Biotransformation and toxicokinetics of 2-phenoxyethanol after oral exposure in humans: a volunteer study.

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

Comprehensive monitoring of a special mixture of prominent endocrine disrupting chemicals in human urine using a carefully adjusted hydrolysis of conjugates.

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

Assessment of the plasticizer exposure of hospital workers regularly handling medical devices: A pilot study.

Plastic medical devices, e.g. infusion sets, blood bags or tubing material, that are used manifold in the medical treatment of hospital patients, usually contain considerable amounts of plasticizers. Whereas several studies showed highly elevated inner plasticizer levels of patients treated with plasticized medical devices, little is known about the exposure situation of hospital staff. The present pilot study aimed to evaluate the urinary plasticizer metabolite levels of selected hospital workers of the blood bank (medical technical assistants, MTA) and of perfusionists that are regularly handling plasticized medical devices in order to estimate the work-related amount of the inner individual plasticizer exposure. The study subjects were asked to collect pre- and post-shift spot urine samples over the course of a working week, that were subsequently analyzed for selected urinary metabolites of the plasticizers DEHP, DINCH, DEHTP and TEHTM. Although the observed differences were rather low, a differentiated approach revealed a perceptible impact of the respective workplace environment on the individual urinary plasticizer metabolite levels. Thus, the group of blood bank MTA showed significantly elevated increment levels of urinary DEHP and DINCH metabolites, while the group of perfusionists, showed a considerable higher detection frequency of the main urinary TEHTM metabolite. All in all, however, it can be cautiously concluded by the results of the presented pilot study that a regular handling of plasticized medical devices by hospital employees (via inhalation or dermal contact) contributes demonstrably but yet only marginally to the individual internal plasticizer exposure.

Human metabolism and excretion kinetics of benzotriazole UV stabilizer UV-327 after single oral administration.

UV-327 (2-(5-chloro-benzotriazol-2-yl)-4,6-di-(tert-butyl)phenol) is used as an ultraviolet (UV) absorber in plastic products and coatings. Due to its ubiquitous distribution in the environment, human exposure is conceivable. In the study presented herein, initial information on the human in vivo metabolism of UV-327 was obtained by single oral administration to three volunteers. Urine and blood samples were collected up to 72 h after exposure. One study participant additionally donated plasma samples. Maximum blood and plasma levels of UV-327 and its two monohydroxylated metabolites UV-327-6-mOH and UV-327-4-mOH were reached 6 h post-exposure. Almost the entire amount found in blood and plasma samples was identified as UV-327, whereas the two metabolites each accounted for only 0.04% of the total amount, indicating that UV-327 is well-absorbed from the intestine, but only partially metabolized. Plasma to blood ratios of UV-327, UV-327-6-mOH, and UV-327-4-mOH ranged from 1.5 to 1.6. Maximum urinary excretion rates of UV-327, UV-327-6-mOH, UV-327-4-mOH, and UV-327-4 + 6-diOH were reached 9-14 h post-exposure. However, only about 0.03% of the orally administered dose of UV-327 was recovered as UV-327 and its metabolites in urine, indicating that biliary excretion may be the major route of elimination of UV-327 and its hydroxylated metabolites. The present study complements the insight in the complex absorption, distribution, metabolism, and elimination (ADME) processes of benzotriazole UV stabilizers (BUVSs).

Long-term monitoring of mercury in young German adults: Time trend analyses from the German Environmental Specimen Bank, 1995-2018.

