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Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K-ras-2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K-ras-2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K-ras-2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n = 8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K-ras-2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status ofp16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K-ras-2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G → A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G → A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5' CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K-ras-2 mutations, 5 specimens also showed methylated p16. Within the control group, K-ras-2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K-ras-2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K-ras-2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that... [ABSTRACT FROM AUTHOR]

This paper presents the strategy and results of in-flight measurements of airborne aldehydes during normal operation and reported "smell events" on commercial aircraft. The aldehyde-measurement is a part of a large-scale study on cabin-air quality. The aims of this study were to describe cabin-air quality in general and to detect chemical abnormalities during the so-called "smell-events". Adsorption and derivatization of airborne aldehydes on 2,4-dinitrophenylhydrazine coated silica gel (DNPH-cartridge) was applied using tailor-made sampling kits. Samples were collected with battery supplied personal air sampling pumps during different flight phases. Furthermore, the influence of ozone was investigated by simultaneous sampling with and without ozone absorption unit (ozone converter) assembled to the DNPH-cartridges and found to be negligible. The method was validated for 14 aldehydes and found to be precise (RSD, 5.5-10.6%) and accurate (recovery, 98-103 %), with LOD levels being 0.3-0.6 μg/m(3). According to occupational exposure limits (OEL) or indoor air guidelines no unusual or noticeable aldehyde pollution was observed. In total, 353 aldehyde samples were taken from two types of aircraft. Formaldehyde (overall average 5.7 μg/m(3), overall median 4.9 μg/m(3), range 0.4-44 μg/m(3)), acetaldehyde (overall average 6.5 μg/m(3), overall median 4.6, range 0.3-90 μg/m(3)) and mostly very low concentrations of other aldehydes were measured on 108 flights. Simultaneous adsorption and derivatization of airborne aldehydes on DNPH-cartridges to the Schiff bases and their HPLC analysis with UV absorbance detection is a useful method to measure aldehydes in cabin-air of commercial aircraft., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: Systematic collaboration between occupational physicians (OPs) and rehabilitation physicians (RPs) can improve occupational rehabilitation processes and outcomes. The JobReha discharge letter (JR-DL) is a key element of JobReha, a multilevel intervention for specific occupational rehabilitation of workers with musculoskeletal disorders. This feasibility study aims to analyse the perceived benefit and acceptance of the JR-DL as an instrument for improving the communication interface between RPs and OPs., Methods: On the day of discharge from rehabilitation, the rehabilitation physician completed a JR-DL form containing relevant information on the rehabilitation measures undertaken during treatment and recommendations for return to work. The JR-DL was either transmitted to the patient's occupational physician directly or given to the patients to bring to the OP to support the reintegration process. The JR-DL as an instrument for improving the communication interface was evaluated using data from patient questionnaires (n = 250), JR-DLs (n = 247), OP questionnaires (n = 224) and RP questionnaires (n = 232)., Results: All rehabilitation physicians sent a JR-DL to the respective occupational physician on the day of discharge. OPs received the reports a median 2 days after discharge. The content quality and relevance of the JR-DL for the reintegration process were rated high to moderate by more than 97.0 % of the OPs; 92.3 % of the patients received a recommendation to return to their previous workplace; 43.3 % returned with minor limitation; and the remaining 31.6 % with a recommendation for individual reintegration; 74.0 % of the workers returned to work within 3 days of discharge., Conclusions: Use of the JR-DL for the improvement of communication and exchange of relevant information is feasible and supportive for both rehabilitation and occupational physicians. Its positive impact on reintegration and return to work was apparent. Delays in receipt of the JR-DL should be eliminated by appropriate quality assurance measures.

N-Methyl-2-pyrrolidone (NMP) is a versatile organic solvent frequently used for surface cleaning such as paint stripping or graffiti removal. Liquid NMP is rapidly absorbed through the skin but dermal vapour phase absorption might also play an important role for the uptake of the solvent. This particular aspect was investigated in an experimental study with 16 volunteers exposed to 80 mg/m(3) NMP for 8 h under either whole-body, i.e. inhalational plus dermal, or dermal-only conditions. Additionally, the influence of moderate physical workload on the uptake of NMP was studied. The urinary concentrations of NMP and its metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) were followed for 48 h and analysed by gas chromatography-mass spectrometry (GC-MS). Percutaneous uptake delayed the elimination peak times and the apparent biological half-lives of NMP and 5-HNMP. Under resting conditions, dermal-only exposure resulted in the elimination of 71 +/- 8 mg NMP equivalents as compared to 169 +/- 15 mg for whole-body exposure. Moderate workload yielded 79 +/- 8 mg NMP (dermal-only) and 238 +/- 18 mg (whole-body). Thus, dermal absorption from the vapour phase may contribute significantly to the total uptake of NMP, e.g. from workplace atmospheres. As the concentration of airborne NMP does not reflect the body dose, biomonitoring should be carried out for surveillance purposes.

