried because of possible health effects. The Bavarian Minister for Health, Nutrition and Consumer Protection asked us to examine school children and teachers with regard to their internal PCB exposure and health complaints. A group of school children from a non-contaminated school served as controls. For the determination of PCB levels the plasma samples were blinded before analysis. Lower chlorinated PCB (PCB 28, 52, 101) were detected more often and in higher concentrations in plasma samples of school children of the contaminated school compared to the controls. The plasma levels of the higher chlorinated PCBs (PCB 138, 153, 180) did not show similar differences between exposed and non-exposed school children. The relative PCB doses additionally taken up in the contaminated school were less then 5% of the background exposure of the children. That is why it could finally be concluded that no appreciable additional health risk may result from inhalation of PCB contaminated indoor air in this school. Due to the design, performance and interpretation of this study, including representatives of parents and teachers, these results were widely accepted by most of the parents who initially had been very concerned about possible health effects.

The aims of this study were to determine external and internal polycyclic aromatic hydrocarbon (PAH) exposure in a coke plant and to contribute to the evaluation of biological limit values.Personal air sampling was carried out on a study population of 24 coke plant workers. In detail, 16 PAHs were determined, among them phenanthrene, pyrene and benzo[ a]pyrene. For the determination of internal exposure, post-shift urine samples from the workers were examined for hydroxylated metabolites of pyrene (1-hydroxypyrene, 1-OHP) and phenanthrene (1-, 2+9-, 3-, 4-hydroxyphenanthrene, 1-, 2+9-, 3-, 4-OHPhe). In both cases, approved HPLC methods were used.The workers were classified into three groups. The group most exposed was that on the top side of the coke oven, with a mean value of 491.2 microg/m(3) for the sum of all sixteen PAHs. The mean value at the bench side was 26.61 microg/m(3), while it was 76.18 microg/m(3) in the group of workers with no dedicated location (=complete area). Both the excretion of 1-OHP and the sum of hydroxyphenanthrenes had the highest mean levels in the top side group of workers (mean: 19.70 microg/g creatinine (crea.) and 39.18 microg/g crea.), followed by the bench-side workers (mean: 7.01 microg/g crea. and 12.95 microg/g crea.) and the whole-area workers (mean: 3.57 microg/g crea. and 8.70 micorg/g crea.). The concentrations of all urinary metabolites correlated significantly with benzo[ a]pyrene (BaP) in the air.According to these correlations, urinary concentrations of 8 and 11 microg 1-OHP/g crea., respectively 16 and 23 microg/g crea. for the sum of hydroxyphenanthrenes, correspond to BaP concentrations in air of 2 and 5 micorg/m(3), the German technical guiding concentration (TRK value). Our results are in line with others reported in the literature. That means that it should be possible today to define a standard of occupational hygiene and medicine in coke plants using the elimination of hydroxyphenanthrenes and hydroxypyrene in urine as markers for internal PAH exposure.

© 2014 Elsevier Inc. All rights reserved., In 2004 the European Commission and Member States initiated activities towards a harmonized approach for Human Biomonitoring surveys throughout Europe. The main bjective was to sustain environmental health policy by building a coherent and sustainable framework and by increasing the comparability of data across countries. A pilot study to test common guidelines for setting up surveys was considered a key step in this process. Through a bottom-up approach that included all stakeholders, a joint study protocol was elaborated. From September 2011 till February 2012, 17 European countries collected data from 1844 mother–child pairs in the frame of DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES).1 Mercury in hair and urinary cadmium and cotinine were selected as biomarkers of exposure covered by sufficient analytical experience. Phthalate metabolites and Bisphenol A in urine were added to take into account increasing public and political awareness for emerging types of contaminants and to test less advanced markers/markers covered by less analytical experience. Extensive efforts towards chemo-analytical comparability were included. The pilot study showed that common approaches can be found in a context of considerable differences with respect to experience and expertize, socio-cultural background, economic situation and national priorities. It also evidenced that comparable Human Biomonitoring results can be obtained in such context. A European network was built, exchanging information, expertize and experiences, and providing training on all aspects of a survey. A key challenge was finding the right balance between a rigid structure allowing maximal comparability and a flexible approach increasing feasibility and capacity building. Next steps in European harmonization in Human Biomonitoring surveys include the establishment of a joint process for prioritization of substances to cover and biomarkers to develop, linking biomonitoring surveys with health examination surveys and with research, and coping with the diverse implementations of EU regulations and international guidelines with respect to ethics and privacy., Financial support: COPHES (COnsortium to Perform Human Biomonitoring on a European Scale) was funded by the Seventh EU Framework Programme 2007–2011 under grant agreement no [244237]. DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale) was co-funded (50%:50%) by the European Commission LIFE+ Programme (LIFE09/ENV/BE/000410) and the partners.