As highlighted in the Minamata Convention, Mercury (Hg) in its various forms poses a substantial risk to human health and the environment. The health relevance of Hg is also recognized by the European Human Biomonitoring Initiative (HBM4EU), which classifies Hg as a priority substance, since considerable knowledge and data gaps on Hg exposure levels and their changes over time still exist in Europe. The German Environmental Specimen Bank (German ESB) provides valuable policy relevant data and long-term trends of substance exposure on a national level for international comparison and evaluation. In this study we analysed data of the German ESB on Hg exposure of young adults aged 20 to 29 including data on urinary Hg levels from 1995 to 2018 and whole blood Hg levels from 2001 to 2010. Results show a clear decrease in both, about 86% in urine total daily Hg excretion from 1995 (0.76 µg/L) to 2018 (0.11 µg/L) (n = 10,069) and about 57% in blood concentrations of Hg from 2001 (1.76 µg/L) to 2010 (0.77 µg/L) (n = 4085). Over the investigated timeframe only a few values exceeded the toxicologically derived health based guidance value HBM I for blood and urine, with these exceedances decreasing over time in line with the general trend. The factors mostly influencing Hg excretion identified in this study are dental amalgam as well as fish and seafood consumption. Besides other factors (e.g. age and sex), also airborne Hg exposure appears to be a low but evident influencing factor in Germany. Although a considerable decrease in internal Hg exposure is recognized in the last decades, the current low-level exposure may cause adverse health effects especially to vulnerable groups such as pregnant women and children. To further elucidate and evaluate current exposure sources and to reduce human exposure to Hg, continuous environmental and human biomonitoring is needed.

European interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for the analysis of bisphenol A, S and F in human urine: Results from the HBM4EU project.

The Human Biomonitoring for Europe initiative (HBM4EU) aims to study the exposure of citizens to chemicals and potentially associated health effects. One objective of this project has been to build a network of laboratories able to answer to the requirements of European human biomonitoring studies. Within the HBM4EU quality assurance and quality control scheme (QA/QC), a number of interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) were organized to ensure data consistency, comparability and reliability. Bisphenols are among the prioritized substance groups in HBM4EU, including bisphenol A (BPA), bisphenol S (BPS) and bisphenol F (BPF) in human urine. In four rounds of ICI/EQUAS, two target concentration levels were considered, related to around P25 and P95 of the typical exposure distribution observed in the European general population. Special attention was paid to the conjugated phase II metabolites known to be most dominant in samples of environmentally exposed individuals, through the analysis of both native samples and samples fortified with glucuronide forms. For the low level, the average percentage of satisfactory results across the four rounds was 83% for BPA, 71% for BPS and 62% for BPF. For the high level, the percentages of satisfactory results increased to 93% for BPA, 89% for BPS and 86% for BPF. 24 out of 32 participating laboratories (75%) were approved for the analyses of BPA in the HBM4EU project according to the defined criterion of Z-scores for both low and high concentration levels in at least two ICI/EQUAS rounds. For BPS and BPF, the number of qualified laboratories was 18 out of 27 (67%) and 13 out of 28 (46%), respectively. These results demonstrate a strong analytical capability for BPA and BPS in Europe, while improvements may be needed for BPF.

HBM4EU chromates study - Overall results and recommendations for the biomonitoring of occupational exposure to hexavalent chromium.

Exposure to hexavalent chromium [Cr(VI)] may occur in several occupational activities, e.g., welding, Cr(VI) electroplating and other surface treatment processes. The aim of this study was to provide EU relevant data on occupational Cr(VI) exposure to support the regulatory risk assessment and decision-making. In addition, the capability and validity of different biomarkers for the assessment of Cr(VI) exposure were evaluated. The study involved nine European countries and involved 399 workers in different industry sectors with exposures to Cr(VI) such as welding, bath plating, applying or removing paint and other tasks. We also studied 203 controls to establish a background in workers with no direct exposure to Cr(VI). We applied a cross-sectional study design and used chromium in urine as the primary biomonitoring method for Cr(VI) exposure. Additionally, we studied the use of red blood cells (RBC) and exhaled breath condensate (EBC) for biomonitoring of exposure to Cr(VI). Personal measurements were used to study exposure to inhalable and respirable Cr(VI) by personal air sampling. Dermal exposure was studied by taking hand wipe samples. The highest internal exposures were observed in the use of Cr(VI) in electrolytic bath plating. In stainless steel welding the internal Cr exposure was clearly lower when compared to plating activities. We observed a high correlation between chromium urinary levels and air Cr(VI) or dermal total Cr exposure. Urinary chromium showed its value as a first approach for the assessment of total, internal exposure. Correlations between urinary chromium and Cr(VI) in EBC and Cr in RBC were low, probably due to differences in kinetics and indicating that these biomonitoring approaches may not be interchangeable but rather complementary. This study showed that occupational biomonitoring studies can be conducted successfully by multi-national collaboration and provide relevant information to support policy actions aiming to reduce occupational exposure to chemicals.

