DEHP and its active metabolites: leaching from different tubing types, impact on proinflammatory cytokines and adhesion molecule expression. Is there a subsumable context?

INTRODUCTION: Di(2-ethylhexyl)phthalate (DEHP) is suspected to be toxic for several reasons. During contact with a lipophilic medium, DEHP leaks from polyvinylchloride (PVC), but its influence on inflammatory reactions remains unknown. We examined specific DEHP leaching out of different tubing types, the possibly modulated liberation of proinflammatory cytokines and the induction of adhesion molecule expression in primary endothelial cells. MATERIALS AND METHODS: Blood samples were circulated in traditional PVC, nodioctyl phthalate (DOP) PVC and heparin-coated PVC tubing within a Chandler loop model. The blood was tested for the concentration of DEHP and its active metabolites as well as the liberation of the proinflammatory cytokines TNFα and IL1ß. Furthermore, we exposed human endothelial cells to circulated blood and analysed them for the expression of the adhesion molecules ICAM-1, VCAM-1 and E-selectin. RESULTS: In contrast to the other tubing, PVC tubing showed significantly elevated DEHP levels, but no alteration was observed concerning a potential up-regulation of the cytokines or activation of the endothelial adhesion molecule receptors. CONCLUSIONS: Our data conclude that there is no correlation between DEHP leaching and the inflammatory response after ECC support, but this study showed that even DEHP-free material is leaching DEHP and its toxic metabolites.

Influence of plasticizer-free CAPD bags and tubings on serum, urine, and dialysate levels of phthalic acid esters in CAPD patients.

OBJECTIVES: To evaluate the impact of a plasticizer-free device on exposure to di-(2-ethylhexyl) phthalate (DEHP) and its major metabolites in patients on continuous ambulatory peritoneal dialysis (CAPD). DEHP is the most commonly used plasticizer in polyvinyl chloride (PVC) products; it is added to CAPD bags in order to improve the flexibility of the material. Since DEHP leaches out of the plastic matrix, patients on CAPD are exposed to considerable amounts of DEHP and its metabolites. DESIGN: A prospective cross-over study. SETTING: Department of nephrology in a teaching hospital. PARTICIPANTS: Six patients (4 female, 2 male) stable on peritoneal dialysis (PD) for at least 6 months. INTERVENTIONS: Patients were switched from a plasticizer-containing PVC CAPD system (A.N.D.Y. Plus, Fresenius Medical Care, Bad Homburg, Germany) to a polyolefine-made plasticizer-free system (stay-safe, Fresenius). MAIN OUTCOME MEASURES: Prior to and 42 days after the switch, 24-hour effluent dialysate and urine collections were performed and 10 mL blood was drawn. Concentrations of DEHP, mono-(2-ethylhexyl) phthalate (MEHP), phthalic acid (PA), and 2-ethylhexanol (2-EH) in urine, dialysate, and serum were determined using gas chromatography/mass spectrometry. RESULTS: Complete data were obtained from 5 patients. Serum levels of PA decreased significantly during the study period (0.137 +/- 0.078 mg/L vs 0.124 +/- 0.049 mg/L, p = 0.04), and the respective levels of DEHP decreased insignificantly (0.097 +/- 0.076 mg/L vs 0.069 +/- 0.046 mg/L, p = 0.07), whereas the concentrations of MEHP and 2-EH remained unchanged. Urine concentrations of PA were high (0.81 +/- 0.69 mg/L) but did not change substantially (0.70 +/- 0.50 mg/L). Effluent dialysate concentrations of MEHP and PA decreased significantly (0.0176 +/- 0.004 mg/L vs 0.0040 +/- 0.0007 mg/L, p = 0.043 and 0.158 +/- 0.056 mg/L vs 0.111 +/- 0.051 mg/L, p = 0.043, respectively). CONCLUSIONS: Although PD patients seem to be exposed to other sources of phthalates in addition to dialysis, use of plasticizer-free devices may help to reduce potentially immunosuppressive exposure to phthalate esters.

[Insufficient ventilation as the etiology of illness perception in an elementary school]. / Mangelhafte Lüftung als Auslöser von Befindlichkeitsstörungen in einer Grundschule.