The most frequently used pesticide in U.S. homes, as well as in schools and day care centers, is chlorpyrifos. In 1998, this insecticide was detected in household dust from the former U.S. Forces housing estates in Frankfurt am Main, Germany, resulting from its earlier use up to 1993, i.e., at least 4 years ago. This led to great concern in the new inhabitants. To investigate their internal exposure to the substance, they were offered the opportunity of taking part in biomonitoring examinations. Children playing on the floor were assumed to be especially at risk due to increased exposure to chlorpyrifos via oral or dermal intake. A total of 1146 inhabitants took part in this voluntary investigation. All of them stated that they had never used chlorpyrifos in their homes. Spot urine samples of the study participants were analyzed for six metabolites of organophosphorous insecticides [dimethylphosphate (DMP), diethylphosphate (DEP), dimethylthiophosphate (DMTP), diethylthiophosphate (DETP), dimethyldithiophosphate (DMDTP), and diethyldithiophosphate (DEDTP)] using a very sensitive gas chromatographic method with mass-selective detection and a limit of detection of 1 microg/L. No evidence was found of increased internal exposure due to former chlorpyrifos application in these homes (4 years ago), either in children or in adults. The median values and 95th percentiles of the urinary metabolite concentrations in 484 adults were (microg/g creatinine): DMP, 15.5 and 102.5; DMTP, 13.5 and 125.8; DMDTP,1 and 13.1; DEP, 2.1 and 11.6; DETP,1 and 6.4; DEDTP, both1. The urinary metabolite concentrations in children6 years of age were higher; this was caused mainly by lower creatinine concentrations. To conclude, no increase in internal exposure due to former indoor application of chlorpyrifos could be found, and the reference values published for internal organophosphate exposure in adults in Germany were confirmed. However, as shown in other environmental studies, the urinary excretion of organophosphorous metabolites exceeds dietary intake several fold; this has been estimated from the data in various duplicate dietary studies. This observation calls for further investigation.

Pyrethroids are important insecticides used in agriculture, forestry, horticulture, and in the home. In humans, they are rapidly metabolized and renally eliminated. In numerous studies, pyrethroid metabolites have been detected in urine after occupational exposure to insecticides. In this study, we used a new, reliable, easy, and sensitive analytical method to assess the internal pyrethroid exposure of an urban population without exposure to pyrethoids at home or at work (children and adults). A total of 1,177 persons took part in this investigation, including 331 children under 6 years of age and 247 children between 6 and 12 years of age. None of them reported exposure to pyrethroids at home or at work. Accordingly, the levels of permethrin found in household dust from their homes were lower than expected (median < limit of detection; 95th percentile, 4.8 mg/kg; maximum value, 19 mg/kg). Urine specimens were analyzed for cis-3-(2,2-dibromo-vinyl)-2,2-dimethylcyclo-propanecarboxylic acid (Br(2)CA), cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-carboxylic acid (cis-Cl(2)CA and trans-Cl(2)CA), and 4-fluoro-3-phenoxybenzoic acid (F-PBA) using a gas chromatographic method with mass-selective detection. The limit of detection for pyrethroid metabolites was between 0.1 and 0.2 microg/L. trans-Cl(2)CA was detected in 65% of the urine specimens tested, cis-Cl(2)CA was detected in 30%, and Br(2)CA and F-PBA were found in 19% and 16%, respectively, of the urine specimens. The urinary metabolite levels in children did not differ from those in adults, and there was no correlation between the levels of metabolites and indoor exposure to permethrin in household dust. Moreover, no seasonal correlations could be found. The 95th percentile levels in urine specimens were as follows: Br(2)CA, 0.30 microg/L; cis-Cl(2)CA, 0.51 microg/L; trans-Cl(2)CA, 1.43 microg/L; F-PBA, 0.27 microg/L. Background exposure to pyrethroids was found in the general population; it seems to be caused by the uptake of pyrethroids with the diet. This hypothesis needs to be tested in duplicate diet studies combined with biomonitoring. As long as representative data are lacking, however, the rounded 95th percentile values obtained in our study may be used as reference values for pyrethroid metabolites in urine samples from the population in Germany; 95th percentile values for children and adults are as follows: Br(2)CA, 0.3 microg/L; cis-Cl(2)CA, 0.5 microg/L; trans-Cl(2)CA, 1.5 microg/L; and F-PBA, 0.3 microg/L.