Pentachlorophenol and nine other chlorophenols in urine of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V).

Chlorophenols comprise of a large group of chemicals used inter alia for the production of biocides, pharmaceuticals, other industrial products and are used e.g. as antiseptics or wood preservatives due to their biocidal properties. Several of them are classified as toxic to aquatic life and harmful to humans by ingestion, inhalation, or dermal contact, causing skin and eye irritation. Moreover, chlorophenols are possibly carcinogenic to humans. The most prominent chlorophenol - pentachlorophenol - is carcinogenic to humans, was banned in Germany in 1989 and further regulated by the European Commission in 2006 and included in the Stockholm Convention in 2017. Some chlorophenols are persistent in the environment and are also biodegradation products of precursor substances. To evaluate the health-relevance of recent exposure and monitor the effectiveness of regulatory measures, chlorophenols were analysed in the population-representative German Environmental Survey on Children and Adolescents 2014-2017 (GerES V). First-morning void urine samples of 485 3-17-year-old children and adolescents were analysed for ten chlorophenols. Pentachlorophenol was still quantified in 87% of the children and adolescents with a geometric mean (GM) concentration of 0.19 µg/L (0.16 µg/gcrea) and a maximum concentration of 6.7 µg/L (5.4 µg/gcrea). The maximum concentration was well below the health-based guidance value HBM-I of 25 µg/L (20 µg/gcrea). 4-Monochlorophenol was quantified in all samples with a GM concentration of 1.38 µg/L (1.14 µg/gcrea). 2-Monochlorophenol, 2,4-dichlorophenol, and 2,5-dichlorophenol were quantified in 97%, 98%, and 95% of the samples, with GMs of 0.26 µg/L (0.21 µg/gcrea), 0.24 µg/L (0.20 µg/gcrea), and 0.26 µg/L (0.21 µg/gcrea). 2,6-dichlorophenol, 2,3,4-trichlorophenol, and 2,4,5-trichlorophenol were quantified in 17-25% of the samples with GMs below the limit of quantification (LOQ) of 0.1 µg/L 2,4,6-trichlorophenol was quantified in 72% of the samples (GM: 0.13 µg/L, 0.11 µg/gcrea), 2,3,4,6-tetrachlorophenol in 44% of the samples (GM < LOQ). Comparison to previous cycles of GerES revealed substantially lower exposure to most of the chlorophenols in GerES V. Exposure levels found in Germany were comparatively low in contrast to North American results.

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).

The UV filter 4-methylbenzylidene camphor (4-MBC), used in cosmetics, the antioxidant butylated hydroxytoluene (BHT), used inter alia as a food additive and in cosmetics, and the plasticizer tris(2-ethylhexyl) trimellitate (TOTM), used mainly in medical devices as substitute for di-(2-ethylhexyl) phthalate (DEHP), are suspected to have endocrine disrupting effects. Human biomonitoring methods that allow for assessing the internal exposure of the general population to these substances were recently developed in a German cooperation to enhance the use of human biomonitoring. First-morning void urine samples from 3- to 17-year-old children and adolescents living in Germany were analysed for metabolites of 4-MBC (N = 447), BHT (N = 2091), and TOTM (N = 431) in the population-representative German Environmental Survey on Children and Adolescents 2014-2017 (GerES V). 4-MBC metabolites were found in quantifiable amounts only in single cases and exposure levels remained well below health-based guidance values. In contrast, ubiquitous exposure to BHT became evident with a geometric mean (GM) urinary concentration of the metabolite BHT acid of 2.346 µg/L (1.989 µg/gcreatinine) and a maximum concentration of 248 µg/L (269 µg/gcrea). The highest GM concentration was found in young children aged 3-5 years, yet no specific sources of exposure could be identified. Also, TOTM metabolites were found in quantifiable amounts only in very few samples. None of these findings could be related to previous hospital treatment or exposure via house dust. The presented results will be the basis to derive reference values for exposure of children and adolescents in Germany to BHT and will facilitate to identify changing exposure levels in the general population.

Interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) for flame retardant analysis in biological matrices: Results from the HBM4EU project.

