Geraniol is a fragrance with a characteristic rose-like smell, naturally occurring in terpene oil and also chemically synthesized on a large scale. Geraniol is widely used in consumer products such ...as cosmetics, personal care products, and household cleaners and as an additive in foods. An experimental study in human volunteers was carried out to investigate the metabolism and elimination kinetics of geraniol. Three subjects were orally exposed to geraniol in two different dosages (25 or 250 mg). In each case, one pre-exposure urine sample and all urine voids for 72 h after exposure were collected separately. The geraniol metabolites Hildebrandt acid, geranic acid, 3-hydroxycitronellic acid, and 8-carboxygeraniol were analyzed in every sample after enzymatic hydrolysis and liquid–liquid extraction using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Maximum urinary concentrations of the metabolites were measured between 1 and 5 h after oral dosing, and elimination half-lives were determined to be about 2–4 h. The predominant metabolite found in urine was Hildebrandt acid with 34.4 ± 5.6% of the ingested dose, followed by geranic acid (12.7 ± 5.6%), 3-hydroxycitronellic acid (2.2 ± 0.4%), and 8-carboxygeraniol (0.19 ± 0.09%). In total, the four metabolites determined represent 41.7–55.5% of the ingested dose. Only 8-carboxygeraniol is, however, a specific metabolite, while the other three target analytes are also formed from other terpenes like citral. Within this study, conversion factors were calculated, which allow for a rough estimate of the total geraniol uptake by back-calculation from metabolite concentrations of spot urine samples. Taking the conversion factor for all four metabolites into account, a mean daily uptake of geraniol of 1.43 mg was estimated from 41 urine samples of occupationally nonexposed adults. The metabolites Hildebrandt acid, geranic acid, 3-hydroxycitronellic acid, and 8-carboxygeraniol in urine are suitable biomarkers of exposure for geraniol and can be used for human biomonitoring studies.
Glyphosate continues to attract controversial debate following the International Agency for Research on Cancer carcinogenicity classification in 2015. Despite its ubiquitous presence in our ...environment, there remains a dearth of data on human exposure to both glyphosate and its main biodegradation product aminomethylphosphonic (AMPA). Herein, we reviewed and compared results from 21 studies that use human biomonitoring (HBM) to measure urinary glyphosate and AMPA. Elucidation of the level and range of exposure was complicated by differences in sampling strategy, analytical methods, and data presentation. Exposure data is required to enable a more robust regulatory risk assessment, and these studies included higher occupational exposures, environmental exposures, and vulnerable groups such as children. There was also considerable uncertainty regarding the absorption and excretion pattern of glyphosate and AMPA in humans. This information is required to back-calculate exposure doses from urinary levels and thus, compared with health-based guidance values. Back-calculations based on animal-derived excretion rates suggested that there were no health concerns in relation to glyphosate exposure (when compared with EFSA acceptable daily intake (ADI)). However, recent human metabolism data has reported as low as a 1% urinary excretion rate of glyphosate. Human exposures extrapolated from urinary glyphosate concentrations found that upper-bound levels may be much closer to the ADI than previously reported.
During the population representative German Environmental Survey of Children and Adolescents (GerES V, 2014–2017) 2256 first-morning void urine samples from 3 to 17 years old children and adolescents ...were analysed for 21 metabolites of 11 different phthalates (di-methyl phthalate (DMP), di-ethyl phthalate (DEP), butylbenzyl phthalate (BBzP), di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), di-cyclohexyl phthalate (DCHP), di-n-pentyl phthalate (DnPeP), di-(2-ethylhexyl) phthalate (DEHP), di-iso-nonyl phthalate (DiNP), di-iso-decyl phthalate (DiDP) and di-n-octyl phthalate (DnOP)).