Organic solvents are still essential in many industrial applications. To improve safety and health in the working environment lower occupational thresholds limits have been established and less toxic substitutes were introduced. N-Methyl-2-pyrrolidone (NMP) is a versatile solvent that is used as a substitute for dichloromethane in paint strippers. Due to conflicting results, there is a debate whether NMP causes irritations of the upper airways/eyes or not. In a human experimental study we examined the chemosensory effects of NMP under controlled conditions. Fifteen healthy males were investigated in a cross-over study. NMP vapor concentrations were 10, 40 and 80 mg/m(3) for 2 x 4h with an exposure-free lunch break of 30 min. To maximize chemosensory effects a peak exposure scenario (25mg/m(3) baseline, 160 mg/m(3) peaks 4 x 15 min, time-weighted average: 72 mg/m(3)) was tested. The four different conditions were conducted with and without moderate physical workload. Chemosensory effects were measured physiologically by anterior rhinomanometry, eye blink rate and breathing frequency. Subjectively, ratings of acute health symptoms and intensity of olfactory and trigeminal sensations were collected repeatedly throughout the exposures. All physiological variables were unaffected by the different NMP concentrations and even the peak exposures were non-effective on these measures. Olfactory mediated health symptoms increased dose-dependently. For these symptoms a strong adaptation was observable, especially during the first 4h of the exposures. Other acute symptoms were not significantly affected. Comparable to the symptoms, only olfactory sensations increased dose-dependently. Trigeminal sensations (e.g. eye and nose irritations) were evaluated as being barely detectable during the different exposures, only during 160 mg/m(3) exposure peak weak and transient eye irritation were reported. The results clearly suggest that NMP concentrations of up to 160 mg/m(3) caused no adverse sensory irritation or undue annoyance.

A human experimental study was carried out with 16 volunteers to examine the elimination of N-methyl-2-pyrrolidone (NMP) after exposure to the solvent under simulated workplace conditions. The NMP concentrations were 10, 40 and 80 mg/m(3) for 2 x 4 h with an exposure-free interval of 30 min. Additionally, a peak exposure scenario (25 mg/m(3) baseline, 160 mg/m(3) peaks for 4 x 15 min, time-weighted average: 72 mg/m(3)) was tested. The influence of physical activity on the uptake and elimination of NMP was studied under otherwise identical exposure conditions but involving moderate workload on a bicycle ergometer (75 W for 6 x 10 min). The peak times and biological half-lives of urinary NMP and its main metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) in urine were analysed as well as the interrelationships between exposure and biomarkers. All analytes showed a close correlation between their post-shift peak concentrations and airborne NMP. An exposure to the current German workplace limit value of 80 mg/m(3) under resting conditions resulted in urinary peak concentrations of 2,400 microg/L NMP, 117 mg/g creatinine 5-HNMP and 32 mg/g creatinine 2-HMSI (workload conditions: 3,400 microg/L NMP, 150 mg/g creatinine 5-HNMP, 44 mg/g creatinine 2-HMSI). Moderate workload enhanced the total uptake of NMP by approximately one third. Differences between the estimated and the observed total amount of urinary metabolites point to a significant contribution of dermal absorption on the uptake of NMP. This aspect, together with the influence of physical workload, should be considered for the evaluation of a biological limit value for NMP.