The European Human Biomonitoring Initiative (HBM4EU) is coordinating and advancing human biomonitoring (HBM). For this purpose, a network of laboratories delivering reliable analytical data on human exposure is fundamental. The analytical comparability and accuracy of laboratories analysing flame retardants (FRs) in serum and urine were investigated by a quality assurance/quality control (QA/QC) scheme comprising interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs). This paper presents the evaluation process and discusses the results of four ICI/EQUAS rounds performed from 2018 to 2020 for the determination of ten halogenated flame retardants (HFRs) represented by three congeners of polybrominated diphenyl ethers (BDE-47, BDE-153 and BDE-209), two isomers of hexabromocyclododecane (α-HBCD and γ-HBCD), two dechloranes (anti-DP and syn-DP), tetrabromobisphenol A (TBBPA), decabromodiphenylethane (DBDPE), and 2,4,6-tribromophenol (2,4,6-TBP) in serum, and four metabolites of organophosphorus flame retardants (OPFRs) in urine, at two concentration levels. The number of satisfactory results reported by laboratories increased during the four rounds. In the case of HFRs, the scope of the participating laboratories varied substantially (from two to ten) and in most cases did not cover the entire target spectrum of chemicals. The highest participation rate was reached for BDE-47 and BDE-153. The majority of participants achieved more than 70% satisfactory results for these two compounds over all rounds. For other HFRs, the percentage of successful laboratories varied from 44 to 100%. The evaluation of TBBPA, DBDPE, and 2,4,6-TBP was not possible because the number of participating laboratories was too small. Only seven laboratories participated in the ICI/EQUAS scheme for OPFR metabolites and five of them were successful for at least two biomarkers. Nevertheless, the evaluation of laboratory performance using Z-scores in the first three rounds required an alternative approach compared to HFRs because of the small number of participants and the high variability of experts' results. The obtained results within the ICI/EQUAS programme showed a significant core network of comparable European laboratories for HBM of BDE-47, BDE-153, BDE-209, α-HBCD, γ-HBCD, anti-DP, and syn-DP. On the other hand, the data revealed a critically low analytical capacity in Europe for HBM of TBBPA, DBDPE, and 2,4,6-TBP as well as for the OPFR biomarkers.

From inequitable to sustainable e-waste processing for reduction of impact on human health and the environment.

Recycling of electric and electronic waste products (e-waste) which amounted to more than 50 million metric tonnes per year worldwide is a massive and global operation. Unfortunately, an estimated 70-80% of this waste has not been properly managed because the waste went from developed to low-income countries to be dumped into landfills or informally recycled. Such recycling has been carried out either directly on landfill sites or in small, often family-run recycling shops without much regulations or oversights. The process traditionally involved manual dismantling, cleaning with hazardous solvents, burning and melting on open fires, etc., which would generate a variety of toxic substances and exposure/hazards to applicators, family members, proximate residents and the environment. The situation clearly calls for global responsibility to reduce the impact on human health and the environment, especially in developing countries where poor residents have been shouldering the hazardous burden. On the other hand, formal e-waste recycling has been mainly conducted in small scales in industrialized countries. Whether the latter process would impose less risk to populations and environment has not been determined yet. Therefore, the main objectives of this review are: 1. to address current trends and emerging threats of not only informal but also formal e-waste management practices, and 2. to propose adequate measures and interventions. A major recommendation is to conduct independent surveillance of compliance with e-waste trading and processing according to the Basel Ban Amendment. The recycling industry needs to be carefully evaluated by joint effort from international agencies, producing industries and other stakeholders to develop better processes. Subsequent transition to more sustainable and equitable e-waste management solutions should result in more effective use of natural resources, and in prevention of adverse effects on health and the environment.

Human metabolism and kinetics of the UV absorber 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328) after oral administration.