This study was carried out to evaluate the internal exposure to polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDDs/PCDFs) of chimney sweeps in Bavaria compared to a control group without occupational exposure. The PCDD/PCDF concentrations in the blood fat of 227 chimney sweeps were compared with the concentrations in samples from 60 controls. Using an internal standard containing 17 (13)C(12)-labeled PCDD/F congeners, the samples were cleaned up after fat elution using standard methods. The statistical analysis was adjusted to account for demographic differences, dietary habits, smoking status, and both occupational and nonoccupational contact with chlorinated hydrocarbons. Detailed information on the type of heating in the households swept, the length of time the chimney sweeps had carried out the profession (min 34, med 195, max 466 months) and the protective measures employed, were used to examine the influence of the working conditions specific to chimney sweeps on the internal PCDD/PCDF exposure. The correlation between blood-fat PCB concentrations as well as urinary chlorophenol concentrations and the exposure to PCDDs/PCDFs was evaluated. The sum of PCDD/PCDF components in chimney sweeps, expressed by International Toxic Equivalents (I-TEQ), was significantly increased compared to the control group (median: 26.36 versus 20.75 pg I-TEQ/g blood fat). For 37 chimney sweeps (16.3%) the sum of PCDDs/PCDFs exceeded the 95th percentile of the control group, i.e., 38.23 pg I-TEQ/g blood fat. Multiple regression analysis revealed that in addition to occupation, the variables age, district, and proximity to a waste incineration plant seem to have an effect on the internal PCDD/PCDF exposure. An additional influence on the internal exposure could not be determined for any of the special aspects of the work. We identified no high correlations between the concentrations of PCBs and chlorophenols and PCDDs/PCDFs. This study revealed significantly higher internal exposure to PCDDs/PCDFs in chimney sweeps than in the control group. The differences are small and within the range of the internal exposure to PCDDs/PCDFs in blood found in the general population in Germany since 1989. Further investigations in to PCDD/PCDF-related diseases in these study groups were not carried out.

Ethylene oxide is an alkylating agent known to be a directly acting mutagen and carcinogen. This study describes the relationship between workplace ambient air concentrations of ethylene oxide and the concentration of N-2-hydroxyethylvaline in the globin of exposed workers.During the sterilization of medical equipment, 12 workers were occupationally exposed to ethylene oxide. Personal and stationary ambient air measurements were carried out to monitor the external exposure. The determination of the protein adducts was based on the N-alkyl-Edman method, introducing a new commercially available dipeptide standard for calibration purposes.Ethylene oxide concentrations ranging from 0.2 to 8.5 ppm were found in the workplace air. The adduct concentrations ranged from 5,219 to 32,738 pmol N-2-hydroxyethylvaline/g globin in the case of regularly exposed workers (n = 9) and from 518 to 3,321 pmol N-2-hydroxyethylvaline/g globin for three persons with occasional contact with ethylene oxide.The Deutsche Forschungsgemeinschaft established in 1993 a relationship between the ethylene oxide concentration in ambient air and the amount of N-2-hydroxyethylvaline in human globin. By extrapolation, constant exposure to 1 ppm ethylene oxide should yield approximately 4,000 pmol N-2-hydroxyethylvaline/g globin. The ambient air concentrations of ethylene oxide and the amount of N-2-hydroxyethylvaline determined within the present study confirm this extrapolation in practice. In addition, the determination of adducts based on the use of commercially available dipeptide standards for calibration purposes turned out to be an advantageous alternative to the commonly used protein standards.

Objective. Carbon disulphide (CS2) is highly neurotoxic. There is ample evidence of damage to the peripheral and central nervous system. The air concentration at which such adverse effects can first be observed is presently a subject of controversy. Methods. In a cross-sectional study of CS2-exposed workers from the viscose industry and healthy controls, data on neurological complaints, basic laboratory diagnosis, clinical neurological examination and neuropsychological testing were evaluated. Data were from 222 workers in the viscose industry exposed to CS2 and 191 employees from the same factory with similar physical and psychological stress factors but without occupational contact with neurotoxic substances. Multiple linear or multiple logistic regression analysis was used to check for statistical differences. Results. The median of the CS2-measurements using personal air sampling was below the current maximum concentration permissible (MAK value) in Germany (10 ppm) in all departments. The threshold limit value was, however, exceeded in almost 10% of the persons investigated. Exposure fluctuated between