Objectives: N-Methyl-2-pyrrolidone (NMP) is a versatile solvent used in various industrial processes and applications. Apart from its mildly irritating effects on the eyes, the mucous membranes and the skin, NMP has revealed prenatal toxicity in animal experiments after the oral administration of high doses. The dermal absorption of NMP and the urinary elimination of its main metabolites were investigated within an experimental exposure study., Methods: Four male volunteers were exposed to liquid NMP under occlusive conditions on the back of one hand with varying exposure times and solvent concentrations. Urine was collected before, during and after the exposure and analysed for the main NMP metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI)., Results: The urinary concentration of the metabolites upon exposure to undiluted NMP for 2 h increased rapidly with 5-HNMP reaching a maximum at 4-5 h and 2-HMSI after 26-29 h. The application of aqueous NMP solutions resulted in a delay of the peak time for 5-HNMP of approximately 6 h as compared with the undiluted solvent. An average dermal absorption of 5.4+/-1.5 mg NMP cm(-2) h(-1) was calculated for a 2 h exposure to undiluted NMP (6.5+/-2.0 mg NMP cm(-2) h(-1) for a 30 min exposure). Aqueous dilution of NMP to 50% was followed by a decrease of the absorption to 0.9+/-0.5 mg NMP cm(-2) h(-1). NMP metabolite concentrations in the range of the detection limits were found only in isolated urine samples after exposure to 10% NMP in aqueous dilution., Conclusions: NMP is rapidly absorbed across the skin and the dermal route may contribute significantly to the uptake of the solvent. Therefore, a biomonitoring of NMP exposed workers is essential for occupational-medical surveillance. Both urinary metabolites reflect the internal dose after a dermal absorption of NMP and thus qualify as suitable biomarkers for NMP exposure.

Objectives: The exposure of seven workers and three on-site study examiners to N-methyl-2-pyrrolidone (NMP) was studied in an adhesive bonding compound and glue production facility., Methods: Airborne NMP was analysed by personal and stationary sampling on activated charcoal tubes. NMP and its main metabolites, 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI), were analysed in pre-shift and post-shift spot urine samples by gas chromatography-mass spectrometry. The workers were examined with respect to irritation of the eyes, the mucous membranes and the skin, and health complaints before and after the work-shift were recorded., Results: The time-weighted average concentration of NMP in most work areas varied between 0.2 and 3.0 mg/m3. During the manual cleaning of stirring vessels, valves and tools, 8-h TWA exposures of up to 15.5 mg/m3 and single peak exposures of up to 85 mg/m3) were observed. NMP and its metabolites were detected in two pre-shift urine specimens. NMP and 5-HNMP concentrations in post-shift urine samples of five workers and three on-site study examiners were below 125 microg/g creatinine and 15 mg/g creatinine, respectively, while two vessel-cleaning workers showed significantly higher urinary NMP concentrations of 472 and 711 microg/g creatinine and 5-HNMP concentrations of 33.5 and 124 mg/g creatinine. 2-HMSI was detectable in four post-shift samples (range: 1.6-14.7 mg/g creatinine). The vessel cleaner with the highest NMP exposure reported irritation of the eyes, the upper respiratory tract and headaches., Conclusions: The results of this study indicate a relatively low overall exposure to NMP in the facility. An increased uptake of NMP occurred only during extensive manual vessel cleaning. Health complaints associated with NMP exposure were recorded in one case and might be related to an excessive dermal exposure due to infrequent and inadequate use of personal protective equipment.

The analysis of protein adducts is a valuable tool for the biomonitoring of humans exposed to alkylating compounds. In case of single or intermittent exposures, however, the significance and validity of adduct analysis is limited due to the typically small increase in adduct levels and a nonlinear adduct elimination kinetic. This issue was addressed in a follow-up observation of four workers accidentally exposed to acrylonitrile (ACN) in a train depot. N-2-Cyanoethylvaline (CEV) in hemoglobin was analyzed in blood samples of the workers and of seven rescue team and hospital members, approximately, 25 days after the accident. Of the 11 potentially exposed persons, only the cleaning workers revealed adduct levels significantly above the general background. Further blood samples of the workers were analyzed after 85, 115 and 175 days, respectively. In these cases, the adduct concentrations declined to background levels associated with individual smoking habits. A linear regression analysis of the data points to a total elimination interval of 148 days, 2 weeks longer than the standard lifespan of erythrocytes and possibly due to a period of acrylonitrile circulation in the blood stream or release from unstable intermediates. The data allow a rough estimate of the initial protein adduct concentration and an evaluation of the internal dose on the basis of biological exposure equivalents. In conclusion, adduct analyses offer valuable information even in the case of short-term exposures.