2-(2H-Benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328; CAS: 25973-55-1) is an ultraviolet light (UV) absorber which belongs to the class of hydroxy phenol benzotriazoles. Therefore, UV 328 is added to plastics and other polymers due to its photostability to prevent discoloration and prolong product stability which may result in an exposure of consumers. However, information about the toxic effects on humans and the human metabolism are still lacking. In the present study, human metabolism pathways of UV 328 and its elimination kinetics were explored. For that purpose, three healthy volunteers were orally exposed to a single dose of 0.3 mg UV 328/kg bodyweight. UV 328 and its metabolites were investigated in blood and urine samples collected until 48 and 72 h after exposure, respectively. Thereby, previously published analytical procedures were applied for the sample analysis using dispersive liquid-liquid microextraction and subsequent measurement via gas chromatography coupled to tandem mass spectrometry with advanced electron ionization. UV 328 was found to be oxidized at its alkyl side chains leading to the formation of hydroxy and/or oxo function with maximum blood concentrations at 8-10 h after exposure for UV 328-6/3-OH, UV 328-4/3-OH and UV 328-4/3-CO. In contrast, a plateau for UV 328-4/3-CO-6/3-OH levels was reached around 10 h post-dosage. The highest blood levels were found for native UV 328 at 8 h after ingestion. Furthermore, biphasic elimination kinetics in blood were revealed for almost all detected metabolites. UV 328 and its metabolites did not occur in blood as conjugates. The renal elimination kinetics were very similar with the kinetics in blood. However, the prominence of the metabolites in urine was somewhat different compared to blood. In contrast, mostly conjugated metabolites occurred for renal elimination. In urine, UV 328-4/3-CO-6/3-OH was found to be the most dominant urinary biomarker followed by UV 328-6/3-OH and UV 328-4/3-OH. In total, approximately 0.1% of the orally administered dose was recovered in urine within 72 h. Although high levels of UV 328 in blood proved good resorption and high systemic availability of the substance in the human body, the urine results revealed a rather low quantitative metabolism and urinary excretion rate. Consequently, biliary excretion as part of the enterohepatic cycle and elimination via feces are assumed to be the preferred pathways instead of renal elimination.

Inhalation and dermal exposure of workers during timber impregnation with creosote and subsequent processing of impregnated wood.

OBJECTIVES: Coal tar creosote oils are used as highly effective wood protectants for, e.g., railway sleepers, utility poles and marine pilings. For impregnation of wood, the hot creosote oil is mostly applied in vacuum processes and by hot-and-cold dipping. From the perspective of an occupational hygienist, creosote tar oils are problematic because they have a number of hazardous properties, including carcinogenicity. We have studied inhalation and dermal exposure in six and four impregnation plants, respectively, in Germany. Some plants were visited repeatedly, for up to five measurement campaigns conducted over several years. Inhalation and dermal exposure resulting from vacuum impregnation and from hot-and-cold dipping, as well as secondary exposure resulting from assembly of impregnated railway sleepers have been measured. Accompanying, human biomonitoring of the employees has been performed. METHODS: Inhalation exposure was measured using personal air samplers, collecting particles and vapours simultaneously. Dermal exposure was investigated by whole body dosimetry using disposable chemical protective coveralls and split leather gloves. 18 polycyclic aromatic hydrocarbons (PAHs) have been determined separately by high performance liquid chromatography (HPLC) or gas chromatography-mass spectrometry (GC-MS), respectively. For human biomonitoring 1-hydroxypyrene (1-OHP) in urine related to creatinine has been measured using HPLC. Both, pre- and post-shift values have been determined for this metabolite. RESULTS: Dermal exposure towards pyrene and the sum of the determined 18 PAHs as well as inhalation exposure to naphthalene, pyrene and the sum of the determined 18 PAHs are presented in this paper. The plants performing vacuum impregnation have employed different constructive, technical and organisational measures, and some measures have also changed between the different measurement campaigns. We have found that cooling the vacuum impregnation vessel before unloading can reduce inhalation exposure to about one-third. However, our data shows that installation of structural or technical risk management measures (RMM) did not always reduce the exposure as intended, and can even lead to increased exposure in adverse constellations. Dermal exposure was strongly affected by differences in the working procedures. Measurements performed during assembly of impregnated railway sleepers indicate that secondary exposure leads to lower inhalation, but similar dermal exposure compared to the impregnation processes. Also 1-OHP excretion rates are similar after impregnation process and after assembly of impregnated railway sleepers. CONCLUSION: Our recent data underlines that efficient reduction of the exposure resulting from impregnation with creosote requires sophisticated risk reduction strategies. Structural measures such as the enclosure of the loading area and technical measures like local exhaust ventilation shall be coordinated carefully with organisational measures and provision of personal protective equipment. The data presented here represents a broad bandwidth of current workplace situations in the creosote oil processing industry and is therefore suitable for risk assessment in related plants as well as under regulatory frameworks like the European Biocides Regulation. Each plant in this investigation was unique. Together they represent the whole width of this branch in Germany. Additionally, the number of plants and exposed workers is limited and relative low. Therefore, a comprehensive consideration and statistical analysis were not feasible.