PURPOSE: Two years after renovation of the classrooms in a primary school (installation of insulated windows and closing of the ventilation shaft) pupils and teachers complained about offensive odours, irritation of the eyes and of the nose, complaints of the respiratory tract, headaches and disturbed mental concentration. The presented study determines the causes, suggests measures for help and checks their effectiveness by means of measurements. METHODS: Before starting our measurements, the air quality had already been assessed by an expert. There was no evidence of elevated concentrations of air contaminants. Because of the content of phthalate plasticizers and flame retardants in the linoleum sealants there was an offensive odour. To determine the cause, the air in the subjective mostly affected classroom was analysed for phthalate plasticizers, their metabolites and alkyl phosphates. We also made aerosol measurements with a cascade impactor, determined bacterial counts in the air, and measured the indoor climate and the internal air flow. RESULTS: The concentrations of phthalate plasticizers and their metabolites in the air were not elevated significantly. The screening for alkyl phosphates was negative. The amount of inhalable particles was 0.046 mg/m3. The bacterial count in the air was negligible. On the other hand the indoor climate during the heating period in winter was remarkably changed. The average room temperature was 26 degrees C (reaching a maximum of 36 degrees C with direct sunlight in the classroom), the average humidity was 21% (minimum 7%) and the change of air was approximately 0.5 per hour. Reopening the ventilation shaft and tilting of only one window resulted in a much greater rate of air change. After installation of temperature regulators and regular use of the venetian blinds in the classroom, the room temperature and the relative humidity during the morning lessons were, as a rule, normalised. Among both pupils and teachers the reports of offensive odours and health disorders were subsequently clearly reduced. CONCLUSIONS: To determine the cause of health disorders indoors, it is apparently to be of great importance to carry out measurements of the climate as well as to assess the level of air contaminants. By use of modern energy-saving construction possible effects on the indoor climate should be be taken into account during the planning stage of changes to avoid health disorders resulting from changed interior climate conditions.

Uraemic pruritus and exposure to di(2-ethylhexyl) phthalate (DEHP) in haemodialysis patients.

Uraemic pruritus is a frequent and disabling symptom in patients on dialysis. The pathogenesis of uraemic pruritus is nevertheless still obscure. We investigated whether di(2-ethylhexyl)phthalate (DEHP), the most commonly used plasticizer in polyvinylchloride (PVC) haemodialysis tubings, is a possible pathogenetic factor in uraemic pruritus. Serum concentrations of DEHP and its major derivatives mono-(2-ethylhexyl)phthalate (MEHP), 2-ethylhexanol (2-EH) and phthalic acid (PA) were determined in uraemic patients before and after a haemodialysis session and compared with the occurrence and intensity of pruritus in these patients. Twenty-one patients on regular haemodialysis for at least 6 months were examined. The severity of uraemic pruritus was assessed using a standard questionnaire (pruritus score). The quantitative analysis of DEHP and its derivatives was carried out by GC/selected ion monitoring mass spectrometry. Fourteen out of 21 patients (66%) complained about uraemic pruritus to a variable degree. The post-dialysis serum concentrations of DEHP, MEHP and 2-EH were significantly higher than the corresponding pre-dialysis values, whereas the post-dialysis concentrations of PA (0.122 +/- 0.078 microgram/microliter) were significantly lower than pre-dialysis levels (0.194 +/- 0.101 microgram/microliter, P = 0.00068). Neither pre- nor post-dialysis serum concentrations of DEHP, MEHP, PA or 2-EH were correlated with the severity of uraemic pruritus. Additionally, serum concentrations of DEHP and its metabolites did not differ significantly in patients with and without pruritus. These findings suggest that patients on haemodialysis are regularly exposed to considerable amounts of DEHP and metabolites. Phthalic acid, one of the presumed end products of DEHP metabolism, might be eliminated at least in part by haemodialysis. The exposition to DEHP and metabolites during haemodialysis, as assessed by measuring serum concentrations, bears no immediate relation to the occurrence or intensity of uraemic pruritus.

Occurrence of polychlorinated terphenyls (PCTs) in indoor particulate matter.