Objectives: The dermal absorption of the solvent N-methyl-2-pyrrolidone (NMP) and its elimination in urine was investigated in an experimental study., Methods: Seven volunteers were exposed to 1045 mg of liquid NMP under occlusive conditions for 2 h. Urine was collected before, during and up to 72 h after the exposure and analysed for NMP by GC/MS after liquid-liquid extraction. Additionally, the remaining NMP in the pads was determined to estimate the total dermal uptake., Results: The concentration of NMP in urine increased rapidly after beginning of the exposure up to 1 h after the exposure was completed. A peak concentration of 1,836+/-863 microg/l was observed, the half-life in urine was 3.2 h. About 0.5% of the absorbed dose was excreted metabolically unchanged. An average dermal absorption of 5.5 mg cm(-2) h(-1) was calculated., Conclusions: The results of this study show that the percutaneous absorption of NMP may contribute significantly to the overall uptake of the solvent, e.g. in the workplace. Therefore, a biological monitoring of NMP exposed workers is essential for occupational-medical surveillance.

Germany continues to be iodine deficient despite considerable improvement in the past years. To assess the current prevalence of diffuse and/or nodular thyroid disorders, a cross-sectional observational study in a nonrandom sample of the working population was carried out throughout Germany in 2001 and 2002. A total of 96,278 employees 18-65 years of age from 214 companies or other private or public institutions voluntarily underwent ultrasonographic examinations by 230 experienced investigators. To compare the prevalence of different abnormal findings in relation to age and gender, descriptive statistics and the Kruskal-Wallis test were used. Data from volunteers with previous thyroid treatment (13.0% of total sample) were not included in the analysis. Abnormal findings (goiter and/or nodules > 0.5 cm) were observed in 33.1% (men, 32.0%; women, 34.2%) of the examined patient population, an enlarged thyroid without nodules in 9.7% (men, 11.9%; women, 7.6%), nodules only without enlargement of the thyroid in 14.3% (men, 11.5%; women, 17.0%), and nodular goiter in 9.1% (men, 8.6%; women, 9.6%). Nodules (with or without goiter) between 0.5 and up to 1.0 cm were found in 10.0%, and nodules above 1.0 cm in 11.9% of the population. Rates of abnormal findings increased with age in both genders. Goiter was more common in men, nodules in women. In light of these findings, the prevalence of thyroid disorders in Germany continues to be high. Although the study may slightly overestimate the prevalence, about one third of the working population is affected and remains unaware of this condition. These results emphasize the importance of effective sonographic screening to detect early thyroid abnomalities in order to initiate preventive and therapeutic measures to prevent the onset or progression of disease and its sequels.

Exposure to metals at workplaces is well known and in many cases occupational studies led to an adoption of limit values. For airborne concentrations of substances as metals refer to the "Maximaleo Arbeitsplatz-Konzentration" (MAK) in Germany or the "Threshold Limit Value" (TLV) in USA. Biological monitoring consists of an assessment of overall exposure to chemicals at the workplace and in the environment. The "Biologischer Arbeitsstoff Toleranzwert" (BAT) in Germany and the "Biological Exposure Index" in the USA serve as reference values. Besides these occupational limit values, reference values exist in Germany for the background exposure of the non occupationally exposed general population. In some cases the reference values are exceeded without any occupational exposure. Several cases of unusual environmental exposure to cobalt, mercury and manganese are reported. In such cases, it is often difficult to evaluate the measured concentration. In Germany, therefore, the "Human-Biomonitoring-Werte" (HBMValues) have been adopted in order to evaluate such high background exposures. The HBM-concept is presented. Environmental exposure to metals is usual within some limits. Reference values are helpful for an assessment. Unusual exposure occurs and the physician should be alert to symptoms of poisoning.