Organophosphate pesticide exposure in children in Israel: Dietary associations and implications for risk assessment.

BACKGROUND: Human biomonitoring (HBM) data is increasingly being compared to risk-based screening values to assess human health risk. However, as screening values have not been established for assessing biomarker concentrations of organophosphate (OP) pesticide metabolites, there are few studies using HBM data on urinary OP concentrations to assess human health risk. The purpose of the current study was to measure OP exposure in a sample of children in Israel; to explore associations between dietary patterns and OP exposure; and to assess risk of OP pesticides using urinary metabolite concentrations. METHODS: We recruited 103 children in Israel and collected demographic and dietary data and urinary samples, and measured creatinine and dialkyl phosphate (DAP) concentrations. We compared urinary DAP concentrations to international populations and analysed associations between fruit and vegetable consumption and urinary DAP concentrations. Using urinary DAP concentrations, we calculated estimated daily intakes (EDI) of OP pesticides in each child and compared those to the acceptable daily intake (ADI). RESULTS: Concentrations of several dialkyl phosphate metabolites (dimethylphosphate (DMP) and dimethylthiophosphate (DMTP)) were higher in our study population of Israeli children (geometric mean concentrations of DMP and DMTP were 6.6 µg/L and 7.6 µg/L, respectively) compared to children in the US, Canada, Spain, and Denmark. We found positive correlations between total fruit consumption and creatinine adjusted log transformed urinary DMP, DMTP, diethylthiophopshate (DETP), total dimethyl (DM) and total DAP concentrations (p < 0.05), positive correlations between cucumber consumption and diethylphosphate (DEP), DETP and diethyl (DE) concentrations (p < 0.05), and positive correlations between apple consumption and DETP concentrations (p = 0.02). Based on urinary DAP concentrations, we found that a portion of the children in our study had EDIs above the ADI, ranging from 2.9% to 79.4% of the children, depending on the active OP ingredient. CONCLUSIONS: We found that Israeli children in our study are widely exposed to OP pesticides; that levels of dimethyl metabolites were high compared to other international populations; and that fruit consumption was associated with higher urinary DAP levels. Using urinary DAP concentration data, we found that a portion of the children in our study may be exposed to OP pesticides at levels above those considered safe.

Impact of Daily Antiperspirant Use on the Systemic Aluminum Exposure: An Experimental Intervention Study.

BACKGROUND AND OBJECTIVES: Adverse health effects such as neurotoxic and carcinogenic effects through aluminum from cosmetic products have been repeatedly discussed. The dermal uptake and impact on the systemic aluminum load is still poorly understood. Therefore, we investigated the effect of daily antiperspirant use on the systemic aluminum load under real-life conditions. METHODS: 21 healthy subjects meeting certain selection criteria to ensure a low systemic aluminum background load were asked to use a commercial aluminum-containing antiperspirant for 14 days. A questionnaire enquired about shaving habits and other sources of aluminum. Aluminum levels were measured before and after the exposure in 24-h urine and plasma using atomic absorption spectroscopy. Urine samples (n = 6) with <700 mg/day creatinine excretion or more than 30% difference in 24-h creatinine excretion were excluded from further analysis. RESULTS: No significant increase in plasma aluminum concentration or total excreted aluminum per day before and after exposure was measurable. No sample exceeded the reference values of the general population (maximum: 9.42 µg/g creatinine and 2.1 µg/L plasma). Shaving habits did not have a significant influence on the systemic aluminum load. Also, no correlation between the total amount of antiperspirant applied and the systemic aluminum level could be demonstrated. CONCLUSIONS: No measurable contribution to the overall systemically available aluminum load due to daily use of an antiperspirant for 14 days could be shown, but real-life data concerning long-term use or higher concentrations are still lacking. Considering toxicological occupational exposure data, adverse neurotoxic changes are unlikely in the case of urinary excretion of <50 µg aluminum/g creatinine (= no observed adverse effect level), even following long-term exposure.