Metabolites of DMP, DEP, BBzP, DiBP, DnBP, DEHP, DiNP and DiDP were found in 97%–100% of the participants, DCHP and DnPeP in 6%, and DnOP in none of the urine samples. Geometric means (GM) were highest for metabolites of DiBP (MiBP: 26.1 μg/L), DEP (MEP: 25.8 μg/L), DnBP (MnBP: 20.9 μg/L), and DEHP (cx-MEPP: 11.9 μg/L). For all phthalates but DEP, GMs were consistently higher in the 3–5 years old children than in the 14–17 years old adolescents. For DEHP, the age differences were most pronounced. All detectable phthalate biomarker concentrations were positively associated with the levels of the respective phthalate in house dust.
In GerES V we found considerably lower phthalate biomarker levels than in the preceding GerES IV (2003–2006). GMs of biomarker levels in GerES V were only 18% (BBzP), 23% (MnBP), 23% (DEHP), 29% (MiBP) and 57% (DiNP) of those measured a decade earlier in GerES IV.
However, some children and adolescents still exceeded health-based guidance values in the current GerES V. 0.38% of the participants had levels of DnBP, 0.08% levels of DEHP and 0.007% levels of DiNP which were higher than the respective health-based guidance values. Accordingly, for these persons an impact on health cannot be excluded with sufficient certainty.
The ongoing and substantial exposure of vulnerable children and adolescents to many phthalates confirms the need of a continued monitoring of established phthalates, whether regulated or not, as well as of potential substitutes. With this biomonitoring approach we provide a picture of current individual and cumulative exposure developments and body burdens to phthalates, thus providing support for timely and effective chemicals policies and legislation.
•Representative data on 11 phthalate levels in German children and adolescents.•8 phthalates were found in 97%–100% of samples.•Average urinary phthalate concentrations decreased within the last 10 years.•Exceedances of health-based guidance values were found for DnBP, DiNP and DEHP.
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•Human toxicokinetics of homosalate (HMS, cis and trans) after oral dose.•≥15 oxidative metabolites investigated quantitatively/semi-quantitatively.•≥70 % (average; n = 4) of urinary ...excretion of each metabolite within 24 h post dose.•Urinary excretion fraction sums were 100-fold higher for trans-derived metabolites.•Plasma data indicate 10-fold lower oral bioavailability of cis-homosalate.
Homosalate (HMS) is a salicylate UV filter broadly used in sunscreens and personal care products. The aim of this study was the collection of human toxicokinetic data on HMS as a tool for risk assessment. For this purpose, metabolism and urinary excretion after a single oral HMS dose (98.2–149.1 µg (kg body weight)−1) were investigated in four volunteers (two male, two female). As commercial products generally contain a mixture of cis- and trans-HMS, both cis-rich and trans-rich isomer mixtures were studied to investigate possible differences in metabolism. Initial metabolite screening tentatively identified six oxidative metabolite subgroups, of which hydroxylated and carboxylic acid metabolites were studied in more detail. Unchanged parent HMS and the previously identified HMS metabolites 5-((2-hydroxybenzoyl)oxy)-3,3-dimethylcyclohexane-1-carboxylic acid (HMS-CA) and 3-hydroxy-3,5,5-trimethylcyclohexyl 2-hydroxybenzoate (3OH-HMS), respectively, were quantified separately as cis- and trans-isomers via authentic standards by isotope dilution analysis. In addition, further alkyl-hydroxylated and carboxylic acid metabolites were investigated semi-quantitatively. Peak concentrations in urine were reached 1.5–6.3 h post-dose and more than 80 % of each of the quantitatively investigated metabolites (and at least 70 % of the semi-quantitatively investigated metabolites) was excreted within the first 24 h. Plasma and urine data indicated that oral bioavailability of cis-HMS was one order of magnitude below that of trans-HMS. Furthermore, the mean total urinary excretion fraction (Fue) for the metabolites derived from trans-HMS (6.4 %) was two orders of magnitude higher than for the metabolites derived from cis-HMS (0.045 %). Our data proves diastereoselectivity in toxicokinetics of cis- and trans-HMS, emphasizing the necessity to address isomer ratios in future studies including HMS exposure and risk assessments.