In the course of a routine investigation concerned with polychlorinated biphenyl (PCB) contamination of dust collected in classrooms of a junior high school, a group of electron capture detector (ECD)-sensitive compounds with high boiling points were found in addition to PCBs. Using gas chromatographic-mass spectrometric techniques, these compounds were identified as polychlorinated terphenyls (PCTs). Additional measurements indicated that the PCTs were present only in particulate matter collected from the tops of fluorescent light frames but not in air samples obtained concomitantly in the classrooms. Attempts to identify the PCT emission source were unsuccessful. A survey of the literature revealed that PCTs are ubiquitously distributed environmental contaminants, although no data on their indoor occurrence have been reported to date. In view of the toxic effects of PCTs, which seem to be as important as those of PCBs, further attention should be given to the possible presence of PCTs in indoor environments.

The fate of leached di(2-ethylhexyl)phthalate in patients undergoing CAPD treatment.

OBJECTIVES: To evaluate the degree of exposure to and the fate of di(2-ethylhexyl)phthalate (DEHP) and its major derivatives mono(2-ethylhexyl)phthalate (MEHP), 2-ethylhexanol (2-EH), and phthalic acid (PA) in patients undergoing regular continuous ambulatory peritoneal dialysis (CAPD) during a 4-hour dwell period. DESIGN: Prospective, controlled. SETTING: Teaching hospital, Department of Nephrology. PARTICIPANTS: Seven elderly patients on stable CAPD using Fresenius instruments and dialysate and 6 age-matched healthy controls. INTERVENTIONS: During a routinely performed peritoneal equilibration test (PET), blood and dialysate samples were drawn before and 120 and 240 min after the dwell was started. In addition, blood samples were taken from a group of volunteers participating in a pharmacological study. MEASUREMENTS: Quantitative analysis of DEHP and its hydrolysis products was performed by selected ion-monitoring gas chromatography/mass spectrometry, operating the mass spectrometer in a combined positive and negative ion chemical ionization mode. RESULTS: Serum concentrations of DEHP and PA were significantly higher in patients (median: 0.079 microgram/mL, range: 0.032-0.210 microgram/mL; and 0.167 microgram/mL, range: 0.097-0.231 microgram/mL, respectively) than in controls [0.0195 microgram/mL, range: 0.016-0.025 microgram/mL (p = 0.0027) and 0.0120 microgram/mL, range: 0.006-0.034 microgram/mL (p = 0.0026), respectively]. Concentration of MEHP in the fluid of CAPD bags prior to use was four times higher than that of the parent compound. During the first 4 hours of dwell time, the concentrations of MEHP and 2-EH in dialysate consistently decreased from 0.177 (range: 0.137-0.239 microgram/mL) to 0.022 microgram/mL (range: 0.005-0.058 microgram/mL) (p = 0.017), and from 0.087 (range: 0.075-0.097 microgram/mL) to 0.05 microgram/mL (range: 0.023-0.064 microgram/mL) (p = 0.017), respectively, while the concentration of DEHP remained stable. Remarkably high concentrations of PA (0.129 microgram/mL; range: 0.038-0.466 microgram/mL) were found in CAPD bags prior to use, and these concentrations tended to increase during dwell time, without statistical significance, however (0.135 microgram/mL; range: 0.073-0.659 microgram/mL, p = 0.062). CONCLUSIONS: Patients on CAPD are regularly exposed to considerable amounts of phthalic ester derivatives, mainly to MEHP and PA. MEHP seems to be well absorbed by the peritoneal membrane. The long-term effects of this exposure remain to be elucidated.

Determination of butoxyacetic acid and N-butoxyacetyl-glutamine in urine of lacquerers exposed to 2-butoxyethanol.

To determine the fraction of butoxyacetic acid (BAA) which is excreted as the amino acid conjugate N-butoxyacetylglutamine (BAA-GLN), urine samples of six lacquerers exposed to 2-butoxyethanol (BE) were collected before and after work and analysed using an HPLC-method which allows the simultaneous quantification of both BAA species. Whereas the pre-shift samples contained only little or no butoxyethanol-related material, concentrations of BAA and BAA-GLN amounted collectively to up to 7 mmol/l in the samples obtained at the end of work. The ratio BAA-GLN vs. total BAA ranged from 0.16 to 0.64 (mean value 0.48) indicating that a substantial fraction of BAA was eliminated as the amino acid conjugate. The results demonstrate that BAA-GLN is an important metabolite of BE in man. Procedures employed for the biological monitoring of exposure to BE should therefore include the quantification of BAA-GLN, otherwise exposure levels would be underestimated.