Reduction of exposure to plasticizers in stored red blood cell units.

INTRODUCTION: Plastic can be toxic and hazardous to an organism's health, but it is being widely used in our daily lives. Di-2-ethylhexyl-phthalate is the most common plasticizer in medical devices made of polyvinylchloride and is commonly found in soft bags storing red blood cell units. Di-2-ethylhexyl-phthalate and its degradation product mono-2-ethylhexyl-phthalate can migrate into human body fluids, for example, blood and tissues. The aim of the study was to assess the concentration of plasticizers in red blood cell units according to storage time and after mechanical rinsing using a cell salvage device. METHODS: Levels of di-2-ethylhexyl-phthalate and mono-2-ethylhexyl-phthalate were analysed in 50 unwashed red blood cell units using liquid chromatography coupled with tandem mass spectrometry. In addition, phthalate concentrations were measured before and after mechanical rinsing in six more washed red blood cell units with storage times ranging between 36 and 56 days. A linear regression model was determined by the daily increase of di-2-ethylhexyl-phthalate and mono-2-ethylhexyl-phthalate in the stored red blood cell units subject to their storage time (range = 4-38 days), and the effect of mechanical rinsing on their phthalate concentration was calculated. RESULTS: A linear correlation was found between storage time of unwashed red blood cell units and the concentration of di-2-ethylhexyl-phthalate (p < 0.001) or mono-2-ethylhexyl-phthalate (p < 0.001). Stored red blood cell units older than 14 days had significantly higher concentrations of both contaminants than red blood cell units of shorter storage time (p < 0.001). Mechanical rinsing in washed red blood cell units attained a reduction in the di-2-ethylhexyl-phthalate and mono-2-ethylhexyl-phthalate concentration by a median of 53% (range = 18-68%; p = 0.031) and 87% (range = 68-96%; p = 0.031), respectively. CONCLUSION: Leaching of di-2-ethylhexyl-phthalate and mono-2-ethylhexyl-phthalate into red blood cell units depends on the duration of storage time. Plasticizers can be significantly reduced by mechanical rinsing using cell salvage devices, and thus, red blood cell units can be regenerated with respect to chemical contamination.

Immunological methods for diagnosis and monitoring of IgE-mediated allergy caused by industrial sensitizing agents (IMExAllergy).

Industrial sensitizing agents (allergens) in living and working environments play an important role in eliciting type 1 allergic disorders including asthma and allergic rhinitis. Successful management of allergic diseases necessitates identifying their specific causes (ie, identify the causative agent(s) and the route of contact to allergen: airborne, or skin contact) to avoid further exposure. Identification of sensitization by a sensitive and validated measurement of specific IgE is an important step in the diagnosis. However, only a limited number of environmental and occupational allergens are available on the market for use in sIgE testing. Accordingly, specific in-house testing by individual diagnostic and laboratory centers is often required. Currently, different immunological tests are in use at various diagnostic centers that often produce considerably divergent results, mostly due to lack of standardized allergen preparation and standardized procedures as well as inadequate quality control. Our review and meta-analysis exhibited satisfactory performance of sIgE detection test for most high molecular weight (HMW) allergens with a pooled sensitivity of 0.74 and specificity of 0.71. However, for low molecular weight (LMW) allergens, pooled sensitivity is generally lower (0.28) and specificity higher (0.89) than for HMW tests. Major recommendations based on the presented data include diagnostic use of sIgE to HMW allergens. A negative sIgE result for LMW agents does not exclude sensitization. In addition, the requirements for full transparency of the content of allergen preparations with details on standardization and quality control are underlined. Development of standard operating procedures for in-house sIgE assays, and clinical validation, centralized quality control and audits are emphasized. There is also a need for specialized laboratories to provide a custom service for the development of tests for the measurement of putative novel occupational allergens that are not commercially available.

Setting up a collaborative European human biological monitoring study on occupational exposure to hexavalent chromium.