To assess the influence of clothing on dermal uptake of semi-volatile organic compounds (SVOCs), we measured uptake of selected airborne phthalates for an individual wearing clean clothes or ...air-exposed clothes and compared these results with dermal uptake for bare-skinned individuals under otherwise identical experimental conditions. Using a breathing hood to isolate dermal from inhalation uptake, we measured urinary metabolites of diethylphthalate (DEP) and di-n-butylphthalate (DnBP) from an individual exposed to known concentrations of these compounds for 6 h in an experimental chamber. The individual wore either clean (fresh) cotton clothes or cotton clothes that had been exposed to the same chamber air concentrations for 9 days. For a 6-h exposure, the net amounts of DEP and DnBP absorbed when wearing fresh clothes were, respectively, 0.017 and 0.007 μg/kg/(μg/m(3)); for exposed clothes the results were 0.178 and 0.261 μg/kg/(μg/m(3)), respectively (values normalized by air concentration and body mass). When compared against the average results for bare-skinned participants, clean clothes were protective, whereas exposed clothes increased dermal uptake for DEP and DnBP by factors of 3.3 and 6.5, respectively. Even for non-occupational environments, wearing clothing that has adsorbed/absorbed indoor air pollutants can increase dermal uptake of SVOCs by substantial amounts relative to bare skin.
•Phthalate mixture risk assessment for changing exposure patterns over 27 years.•Application of updated reference doses for anti-androgenic effects.•Use of the Hazard Index approach for five ...phthalates.•Analysis of the contribution of single phthalates to combined risks.•Caution against the use of HI = 1 as signalling acceptable combined exposures.•Approach for taking account of exposures to other anti-androgens.
In several human biomonitoring surveys, changes in the usage patterns of phthalates have come to light, but their influence on the risks associated with combined exposures is insufficiently understood. Based on the largest study to date, the 27-year survey of urinary phthalate metabolite levels in 24-hour urine samples from the German Environmental Specimen Bank, we present a deep analysis of changing phthalate exposures on mixture risks. This analysis adopts the Hazard Index (HI) approach based on the five phthalates DBP, DIBP, BBP, DEHP and DINP. Calculations of the hazard index for each study participant included updated phthalate reference doses for anti-androgenicity (RfDAAs) that take account of new evidence of phthalates’ developmental toxicity.
The Maximum Cumulative Ratio (MCR) approach was used to establish whether a subject’s combined exposure was dominated by one phthalate or was influenced by several phthalates simultaneously. Generally, over the years there was a shift towards lower HIs and higher MCRs, reflecting an increased complexity of the combined exposures. The decade from 1988 to about 1999 was characterised by rather high HIs of between 3 and 7 (95th percentile) which were driven by exposure to DBP and DEHP, often exceeding their single acceptable exposures. Traditional single phthalate risk assessments would have underestimated these risks by up to 50%. From 2006 onwards, no study participant experienced exposures above acceptable levels for a single phthalate, but combined exposures were still in excess of HI = 1. From 2011 onwards most individuals stayed below HI = 1. In interpreting these results, we caution against the use of HI = 1 as an acceptable limit and develop proposals for improved and more realistic mixture risk assessments that take account of co-exposures to other anti-androgenic substances also capable of disrupting the male reproductive system. From this perspective, we regard HIs between 0.1 and 0.2 as more appropriate for evaluating combined phthalate exposures. Assessed against lowered HIs of 0.1 – 0.2, the combined phthalate exposures of most study participants exceeded acceptable levels in all study years, including 2015. Continued monitoring efforts for phthalate combinations are required to provide the basis for appropriate risk management measures.
