Gerhard Andreas Wiesmüller

Fetal exposure to phthalates--a pilot study.

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<0.001) in the AF and MU samples. We also found a significant correlation for the DEHP monoester (MEHP) (r=0.91; p<0.001), although there was a most likely external contamination with MEHP in the MU samples. Our results suggest that several phthalates or their metabolites, respectively, reach the human fetus, which might be able to affect fetal health. Further research is needed to elucidate fetal metabolism of phthalates and to evaluate the in utero phthalate exposure and the potential effects on fetal reproductive development. Due to the continuous turn over of AF, urinary levels may be most appropriate for assessing both maternal and fetal phthalate exposure.

Trends of the internal phthalate exposure of young adults in Germany—Follow-up of a retrospective human biomonitoring study

The exposure of the general population to phthalates is of increasing public health concern. Variations in the internal exposure of the population are likely, because the amounts, distribution and application characters of the phthalate use change over time. Estimating the chronological sequences of the phthalate exposure, we performed a retrospective human biomonitoring study by investigating the metabolites of the five most prominent phthalates in urine. Therefore, 24h-urine samples from the German Environmental Specimen Bank (ESB) collected from 240 subjects (predominantly students, age range 19-29 years, 120 females, 120 males) in the years 2002, 2004, 2006 and 2008 (60 individuals each), were analysed for the concentrations of mono-n-butyl phthalate (MnBP) as metabolite of di-n-butyl phthalate (DnBP), mono-iso-butyl phthalate (MiBP) as metabolite of di-iso-butyl phthalate (DiBP), mono-benzyl phthalate (MBzP) as metabolite of butylbenzyl phthalate (BBzP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), mono-(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP) and mono-(2-carboxymethyl hexyl) phthalate (2cx-MMHxP) as metabolites of di(2-ethylhexyl) phthalate (DEHP), monohydroxylated (OH-MiNP), monooxidated (oxo-MiNP) and monocarboxylated (cx-MiNP) mono-iso-nonylphthalates as metabolites of di-iso-nonyl phthalates (DiNP). Based on the urinary metabolite excretion, together with results of a previous study, which covered the years 1988-2003, we investigated the chronological sequences of the phthalate exposure over two decades. In more than 98% of the urine samples metabolites of all five phthalates were detectable indicating a ubiquitous exposure of people living in Germany to all five phthalates throughout the period investigated. The medians in samples from the different years investigated are 65.4 (2002), 38.5 (2004), 29.3 (2006) and 19.6 μg/l (2008) for MnBP, 31.4 (2002), 25.4 (2004), 31.8 (2006) and 25.5 μg/l (2008) for MiBP, 7.8 (2002), 6.3 (2004), 3.6 (2006) and 3.8 μg/l (2008) for MBzP, 7.0 (2002), 5.6 (2004), 4.1 (2006) and 3.3 μg/l (2008) for MEHP, 19.6 (2002), 16.2 (2004), 13.2 (2006) and 9.6 μg/l (2008) for 5OH-MEHP, 13.9 (2002), 11.8 (2004), 8.3 (2006) and 6.4 μg/l (2008) for 5oxo-MEHP, 18.7 (2002), 16.5 (2004), 13.8 (2006) and 10.2 μg/l (2008) for 5cx-MEPP, 7.2 (2002), 6.5 (2004), 5.1 (2006) and 4.6 μg/l (2008) for 2cx-MMHxP, 3.3 (2002), 2.8 (2004), 3.5 (2006) and 3.6 μg/l (2008) for OH-MiNP, 2.1 (2002), 2.1 (2004), 2.2 (2006) and 2.3 μg/l (2008) for oxo-MiNP and 4.1 (2002), 3.2 (2004), 4.1 (2006) and 3.6 μg/l (2008) for cx-MiNP. The investigation of the time series 1988-2008 indicates a decrease of the internal exposure to DnBP by the factor of 7-8 and to DEHP and BzBP by the factor of 2-3. In contrast, an increase of the internal exposure by the factor of 4 was observed for DiNP over the study period. The exposure to DiBP was found to be stable. In summary, we found decreases of the internal human exposure for legally restricted phthalates whereas the exposure to their substitutes increased. Future investigations should verify these trends. This is of increasing importance since the European Commission decided to require ban or authorization from 1.1.2015 for DEHP, DnBP, DiBP and BzBP according to REACh Annex XIV.