The EU human biomonitoring initiative, HBM4EU, aims to co-ordinate and advance human biomonitoring (HBM) across Europe. Within its remit, the project is gathering new, policy relevant, EU-wide data on occupational exposure to relevant priority chemicals and developing new approaches for occupational biomonitoring. In this manuscript, the hexavalent chromium [Cr(VI)] study design is presented as the first example of this HBM4EU approach. This study involves eight European countries and plans to recruit 400 workers performing Cr(VI) surface treatment e.g. electroplating or stainless steel welding activities. The aim is to collect new data on current occupational exposure to Cr(VI) in Europe and to test new methods for Cr biomonitoring, specifically the analysis of Cr(VI) in exhaled breath condensate (EBC) and Cr in red blood cells (RBC) in addition to traditional urinary total Cr analyses. Furthermore, exposure data will be complemented with early biological effects data, including genetic and epigenetic effects. Personal air samples and wipe samples are collected in parallel to help informing the biomonitoring results. We present standard operational procedures (SOPs) to support the harmonized methodologies for the collection of occupational hygiene and HBM samples in different countries.

Aluminium in plasma and tissues after intramuscular injection of adjuvanted human vaccines in rats.

Aluminium (Al) toxicokinetics after intramuscular (IM) injection of Al-adjuvanted vaccines is unknown. Since animal data are required for modeling and extrapolation, a rat study was conducted measuring Al in plasma and tissues after IM injection of either plain Al-hydroxide (pAH) or Al-phosphate (pAP) adjuvant (Al dose 1.25 mg), single human doses of three Al-adjuvanted vaccines (V1, V2, and V3; Al doses 0.5-0.82 mg), or vehicle (saline). A significant increase in Al plasma levels compared to controls was observed after pAP (AUC(0-80 d), mean ± SD: 2424 ± 496 vs. 1744 ± 508 µg/L*d). Percentage of Al dose released from injected muscle until day 80 was higher after pAP (66.9%) and AP-adjuvanted V3 (85.5%) than after pAH and AH-adjuvanted V1 (0 and 22.3%, resp.). Estimated absolute Al release was highest for pAP (836.8 µg per rat). Al concentration in humerus bone was increased in all groups, again strongest in the pAP group [3.35 ± 0.39 vs. 0.05 ± 0.06 µg/g wet weight (ww)]. Extrapolated amounts in whole skeleton corresponded to 5-12% of the released Al dose. Very low brain Al concentrations were observed in all groups (adjuvant group means 0.14-0.29 µg/g ww; control 0.13 ± 0.04 µg/g ww). The results demonstrate systemically available Al from marketed vaccines in rats being mainly detectable in bone. Al release appears to be faster from AP- than AH-adjuvants. Dose scaling to human adults suggests that increase of Al in plasma and tissues after single vaccinations will be indistinguishable from baseline levels.

Toxicokinetics of urinary 2-ethylhexyl salicylate and its metabolite 2-ethyl-hydroxyhexyl salicylate in humans after simulating real-life dermal sunscreen exposure.

Chemical UV filters are common components in sunscreens and cosmetic products. The question of adverse health risks is not completely resolved, partly owing to lacking human data from dermal exposure, which are essential for sound risk assessment. Therefore, we investigated the urinary toxicokinetics of 2-ethylhexyl salicylate (EHS) after a 1-day dermal real-life sunscreen application scenario. Twenty human volunteers were dermally exposed to a commercial sunscreen for 9 h under real-life conditions (2 mg/cm2 body surface area; double re-application; corresponding to 3.8 g EHS). Urine samples were analyzed for EHS and one of its specific metabolites 2-ethyl-5-hydroxyhexyl salicylate (5OH-EHS) using a two-dimensional liquid chromatographic electrospray-ionization tandem mass spectrometric procedure. EHS and 5OH-EHS were excreted after sunscreen application and reached up to 525 µg/g and 213 µg/g creatinine, respectively. The toxicokinetic models showed concentration peaks between 7 and 8 h after first application. First-phase terminal half-lives were 8-9 h. For 5OH-EHS, a second-phase terminal half-life could be determined (87 h). EHS and 5OH-EHS showed a faster elimination with 70-80% of the overall excretion occurring within 24 h after application compared to more lipophilic UV filters. Cumulative excreted amounts over 24 h reached up to 334 µg EHS and 124 µg of 5OH-EHS. Simulated real-life sunscreen use for 1 day leads to the bioavailability of the UV filter EHS in humans. The kinetic profiles with a prolonged systemic availability indicate a skin depot and make accumulation during consecutive multi-day exposure likely.