Objective: An analytical method has been established to determine the concentration of antimony (Sb), bismuth (Bi), lead (Pb), cadmium (Cd), mercury (Hg), palladium (Pd), platinum (Pt), tellurium (Te), tin (Sn), thallium (Tl) and tungsten (W) in urine. The aim was to develop a method which is equally suitable for the determination of environmentally as well as occupationally caused metal excretion. Methods: Inductively coupled plasma-mass spectroscopy (ICP-MS) was used for the determination of metals. Calibration was done using aqueous solutions and standard addition respectively. Results: Urine samples of 14 persons occupationally non-exposed to metals were analysed. With the exception of Pt and Bi all the metals were found in these urine samples. The detection limits for these metals lie between 5 and 50 ng/l. Conclusions: For some metals, which are important from an occupational as well as an environmental viewpoint, ICP-MS is more sensitive than atomic absorption spectrometry (AAS). ICP-MS, moreover, is welcome as a reference method for AAS with the additional advantage of multi-element measurement.

A framework of "Common Criteria" (i.e. a series of questions) has been developed to inform the use and evaluation of biomonitoring data in the context of human exposure and risk assessment. The data-rich chemical benzene was selected for use in a case study to assess whether refinement of the Common Criteria framework was necessary, and to gain additional perspective on approaches for integrating biomonitoring data into a risk-based context. The available data for benzene satisfied most of the Common Criteria and allowed for a risk-based evaluation of the benzene biomonitoring data. In general, biomarker (blood benzene, urinary benzene and urinary S-phenylmercapturic acid) central tendency (i.e. mean, median and geometric mean) concentrations for non-smokers are at or below the predicted blood or urine concentrations that would correspond to exposure at the US Environmental Protection Agency reference concentration (30 µg/m(3)), but greater than blood or urine concentrations relating to the air concentration at the 1 × 10(-5) excess cancer risk (2.9 µg/m(3)). Smokers clearly have higher levels of benzene exposure, and biomarker levels of benzene for non-smokers are generally consistent with ambient air monitoring results. While some biomarkers of benzene are specific indicators of exposure, the interpretation of benzene biomonitoring levels in a health-risk context are complicated by issues associated with short half-lives and gaps in knowledge regarding the relationship between the biomarkers and subsequent toxic effects.

Ambient-air and biological monitoring of occupational xylene exposure were carried out on 2 groups of workers (13 and 10 men, respectively) exposed to a mixture of xylenes during the production of paints or during spraying. Methods: Personal ambient-air monitoring was performed for one complete work shift. Blood and urine samples were collected directly at the end of the shift. Biological monitoring was based on the determination of the concentration of xylenes in blood and on the quantification of the sum of the three methylhippuric acids in urine. Results: Average xylene ambient-air concentrations were 29 ppm (production) and 8 ppm (spraying), ranging from 5 to 58 ppm and from 3 to 21 ppm, respectively. The concentrations of xylenes in blood ranged from 63 to 715 μg/l and from 49 to 308 μg/l, with average values being 380 and 130 μg/l, respectively. Accordingly, the workers engaged in paint production also excreted more methylhippuric acids in their urine (average 1221 mg/l, range 194–2333 mg/l) than did the sprayers (average 485 mg/l, range 65–1633 mg/l). Discussion: Our results as well as a literature review indicate that occupational xylene exposure on average barely exceeds the threshold limit value of 100 ppm as proposed by both American and German institutions. Biological monitoring based on the determination of xylenes in blood and of methylhippuric acids in urine provides sufficient sensitivity and specificity for occupational health surveillance. The results also confirm the current limit values (BAT values) proposed by the Deutsche Forschungsgemeinschaft for xylenes in blood (1500 μg/l) and methylhippuric acids in urine (2000 mg/l).

The reported investigations on the uptake of carbon disulphide (CS 2 ) and the excretion of its metabolite 2-thiothiazolidine-4-carboxylic acid (TTCA) were based on results from 403 personal air samples (352 passive and 51 active samples) and 362 TTCA determinations in biological material measured during a field study on the adverse effects due to CS 2 exposure. The external exposure ranged from below the detection limit (0.2 ppm) to 66 ppm and the urinary TTCA excretion from below the detection limit (0.16 mg./1) to 33.4 mg/1. The excretion of TTCA in postshift urine related to creatinine and volume showed a linear correlation to the CS 2 air concentration. On the basis of these results the influence on the internal exposure of physical work load, dermal exposure and individual parameters (age, Brocaindex, disturbed skin barrier) was evaluated. Correlations between the TTCA values in the postshift urine and the individually measured CS 2 concentrations were carried out separately for individual departments and persons with and without indications of a disturbed skin barrier. In order to be able to judge the individual internal exposure related to external exposure, a personal quotient was formed from the TTCA level in the urine and the CS 2 air concentration measured on the same day (relative interal exposure RIE index = TTCA mg/g creatinine/CS 2 in ppm). On investigating interindividual differences, higher relative internal exposures were found in persons with a heavy physical work load and more intensive skin contact. It could be shown for a large group of persons exposed to CS 2 that a pathological skin condition leads to an increase in the dermal penetration rate of hazardous substances. By means of the RIE index it could be shown that the TTCA excretion related to the individual external exposure increases significantly with a decreasing Broca index, which must be taken into consideration with greatly overweight persons and exposures in the range of the currently valid threshold limit values. The interindividual differences in internal exposure found at the same ambient air concentration emphasize the importance of biological monitoring for individual health protection and the setting of biological threshold limit values