The UV filter 2‑ethylhexyl salicylate (EHS) is widely used in sunscreens and other personal care products (PCP). EHS has been detected in a variety of environmental matrices. However, data on the ...internal EHS exposure in humans is not available, due to the lack of exposure biomarkers and analytical methods for their determination. Here, we report a method for the determination of three oxidative EHS metabolites in human urine: 2‑ethyl‑5‑hydroxyhexyl 2‑hydroxybenzoate (5OH-EHS), 2‑ethyl‑5‑oxohexyl 2‑hydroxybenzoate (5oxo-EHS), and 5‑(((2‑hydroxybenzoyl)oxy)methyl)heptanoic acid (5cx-EPS). Urine samples are incubated with β‑glucuronidase and analyzed by liquid chromatography-electrospray ionization-triple quadrupole-tandem mass spectrometry, coupled with online sample clean-up and analyte enrichment using turbulent flow chromatography (online-SPE-LC-MS/MS). Quantification is performed by stable isotope dilution analysis, using deuterium-labeled standards of each of the three metabolites. The described method is precise (coefficient of variation <5% within-series and interday), accurate (mean relative recoveries between 96% and 105%), and sensitive, with limits of quantification (LOQ) of 0.01 μg/L (5cx-EPS), 0.05 μg/L (5OH-EHS), and 0.15 μg/L (5oxo-EHS). After dermal application of an EHS containing sunscreen to a human volunteer, we were able to quantify all three metabolites in urine samples collected post application, showing clear elimination kinetics. In spot urine samples from the general population (n = 35) we were able to quantify EHS biomarkers in 91% of all samples, with highest concentrations in individuals (n = 11) who stated use of PCPs containing UV filters within 5 days prior to sampling. We will apply the method for investigating human EHS metabolism and in future human biomonitoring studies for EHS exposure and risk assessment.
•Determination of three urinary metabolites of the UV filter 2‑ethylhexyl salicylate•All three metabolites are specific side chain oxidation products.•LC-MS/MS coupled with online sample clean-up using turbulent flow chromatography•After sunscreen use detection of all metabolites with clear excretion kinetics•Metabolites found >LOQ in 91% of urine samples from pilot population (n = 35)
Phthalates are a class of chemicals widely used as plasticisers in a multitude of common consumer products. Through contact with such products, people are regularly exposed to phthalates, which are ...suspected to contribute to adverse health effects, particularly in the reproductive system.
In the present study, 14 urinary phthalate metabolites of 10 parent phthalates were analysed by HPLC–MS/MS among the Austrian population aged 6–15 and 18–81 years in order to assess phthalate exposure. In the total study population, ranges of urinary phthalate metabolite concentrations were n.d.–2,105μg/l (median 25μg/l) for monoethyl phthalate (MEP), n.d.–88μg/l (10μg/l) for mono-n-butyl phthalate (MnBP), n.d.–248μg/l (28μg/l) for mono-isobutyl phthalate (MiBP), n.d.–57μg/l (1.8μg/l) for mono-benzyl phthalate (MBzP), n.d.–20μg/l (n.d.) for mono-(2-ethylhexyl) phthalate (MEHP), n.d.–80μg/l (2.6μg/l) for mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), n.d.–57μg/l (1.9μg/l) for mono-(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), n.d.–219μg/l (11μg/l) for mono-(5-carboxy-2-ethylpentyl) phthalate (5cx-MEPP), n.d.–188μg/l (1.6μg/l) for 3-carboxy-mono-proply phthalate (3cx-MPP), n.d.–5.5μg/l (n.d.) for mono-cyclohexyl phthalate (MCHP), n.d.–4.5μg/l (n.d.) for mono-n-pentyl phthalate (MnPeP), n.d.–3.4μg/l (n.d.) for mono-n-octyl phthalate (MnOP), n.d.–13μg/l (n.d.) for mono-isononyl phthalate (MiNP), and n.d.–1.1μg/l (n.d.) for mono-isodecyl phthalate (MiDP). Generally, children exhibited higher levels of exposure to the majority of investigated phthalates, except to MEP, which was found in higher concentrations in adults and senior citizens at a maximum concentration of 2,105μg/l. Individual daily intakes were estimated based on urinary creatinine and urinary volume excretion and were then compared to acceptable exposure levels, leading to the identification of exceedances of mainly the Tolerable Daily Intakes (TDI), especially among children. The execution of a cumulative risk assessment based on Hazard Indices showed cause for concern mainly for children, as well as in rare cases for adults.