Perfluorinated compounds in the vicinity of a fire training area--human biomonitoring among 10 persons drinking water from contaminated private wells in Cologne, Germany.

In Cologne, Germany, increased concentrations of perfluorinated compounds (PFC) have been observed in two private wells used for drinking water purposes. Both wells are located in the vicinity of a fire training area. Use of well water as a source of drinking water was prohibited by the Public Health Department of the City of Cologne. A human biomonitoring (HBM) survey was performed among all persons, who consumed water from these private wells (N=10). PFC concentrations in water of the private wells and in blood samples were analysed by tandem mass spectrometry with electrospray ionization (LC-ESI-MS/MS). Repeated water analyses (seven measurements between December 2009 and November 2010) indicated a decrease of PFOS from 8.35 to 1.60 μg/l, (PFHxS: 2.36-0.15 μg/l; PFOA: 0.16-0.03 μg/l) in one private well. Although situated close together, PFC-concentrations in the other private well were significantly lower. PFOS-concentrations in blood samples of private well water consumers ranged from 4.8 to 295 μg/l (PFHxS: 12.1-205 μg/l; PFOA: 4.0-18 μg/l). Although no data on the formulation of the firefighting foams applied on the fire training area is available, firefighting foams are supposed to be the most likely source of contamination. These findings give reason to track systematically the application of PFC-containing firefighting foams in order to identify contaminations of surface, ground and drinking waters.

Preliminary observations on perfluorinated compounds in plasma samples (1977-2004) of young German adults from an area with perfluorooctanoate-contaminated drinking water.

In May 2006, a serious environmental contamination with perfluorinated compounds (PFCs) became evident in a rural area of North Rhine-Westphalia (NRW) (Region Sauerland), Germany. In autumn 2006, we performed a human biomonitoring study in which a 4-8-fold increase in perfluorooctanoate (PFOA)-plasma concentrations of children, their mothers and men living in Arnsberg (District Hochsauerlandkreis, NRW) was observed compared with a reference population. The exposure was clearly related to the consumption of PFOA-contaminated tap water. However, there is no clear information on the duration of this contamination. The current investigation involves the analysis of PFCs in 30 blood samples of young adults (age 20-31 years) who had ever lived in the affected area. The samples were taken between 1977 and 2004 and stored at the German Environmental Specimen Bank for Human Tissues. Analyses of PFOA, perfluoroctanesulfonate (PFOS), perfluorohexanoate (PFHxA), perfluorohexanesulfonate (PFHxS), perfluoropentanoate (PFPA) and perfluorobutanesulfonate (PFBS) in blood plasma were performed by solid-phase extraction, HPLC and MS/MS detection. PFOA values (median, range) were 6.1, 1.7-40.7 microg/l, PFOS values were 18.8, 8.1-150.7 microg/l and PFHxS values were 1.7, 0.5-4.6 microg/l. The concentrations of PFHxA, PFPA and PFBS in plasma were all below limit of detection. Time-trend analysis showed that between 1977 and 2004 PFOA and PFOS levels remained fairly stable. PFOS and PFOA levels were in the range of current background levels of the general population. In contrast, PFHxS plasma levels have steadily increased since 1977. There was a close association between PFOS and PFOA-plasma levels. From this pilot study there are no indications for an increased exposure to PFCs of residents in Arnsberg in the years 1977-2004 prior to the contamination in 2006.

Sequence variations in subjects with self-reported multiple chemical sensitivity (sMCS): a case-control study.