Published in the series Biomonitoring Methods, Vol. 10 (2006) The article contains sections titled: General principles Equipment, chemicals and solutions Equipment Chemicals Solutions Calibration standards Conditioning of the Isolute®-101 columns Specimen collection and sample preparation Sample preparation Operational parameters Operational parameters for gas chromatography and mass spectrometry Analytical determination Calibration Calculation of the analytical result Standardisation and quality control Evaluation of the method Precision Accuracy Detection limits Sources of error Discussion of the method Keywords: determination in urine; capillary gas chromatography; mass spectrometric detection; analysis in biological materials; occupational monitoring; analytical method; biomarker; metabolites

Published in the series Analyses of Hazardous Substances in Biological Materials, Vol. 8 (2003) The article contains sections titled: General principles Equipment, chemicals and solutions Equipment Chemicals Solutions Calibration standards Specimen collection and sample preparation Sample preparation Operational parameters Operational parameters for gas chromatography and mass spectrometry Analytical determination Calibration Calculation of the analytical result Standardisation and quality control Reliability of the method Precision Accuracy Detection limits Discussion of the method Keywords: determination in urine; capillary gas chromatography; mass spectrometric detection; analysis in biological materials; occupational monitoring; analytical method; biomarker; metabolites

Published in the series Analyses of Hazardous Substances in Biological Materials, Vol. 7 (2000) The article contains sections titled: General principles Equipment, chemicals and solutions Equipment Chemicals Solutions Calibration standard Specimen collection and sample preparation High-pressure digestion (HPA) UV digestion Operational parameters for adsorptive inverse voltammetry (DPP) Analytical determination Calibration Calculation of the analytical result Standardisation and quality control Reliability of the method Precision Accuracy Detection limit Sources of error Discussion of the method Keywords: determination in urine; adsorptive voltammetry; analysis in biological materials; occupational monitoring; analytical method; biomarker; metabolites

Published in the series Biomonitoring Methods, Vol. 12 (2010) The article contains sections titled: Introduction Pre-analytical phase Prevention of external contamination during sample collection Sampling time Sampling material Storage and transport of samples Sample documentation Stability of the chemicals, solutions and calibration standards used Selectivity Detection, identification and quantification limits Visual estimation Determination of the signal/background noise ratio Blank value procedure according to DIN 32 645 Calibration curve procedure according to DIN 32 645 Standard deviation procedure Example Calibration Selection of the calibration points One-point calibration Matrix effects Use of internal standards Linearity of the calibration function Example Precision Example Accuracy Reference material (CRM) Reference methods Inter-laboratory comparability investigations Spiking procedures Arithmetical determination of accuracy Factors influencing accuracy Comparability of methods Examples Measurement uncertainty Combined and extended measurement uncertainty Estimation of the measurement uncertainty Examples Quality assurance Internal quality assurance External quality assurance Summary Glossary Keywords: selectivity; detection limit; identification limit; quantification limit; calibration; precision; accuracy; measurement uncertainty; quality assurance; biological monitoring; occupational monitoring; environmental monitoring; biomonitoring; biomarker

Published in the series Biomonitoring Methods, Vol. 11 (2007) The article contains sections titled: General principles Equipment, chemicals and solutions Equipment Chemicals Solutions Calibration standards Specimen collection and sample preparation Sample preparation Operational parameters Operational parameters for high performance liquid chromatography Operational parameters for mass spectrometry Analytical determination Calibration Calculation of the analytical result Standardisation and quality control Evaluation of the method Precision Accuracy Detection limit Sources of error Discussion of the method Keywords: determination in urine; high performance liquid chromatography; tandem mass spectrometric detection; LC/MS/MS; analysis in biological materials; occupational monitoring; analytical method; biomarker; metabolites