Although phthalate exposure seems to have decreased in previous years, the wide distribution and existing exceedances of acceptable levels indicate that phthalate exposure should be further monitored in order to identify exposure sources and enable appropriate minimisation measures.
Prenatal exposure to bisphenol A (BPA) has been associated with adverse birth outcomes, but findings of previous studies have been inconsistent.
We investigated the relation of prenatal BPA exposure ...with intrauterine growth and evaluated the effect of the number of measurements per subject on observed associations.
This study was embedded in a Dutch population-based prospective cohort study, with urine samples collected during early, mid-, and late pregnancy. The study comprised 219 women, of whom 99 had one measurement, 40 had two measurements, and 80 had three measurements of urinary BPA. Fetal growth characteristics were repeatedly measured by ultrasound during pregnancy and combined with measurements at birth. Linear regression models for repeated measurements of both BPA and fetal growth were used to estimate associations between urinary concentrations of creatinine-based BPA (BPACB) and intrauterine growth.
The relationship between BPACB and fetal growth was sensitive to the number of BPA measurements per woman. Among 80 women with three BPA measurements, women with BPACB > 4.22 μg/g crea (creatinine) had lower growth rates for fetal weight and head circumference than did women with BPACB < 1.54 μg/g crea, with estimated differences in mean values at birth of -683 g (20.3% of mean) and -3.9 cm (11.5% of mean), respectively. When fewer measurements were available per woman, the exposure-response relationship became progressively attenuated and statistically nonsignificant.
Our findings suggest that maternal urinary BPA may impair fetal growth. Because previous studies have shown contradictory findings, further evidence is needed to corroborate these findings in the general population.
The production and use of the plasticisers Hexamoll® DINCH (di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate) and DPHP (di-(2-propylheptyl) phthalate) have increased after both chemicals were introduced ...into the market in the early 2000s as substitutes for restricted high molecular weight phthalates.
During the population representative German Environmental Survey (GerES) of Children and Adolescents (GerES V, 2014–2017), we collected urine samples and measured the concentrations of DINCH and DPHP metabolites in 2228 and in a subsample of 516 participants, respectively.
We detected DINCH and DPHP metabolites in 100% and 62% of the 3–17 years old children and adolescents, respectively.
Geometric means of DINCH metabolites were 2.27 μg/L for OH-MINCH, 0.93 μg/L for oxo-MINCH, 1.14 μg/L for cx-MINCH and 3.47 μg/L for DINCH (Σ of OH-MINCH + cx-MINCH). Geometric means of DPHP metabolites were 0.30 μg/L for OH-MPHP, 0.32 µg/L for oxo-MPHP and 0.64 μg/L for DPHP (Σ of OH-MPHP + oxo-MPHP). The 3–5 years old children had almost 3-fold higher DINCH biomarkers levels than adolescents (14–17 years). Higher concentrations of DPHP biomarkers among young children only became apparent after creatinine adjustment. Urinary levels of DINCH but not of DPHP biomarkers were associated with the levels of the respective plasticisers in house dust.
When compared to HBM health-based guidance values, we observed no exceedance of the HBM-I value of 1 mg/L for DPHP (Σ of OH-MPHP + oxo-MPHP). However, 0.04% of the children exceeded the health based guidance value HBM-I of 3 mg/L for DINCH (Σ of OH-MINCH + cx-MINCH). This finding shows that even a less toxic replacement of restricted chemicals can reach exposures in some individuals, at which, according to current knowledge, health impacts cannot be excluded with sufficient certainty.
In conclusion, we provide representative data on DINCH and DPHP exposure of children and adolescents in Germany. Further surveillance is warranted to assess the substitution process of plasticisers, and to advise exposure reduction measures, especially for highly exposed children and adolescents. Providing the results to the European HBM Initiative HBM4EU will support risk assessment and risk management not only in Germany but also in Europe.
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