Polymorphisms in several genes contribute to interindividual differences in the metabolism of xenobiotics, and may lead to toxicity and disease. The balance between activation and/or detoxification processes may influence an individuals susceptibility to disease. One postulated mechanism underlying multiple chemical sensitivity (MCS) is based on increased metabolism of xenobiotics. The aim of the present study was to determine such polymorphisms in cases with self-reported MCS (sMCS) and controls. sMCS cases (14 men, 45 women, mean age: 48 yr) and controls (14 men, 26 women, mean age: 44 yr) of the same anthroposphere were characterized using the MCS-questionnaire from Hüppe and coworkers (2000) and a standardized questionnaire for living conditions and living factors. Allelic frequencies of genomic variations for 5HTT, NAT1, NAT2, PON1, PON2, and SOD2 were determined. The MCS questionnaire from Hüppe et al. (2000) differentiated between cases and controls with 87.5% sensitivity and 90% specificity. Compared to controls the sMCS cases had lower exposures, especially to odorous factors, and worse social conditions. No significant differences of the allelic distribution of genetic polymorphisms in the genes for 5HTT, NAT1, NAT2, PON1, PON2, and SOD2 were found between cases and controls. The results are in contrast to the study of McKeown-Eyssen and coworkers (2004) but in accordance with the German MCS multicenter study. Although the MCS questionnaire from Hüppe et al. (2000) allowed us to differentiate sMCS cases and controls, it was not strong enough for a discrimination based on sequence variations in genes for enzymes involved in xenobiotic metabolism. Therefore, further research needs to focus on a unique phenomenological characterization of MCS.

Internal platinum, palladium, and gold exposure in environmentally and occupationally exposed persons.

In a pilot study the urinary platinum (Pt), palladium (Pd), and gold (Au) excretion was analyzed in 27 dental technicians, 17 road construction workers and 17 school-leavers using sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). Detection limits in urine were 0.24 ng/l for Pt and Au and 0.17 ng/l regarding Pd. A standardized questionnaire was used to assess information about kind and degree of contact to these metals, the physical condition of the volunteers and confounding factors. Significant differences between the three study groups were found. The mean Pt, Pd, and Au excretions of the dental technicians were significantly higher than those of the road construction workers and school-leavers. This indicates that the occupational treatment of dental alloys leads to an internal exposure to these metals which is distinctly higher than that from automobile exhaust exposure. Significant differences between Monday morning (pre-shift) and Thursday afternoon (post-shift) urine samples of the dental technicians were not found. The Pt excretion of road construction workers working near a much traveled highway was comparable with that of school-leavers being less (only environmentally) exposed to automobile exhaust. Regarding Pd and Au the road construction workers showed a tendency to higher levels in urine when compared with the school-leavers, but statistically significant differences were not found. The tendency to higher urinary Pd and Au levels in the road-construction workers may be explained by their slightly greater number of noble metal containing artificial dentures, which may cause an additional exposure. A statistically significant effect of age on the urinary noble metal excretion was not detectable.

C-Reactive Protein Levels and Clinical Symptoms Following Gadolinium Administration in Hemodialysis Patients

BACKGROUND Until recently, gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) has increasingly replaced iodinated contrast agent examinations in dialysis patients, although only limited data existed about the clinical safety of Gd contrast agents in these patients. Specific clinical adverse events (AEs), including nephrogenic systemic fibrosis, were linked to Gd exposure in dialysis patients. An inflammatory reaction or transmetallation may be involved. STUDY DESIGN Secondary analysis of a 5-day observational study in a parent cardiovascular study with repetitive cardiac MRI (32 patients) and patients undergoing Gd-enhanced MRI for clinical indications (6 patients). Clinical information and samples were obtained according to parent protocol. SETTING & PARTICIPANTS Dialysis patients at a university-based dialysis unit. PREDICTOR Gd-chelate complex. 37 of 38 patients underwent 64 MRI studies with Gd-diethylenetriamine penta-acetic acid (Gd-DTPA). 25 of these patients underwent additional MRI studies with gadobutrol (n = 10), 0.9% saline (n = 7), or both (n = 8), and 1 patient received gadobutrol only. OUTCOMES Clinical adverse events; C-reactive protein (CRP) levels on days 1, 3, and 5 after MRI; Gd levels in blood and urine after MRI. RESULTS CRP levels increased 10-fold on day 3 after MRI in 87% of MRI studies with Gd-DTPA (+59.3 +/- 57.9 mg/L [P < 0.001] versus -0.9 +/- 3.7 mg/L with gadobutrol versus -0.9 +/- 8.5 mg/L with 0.9% saline). 77 mild to moderate and 3 serious AEs were observed in 24 patients. CRP levels and adverse events did not correlate with Gd blood concentrations. CRP level increase or AEs were not observed after MRI with gadobutrol or 0.9% saline. LIMITATIONS Observational study without randomization, risk of bias because of multiple MRI studies in a limited patient cohort. CONCLUSION Gd-DTPA, but not gadobutrol, induces an acute-phase reaction and clinical AEs in dialysis patients. Additional investigations have to analyze the underlying pathomechanism.