Different parameters of biological monitoring were applied to 26 benzene-exposed car mechanics. Twenty car mechanics worked in a work environment with probably high benzene exposures (exposed workers); six car mechanics primarily involved in work organization were classified as non-exposed. The maximum air benzene concentration at the work places of exposed mechanics was 13 mg/m3 (mean 2.6 mg/m3). Elevated benzene exposure was associated with job tasks involving work on fuel injections, petrol tanks, cylinder blocks, gasoline pipes, fuel filters, fuel pumps and valves. The mean blood benzene level in the exposed workers was 3.3 micrograms/l (range 0.7-13.6 micrograms/l). Phenol proved to be an inadequate monitoring parameter within the exposure ranges investigated. The muconic and S-phenylmercapturic acid concentrations in urine showed a marked increase during the work shift. Both also showed significant correlations with benzene concentrations in air or in blood. The best correlations between the benzene air level and the mercapturic and muconic acid concentrations in urine were found at the end of the work shift (phenylmercapturic acid concentration: r = 0.81, P0.0001; muconic acid concentration: r = 0.54, P0.05). In conclusion, the concentrations of benzene in blood and mercapturic and muconic acid in urine proved to be good parameters for monitoring benzene exposure at the workplace even at benzene air levels below the current exposure limits. Today working as a car mechanic seems to be one of the occupations typically associated with benzene exposure.

Carbon disulphide (CS2), a reagent of rayon production, is known for its high toxic potential and has therefore been the subject of many clinical studies. The aims of the study presented here were to determine the effective exposure to CS2 and to compare the validity of the different exposure indicators. Internal and external exposure to CS2 was investigated in 362 male workers of a viscose factory. The CS2 air concentrations measured through stationary air monitoring in five different work areas (n = 39) were compared with the values of active personal air monitoring (n = 51) and passive personal air monitoring (n = 352). In addition, in all investigations biological monitoring was carried out by measuring the 2-thio-1,3- thiazolidine-carboxylic acid (TTCA) excretion in urine. A significant correlation was found between the data for active and passive personal air sampling (y = 0.99, x + 0.31, r = 0.968). The results of the stationary measurements led, however, to values which were systematically too low. The validity of TTCA excretion in urine as a parameter of biological monitoring could for the first time be verified in a large sample of subjects. There was a linear correlation between TTCA values in the urine related to both volume and creatinine [y (TTCAmg/g creatinine) = 0.315 x (ml CS2/m3 air) + 0.59] and the CS2 values in the air. Nevertheless, TTCA excretion proved to be dependent upon creatinine so that the excreted amounts related to creatinine described the individual exposure more exactly.

Human biomonitoring (HBM) is widely recognised as a useful tool to aid assessment of exposure to chemical substances, but our ability to detect hazardous substances (or their metabolites and health effects) often exceeds our understanding of their biological relevance. There are only a few established frameworks for developing and using occupational and environmental biological guidance values (BGVs), mostly for data-rich substances that have been in use for some time. BGVs for new substances and those with unknown dose–response relationships are difficult to derive. An accepted framework based on current scientific knowledge and best practice is therefore urgently needed to help scientists, regulators, and stakeholders to design appropriate HBM studies, interpret HBM data (both for groups and individuals) understand the limitations and to take appropriate action when required. The development and application of such a tool is described here. We derived a conceptual framework that was refined by consultation with an advisory group and workshop. The resulting framework comprised four levels defined by increasing data, with increasing confidence for human health risk assessment. Available data were used for 12 chemicals with expert judgement to illustrate the utility of the framework.

Background and Aims: In December 2009 the COnsortium to Perform Human Biomonitoring on a European Scale (COPHES) financed by FP7 EU, began work towards an EU HBM framework. This will be accompanied...

Human biomonitoring (HBM) can be an effective tool to assess human exposure to environmental pollutants and potential health effects and is increasingly seen as an essential element in a strategy when integrating health and environment. HBM can be used (i) to prioritise actions and measures for policy making; (ii) to evaluate policy actions aimed at reducing exposure to potentially hazardous environmental stressors; and (iii) to promote more comprehensive health impact assessments of policy options. In support of the European Environment and Health Action Plan 2004–2010, European scientists, experts from authorities and other stakeholders joined forces to work towards developing a functional framework and standards for a coherent HBM in Europe. Within the European coordination action on human biomonitoring , 35 partners from 27 European countries in the COPHES consortium aggregated their experiences and expertise and developed harmonized approaches and recommendations for better comparability of HBM data in Europe via the elaboration of a harmonized study protocol. This protocol is the product of discussion and compromises on the selection of environmental exposures, national environmental health concerns, and political and health priorities. The harmonised approach includes sampling recruitment, and analytical procedures, communication strategies and biobanking initiatives. The protocols and the harmonised approach are a means to increase acceptance and policy support and to in the future to enable determination of time trends. The common pilot study protocol will shortly be tested, adapted and assessed in the framework of the DEMOCOPHES in 17 European countries, including 16 EU Member States. COPHES and DEMOCOPHES constitute important steps towards establishing human biomonitoring as a tool for EU environmental and health policy and to improve quantification of exposure of the general European population to existing and emerging pollutants.