Stereometabolism of ethylbenzene in man: gas chromatographic determination of urinary excreted mandelic acid enantiomers and phenylglyoxylic acid and their relation to the height of occupational exposure.

Ethylbenzene is an important industrial solvent and a key substance in styrene production. Ethylbenzene metabolism leads to the formation of mandelic acid, which occurs in two enantiomeric forms, and phenylglyoxylic acid. To decide which enantiomer is preferably formed, 70 urine samples of exposed workers were taken at the end of shifts and--after 3-pentyl ester derivatisation--gas chromatographically analysed. The R/S ratio of mandelic acid enantiomers in urine amounts to 19:1, which means that R-mandelic acid is a major metabolite and S-mandelic acid is one of the minor urinary metabolites of ethylbenzene in man. The R/S ratio is independent of ambient air concentration of ethylbenzene within the investigated range. Compared to an ethylbenzene monoexposure the height of total mandelic acid excretion is decreased in the case of coexposure to other aromatic solvents.

Stereometabolism of styrene in man. Urinary excretion of chiral styrene metabolites.

Chiral styrene metabolites obtained during initial styrene exposure of test persons were determined in urine samples using capillary gas chromatography. A typical time-dependent urinary concentration profile of one person over a 49-h period is presented and compared with the results of a previous study of occupationally exposed workers and an unexposed control group. Maximum levels of excretion of all styrene metabolites were observed at about the end of a 9-h workshift. Forty hours after exposure, the L/D-ratio of mandelic acid had subsided to the initial value, and the L/D-ratio of phenylethylene glycol to a value equal or slightly above the initial value.

Primary non-Hodgkin's lymphomas of the CNS.

This paper reports on 10 patients (4 male, 6 female) with primary non-Hodgkin's lymphomas of the brain (CNS-NHL--mean age 46.8 years, mean postdiagnostic survival 10 months). Pathological CSF (cerebrospinal fluid) was found in all 8 patients examined (positive cytology in 7/8 cases). Solitary tumors, diffuse periventricular infiltration or diffuse cerebral infiltration were demonstrated in cerebral computer-assisted tomography (CAT). Angiographical findings were unspecific. The histologic subtypes were lymphoplasmacytoid immunocytoma (4), unclassified low grade (1), centroblastic (1), B-immunoblastic (1), T-immunoblastic (1), lymphoblastic convoluted T-cell type (1), unclassified high grade (1) NHL. Patients who had received radiotherapy (+/- surgery) in this group had a mean survival of 15.66 months (sigma = 7.63). In addition, an overview of 83 well-documented, cases of the literature tries to characterize main histological and topographical distributions, histology-, patient's age-, and therapy-related survival. Patients with primary CNS-NHL have a 5-year survival expectancy of 30% compared with 2.3% in secondary CNS-manifestations of systemic non-Hodgkin's lymphomas. In this report, the beneficial effect of radiotherapy (mean survival 30.3 months) compared to surgery or symptomatic treatment (3.6 or 3.3 months) could be confirmed. It is concluded that primary CNS-NHL frequently present with atypical neuropsychiatric syndromes; diagnosis should be established preferentially with CAT and CSF-examinations or stereotactic biopsies, whereas open surgery should be avoided. An approach to exact classification should be attempted, as survival is clearly related to histological subtypes.

Stereometabolism of styrene in man: gas chromatographic determination of phenylethyleneglycol enantiomers and phenylethanol isomers in the urine of occupationally-exposed persons.

A gas chromatographic procedure for the determination of phenylethyleneglycol enantiomers and phenylethanol isomers is described and applied to the investigation of urine samples from occupationally styrene-exposed workers (11 males, six females) and an unexposed control group. Phenylethyleneglycol enantiomers and 2-phenylethanol were present in the urine samples of exposed and unexposed individuals whereas 1-DL-phenylethanol was not found in control urine. The L/D enantiomer ratio of phenylethyleneglycol was found to be approximately 3 in the exposed group and 1.5 in the control group. Because of the close structural relation of these metabolites to the primarily formed epoxide, the results give further insight into the stereotoxicity of styrene in man.