Clinical Environmental Medicine

INTRODUCTION Clinical environmental medicine deals with environmental effects on human health in individual patients. Patients seek medical advice for problems of many different kinds that may be due to environmental exposures; such exposures must be considered carefully along with other potential causes. An environmental medical assessment should include thorough medical history-taking and physical examination, the formulation of a differential diagnosis, and (whenever indicated) human biomonitoring, site inspections, and ambient monitoring. METHODS This review of clinically relevant environment-related health disturbances is based on a selective evaluation of the pertinent literature and of own experiences. RESULTS Overall, relevant environmental exposures can be identified in up to 15% of patients who attribute their health complaints to environmental factors. (Clinical disorders are more common and more severe in these patients.) 40% to 75% are found to suffer from other physical and/or emotional conditions without any specific environmental aspect, i.e., without any apparent or verifiable exposure. DISCUSSION Despite the relative rarity of verifiable environmentally related health disturbances, these must be clearly identified and delimited to avoid further harmful exposures. Environmental medical counseling should include risk assessment and behavior recommendations for all patients who attribute their medical problems to their environment. Physicians performing specific environmental-medical diagnostic procedures must be aware of their limitations in order to avoid performing tests whose results have no therapeutic consequences and are thus of no help to either the physician or the patient.

Working memory deficiencies in adults associated with low-level lead exposure: implications of neuropsychological test results

BACKGROUND Although lead exposure has steadily decreased in the last few years, some lead is still used in the metal processing industry, mostly for wall paints and plumbing. Recent studies on children showed neurobehavioral effects of low-level exposure, but little is known about the neurocognitive effects of lead concentrations in the upper reference range on adults. METHODS The neuropsychological effects of lead exposure were examined in 39 adult outpatients at the Unit of Environmental Medicine (UEM), University Hospital, Aachen, Germany. All patients underwent a comprehensive medical examination, including psychiatric. Venous blood and urine samples were collected and tested for heavy metals and selenium. Since the neuropsychological examination was not expected to reveal any severe abnormalities, only specific attentiveness functions were analyzed (alertness, working memory, flexibility, intermodal comparison) since these areas were the likeliest to show objectifiable effects. The tests were conducted using a standardized computerized battery. RESULTS Lead blood levels ranged from 1 to 65.6 microg/l (mean 27.4 +/- 16.2 microg/l). Although the neuropsychological test results of all patients were within the normal range, there were significant correlations between blood lead levels and the speed of information processing for working memory. CONCLUSIONS The results indicate working memory dysfunctions in adults, the severity of which correlates directly with blood lead levels, supporting the hypothesis that increased blood lead levels can also be associated with measurable neurocognitive abnormalities.

Predictive value of human biomonitoring in environmental medicine: Experiences at the outpatient unit of environmental medicine (UEM) of the University Hospital Aachen, Germany

There is little data on the distribution of biomonitoring parameters in patients at outpatient Units of Environmental Medicine (UEM). We evaluated the biomonitoring parameters of 646 UEM outpatients from our University Hospital 1988-1998. Few patients were exposed to specific substances. Data of patients who were not obviously exposed was analysed statistically (geometric mean, standard deviation, median, 95th percentile). Results were compared with reference values in literature. Normal distribution of biomonitoring parameters was rare. 95th percentiles for arsenic, chromium, selenium, zinc, phenol and toluene were below standard, 95th percentiles for copper and mercury above, and 95th percentiles for lead, cadmium, pentachlorophenol, lindane, and beta-hexachlorocyclohexane were within the published range of reference values. Thallium as well as most volatile organic compounds analyzed were below detection levels. Aluminum and fluorine exposure was rarely analysed. In view of these results, it is concluded that the indication for biomonitoring needs to be stringent as levels of biomonitoring parameters are generally not risen in patients of the UEM.