Human biomonitoring (HBM) can be an effective tool to assess human exposure to environmental pollutants and potential health effects and is increasingly seen as an essential element in a strategy aiming to integrate health and environment. In support of the European Environment and Health Action Plan, European scientists and other stakeholders within the European coordination action on human biomonitoring(COPHES/DEMOCOPHES) are working towards a functional framework and standards for a coherent HBM in Europe.The COPHES consortium, consisting of 35 partners from 27 European countries, aggregates experiences from existing HBM activities, and, taking into account discrepancies related to environmental exposures, national environmental health concerns, analytical capacities, and political and health priorities, developed harmonized approaches and recommendations for better comparability of HBM data in Europe via the elaboration of a harmonized study protocol. Approaches and recommendations comprise raising awareness, guidance on ethics and risk communication, a recruitment strategy, chemical analysis and quality assurance, data treatment, and statistical analysis.This common pilot study protocol will be tested, adapted and assessed in the framework of the DEMOCOPHES pilot study in 17 European countries, including 16 EU Member States.COPHES and DEMOCOPHES constitute important steps towards establishing human biomonitoring as a tool for EU environmental and health policy and to improve quantification of exposure of the general European population to existing and emerging pollutants. HBM can be used to determine reference values for exposure, to support policy making by, for example, evaluation of policy actions aimed at reducing exposure to potentially hazardous environmental stressors at a European level and to promote more comprehensive health impact assessments of policy options.

In order to assess potential risks of exposure to environmental chemicals, more information on concomitant exposure to different chemicals is needed. We present data on chemicals in human milk of a cohort study (2004, 2005, 2006) of 54 mother/child pairs, where for the first time, cosmetic UV filters, synthetic musks, parabens and phthalate metabolites were analyzed in the same sample along with persistent organochlor pollutants (POPs), i.e., organochlor pesticides and metabolites, polybrominated diphenylethers and polychlorinated biphenyls (PCBs). The two groups of chemicals exhibited different exposure patterns. Six out of seven PCB congeners and a majority of pesticides were present in all milk samples, with significant correlations between certain PCB congener and pesticide levels, whereas the cosmetic-derived compounds, UV filters, parabens and synthetic musks, exhibited a more variable exposure pattern with inter-individual differences. UV filters were present in 85.2% of milk samples, in the range of PCB levels. Comparison with a questionnaire revealed a significant correlation between use of products containing UV filters and their presence in milk for two frequently used and detected UV filters, 4-methylbenzylidene camphor and octocrylene, and for the whole group of UV filters. Concentrations of PCBs and organochlor pesticides were within ranges seen in Western and Southern European countries. For several POPs, mean and/or maximum daily intake calculated from individual concentrations was above recent US EPA reference dose values. Our data emphasize the need for analyses of complex mixtures to obtain more information on inter-individual and temporal variability of human exposure to different types of chemicals.

Fifty-three persons occupied in a municipal waste incinerator were examined with respect to their internal exposure to organic substances which may be produced during pyrolysis of organic matter. For this purpose the levels of benzene in blood, polychlorinated biphenyls (PCBs) and hexachlorobenzene (HCB) in plasma, and mono- (MCPs), di- (DCPs), tri- (TCPs), tetra- (TCEPs) and pentachlorophenol (PCP) and hydroxypyrene in urine were determined. For control purposes, 431 men and women were examined. Significantly higher values for the workers were found for the excretion of hydroxypyrene [median (m): 0.24 vs 0.11 microgram/l; non-smokers], 2,4/2,5-DCP (m: 10.5 vs 3.9 micrograms/l) and 2,4,5-TCP (m: 1.2 vs 0.8 micrograms/l) and for the HCB level in plasma (m: 4.4 vs 2.8 micrograms/l). For the concentrations of 4-MCP and 2,3,4,6/2,3,5,6-TECP, the controls had significantly higher concentrations in urine than did the workers in the incineration plant (m: 4-MCP 1.7 vs 1.2; 2,3,4,6/2,3,5,6-TECP: 1.2 vs 0.3 micrograms/l). No significant differences between workers and controls were detected with respect to benzene in blood (m: 0.20 vs 0.28 microgram/l; non-smokers), 2,4,6-TCP and PCPs in urine (m: 0.85 vs 0.60 and 2.2 vs 2.2 micrograms/l) or the levels of PCB congeners in plasma (m: sigma 138, 153, 180: 5.6 vs 4.1 micrograms/l). The elevated levels of hydroxypyrene, 2,4/2,5-DCP, 2,4,5-TCP and HCB in biological material may be related to the incineration of the waste. These elevations, however, are very small and are of interest more from the environmental than from the occupational point of view.