Styrene metabolism in man: gas chromatographic separation of mandelic acid enantiomers in the urine of exposed persons.

D- and L-mandelic acid are separated by gas chromatography as isopropyl ester or isopropyl ester-isopropyl urethane on capillary columns, coated with Chirasil -Val. For its determination in urine the isopropyl ester procedure gives better results because other components of the urine do not cause interference. Thus D- and L-mandelic acid in the urine of exposed workers could be detected and verified by means of GC/MS. Occupational styrene exposure near the MAK-value (100 ppm) results in a L/D-enantiomer-ratio in urine of nearly 1.5.

The determination of amino-acid enantiomers in human saliva with Chirasil-Val.

The use of polysiloxanes as stationary phase in glass-capillary gas-chromatography carrying chiral groups enables the separation and quantitation of most amino-acid enantiomers and a variety of other compounds in a much shorter time than previously. This phase exhibits low volatility and high thermal stability and may be used in routine analysis with open tubular columns at temperatures of at least 175 degrees C. Most protein amino acids are separated in a temperature programme between 90 and 175 degrees C, thus obviating the need for multiple injections. Resolution factors are lower than those of other diamide phases containing the L-valine-t. butyl-amide group, but are sufficient for resolution of almost all protein amino-acid enantiomers. Incomplete recovery from the sample, incomplete derivatization, hydrolysis and thermal decomposition of the derivative and shifting response factors can be compensated for by adding the unnatural enantiomer. The accuracy of amino-acid analysis by enantiomer labelling is equal or superior to that of known methods and permits complete analysis of peptides with respect to both amino-acid composition and the optical purity of each amino acid. The application of this method to human saliva provided information concerning enzymic and bacterial process in the mouth.

[Reliability of CT diagnosis in cerebral sinus thrombosis]. / Zur Sicherheit der CT-Diagnose bei zerebralen Sinusthrombosen.

There is no reliable CT diagnosis in all cases of cerebral sinovenous thrombosis. The hyperdense sinus structures may indicate an acute thrombotic occlusion, but we know other reasons of this finding. Only the so-called empty triangle sing is pathognomonic, while the unilateral or bilateral hemorrhages, circumscript or diffuse edema with small ventricles and the tentorial hypervascularity are not specific of sinovenous occlusion. We present our findings in 15 cases of sinovenous thrombosis and conclude, that the combination of clinical course and CT-finding with specific or some non-specific signs will give the correct diagnosis of sinus thrombosis with or without angiography.

[Midline-malformations of brain shown by computed tomography (author's transl)]. / Zerebrale Mittellinienfehlbildungen im axialen Computertomogramm.

The so-called midline-malformations of the brain which include alterations of ventricles or arachnoid spaces formerly only were found by invasive procedures performed because of their various clinical signs. Since cranial computerized tomography is available, by this new noninvasive method all these disturbances can be diagnosed safely. The paper is referring to the most frequent and essential exponents of these midline-malformations together with their main features in anatomy, pathomorphology, clinical and radiological signs. The persistent performed cavities especially the cavum septi pellucidi, the cavum Vergae and the cavum veli interpositi, additionally the agenesis of the corpus callosum, the Dandy-Walker-syndrome and the Chiari-malformations are described by typical cases. In conclusion the reliability of diagnosis in all cases of midline-malformations will be mostly sufficient by plain axial computed tomograms due to very clearly defined unmistakable pictures.

[Watershed infarctions--a special type of infarction in cases with carotid artery stenosis or occlusion verified by CT and angiography (author's transl)]. / Der Grenzzoneninfarkt als besondere Infarktkonstellation bei Karotisinsuffizienz. Eine computertomographisch-angiographische Korrelationsstudie.

Watershed infarctions appear in the axial CT-sections mostly as stained or striated hypodense areas in the white matter of the parietal and seldom temporal region, without or with extension into the supply area of the adjacent cerebral arteries. We observed these changes in approximately 40% of our series with carotid artery stenosis or occlusion. These findings may be very subtle, and in such cases angiography should be performed.