Seventeen persons (2 women and 15 men), who were exposed to glycolethers in a varnish production plant, were examined according to their external and internal solvent exposure. The workers in the production plant (n = 12) were exposed to average concentrations of ethoxyethanol, ethoxyethyl acetate, butoxyethanol, 1-methoxypropanol-2, 2-methoxypropyl-1-acetate and xylene of 2.8; 2.7; 1.1; 7.0; 2.8 and 1.7 ppm. In the air of the store (n = 3) and in the laboratory (n = 2) only minor concentrations of xylene respectively xylene and ethoxyethyl acetate could be measured. Internal exposure was estimated by measuring butoxyethanol (BE) in blood as well as ethoxyacetic acid (EAA) and butoxyacetic acid (BAA) in urine samples. Urine samples were taken pre- and post-shift. As expected, the highest values were found in the varnish production. The average post shift concentrations of BE, EAA and BAA were 121.3 micrograms/l; 167.8 and 10.5 mg/l. The relatively high concentrations of EAA and BAA in pre-shift samples can be explained by the long half-lives of these metabolites. According to our findings most of the glycolethers were taken up through the skin. Comparing our results with those reported in the literature we think that a future tolerable limit value for the concentration of ethoxyacetic acid in urine should be in the order of 100 to 200 mg/l.

Several aromatic amines (AA) are human carcinogens. AA are widely-used, e.g., in the rubber industry. The uptake of AA at the workplace occurs by inhalation and percutaneous absorption. At present there are no risk assessment studies for percutaneous AA absorption using occupationally relevant concentrations. We conducted diffusion cell experiments for aniline (ANI), o -toluidine (OT), 4,4′-methylenedianiline (MDA) and N -phenyl-2-naphthylamine (PBNA). Excised human skin was exposed to different AA concentrations in vehicles containing water and solvents. Recovery for ANI in receptor fluid was about 20–38% and for MDA 15% over 24 h. PBNA could not be detected in the receptor fluid. Further data for OT and β-naphthylamine (BNA) were considered from our recent study. A semi-quantitative percutaneous absorption ranking for AA was derived: BNA > OT > ANI > MDA > PBNA. For aqueous ANI solutions up to saturation a linear relationship of exposed dose and penetrated amount was observed. However, a linear extrapolation of the flux of neat compounds, as often recommended for risk assessment policies, underestimates considerably the percutaneous uptake. The in vitro data support our recent findings in rubber industry workers that the percutaneous absorption may significantly contribute to overall exposure of AA.

Objective: In 1997 a new source of potential polycyclic aromatic hydrocarbon (PAH) exposure was discovered: very high levels of (PAHs) and benzo-a-pyrene (BaP) were detected in household dust from former American Forces housing in Frankfurt am Main, Germany, built in 1955/1956. This contamination was caused by a parquet glue containing coal tar, the use of which was formerly a standard building practice in Germany. Children were considered to be at special risk for exposure to PAHs when playing on the floor via mouthing. Therefore, the children’s symptoms and complaints were analysed for association with PAH contamination in parquet glue and household dust as well as with internal exposure to PAHs via determination of 1-hydroxypyrene in urine samples. Participants and methods: Two hundred and eighty seven children

Pesticides are widely used throughout the world in agriculture to protect crops, and in public health to control diseases transmitted by animal vectors or intermediate hosts. After the prohibition of organochlorines such as DDT internal exposure of the general population to the organochlorines has been reduced markedly. Herein, current internal exposure of children and adolescents in an urban area in Germany to PCP, lindane, and DDT/E is reported. One hundred and thirty children and adolescents took part in this voluntary investigation. All of them stated they had never used pesticides in their homes or for medical reasons. Blood plasma was analysed for pentachlorophenol (PCP), lindane (γ-HCH), and dichloro(diphenyl)ethylene (DDE), a biostable metabolite of dichloro(diphenyl)trichloroethane (DDT), using gas chromatography/electron capture detection according to well established methods approved by the Deutsche Forschungsgemeinschaft. Median (and 95th percentiles) in the age groups