The INK4a-ARF locus, located on chromosome 9p21, encodes 2 cell cycle-regulatory proteins, p16(INKa) and p14(ARF), acting through the Rb-CDK4 and p53 pathways. This study was done to investigate the contribution of the INK4a-ARF locus in tumorigenesis of angiosarcoma of the liver. Alterations of p14(ARF), p16(INKa), and p53 in primary liver angiosarcoma from 19 patients were analyzed by methylation-specific polymerase chain reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR), microsatellite analysis, and DNA sequencing. As a control group, 12 angiosarcomas from other organs were analyzed. Promoter methylation of p14(ARF) was found in 5 of 19 cases (26%), and p16(INKa) showed aberrant promoter methylation in 12 of 19 cases (63%). One tumor (5%) had homozygous deletion of the INK4a-ARF locus. Methylation and deletion correlated with loss of mRNA transcription. Methylated p14(ARF) appeared in the context of a methylated p16(INKa) promoter in 3 cases of the 5 angiosarcomas methylated at p14(ARF). p14(ARF) aberrant methylation was not related to the presence of p53 mutations, which was detected in 6 of 19 (32%) cases. Alterations of the INK4a-ARF locus or p53 as were not established independent prognostic factors in these tumors. In conclusion, our data indicate that the INK4a-ARF locus is frequently inactivated in angiosarcoma of the liver and occurs independently of p53 mutations., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Vinyl chloride (VC) is a potent liver carcinogen that induces angiosarcomas in humans and animals. Recent evidence shows that liver tumors from patients with VC exposure may have a specific K-ras mutation pattern. This study was performed to determine the status of K-ras-2 in liver angiosarcomas (LAS) from workers occupationally exposed to VC. We examined the presence of K-ras-2 mutations in 15 LAS from patients with known exposure to VC (median exposure: 8,260 ppm [range 3,900- 21,000 ppm]]. In all cases, other risk factors for the development of LAS were excluded. Direct DNA sequencing after microdissection of the tumor cells was used for the analysis. Heterozygous mutations of K-ras-2 were detected in 8/15 LAS (53%). Five patients (33%) had a mutation of codon 12 and three of codon 13 (20%). The most common changes were G-->A transitions in five LAS which lead to the substitution of aspartic acid for glycine in the resulting p21 protein. In two patients (13%), mutations of the K-ras-2 gene were identified in the adjacent nonneoplastic liver tissue. These data indicate that VC induces a high frequency of G-->A transitions in human LAS. This mutation pattern is likely a consequence of VC-DNA-adduct formation., (Copyright 2002 Wiley-Liss, Inc.)

Occupational medicine is affected to a much greater extent by national legal and social conditions than by clinical issues. The different preconditions specific to each country serve to restrict the scientific dialogue on issues of occupational medicine. Therefore, in this paper are described the organisation and the under- and postgraduate education of occupational medicine in Germany and other European countries (Austria, Belgium, Denmark, Italy, United Kingdom). In summary one can state that in many member states of the EU there is a lack of undergraduate training in occupational medicine for students and there are distinct systems for the postgraduate training and assessment of occupational physicians. The practice of occupational medicine in the EU countries probably has many similarities. The responsibilities of occupational physicians are rather comparable, though in some countries the approaches of occupational medical prevention and the interest in evaluating the structure, process and outcome of many of the activities of occupational medicine seem to recede something into the background.

One hundred and twenty-two persons employed in an industrial waste incineration plant were examined with respect to organic and inorganic substances which may be produced during the combustion of different waste. The employees were divided into three groups: persons with contact with the incinerator (WI workers, n = 45), periphery workers (n = 54) and management (n = 23). For the evaluation of internal exposure, the levels of lead, cadmium, mercury, benzene, toluene, ethylbenzene and m-xylene in blood, chromium in the erythrocytes, polychlorinated biphenyls, hexachlorobenzene and pentachlorophenol in plasma, and arsenic, chromium, nickel, vanadium, chlorophenols and hydroxypyrene in urine were determined. The internal exposures of the three groups were tested against each other and were compared with the reference values of the general population. Differences between the groups investigated were tested using the U test according to Wilcoxon, Mann and Whitney (P < 0.05). The biological exposure limits valid in Germany (BAT values) were not exceeded in any cases. Compared with the background levels of the German population, certain parameters were exceeded in several employees. Significantly higher levels of the WI workers in comparison to both periphery workers and management were found for toluene in blood (median: 1.1 vs 0.9 vs 0.6 microgram/l). For the lead and cadmium levels in blood and for the urinary excretion of arsenic, 2,4-dichlorophenol and tetrachlorophenols, statistical differences were found only between WI workers and one of the other groups. However, in all cases the elevations were very small and of interest more from the environmental than from the occupational point of view. It must be stressed that this waste incineration plant is very modern in terms of worker health and safety. At older plants without corresponding health and safety measures, higher internal exposure of the employees to hazardous substances may exist.

Chlorophenols occur ubiquitously in the environment. They are taken up as such in man or are formed in intermediary metabolism e.g. from chlorobenzenes. In particular pentachlorophenol (PCP) is one of those chemical substances used up to the early 70's as a component of wood preservatives also indoors; for many years it has been at the centre of discussion about the environment. Mono, di, tri and tetrachlorophenols as well as pentachlorophenol occur in the urine in the general population often in surprisingly high concentrations. An increased chlorophenol excretion under certain circumstances also indicates an increased dioxin exposure (pre-dioxins). Possible sources of emission and routes of absorption for corresponding organochlorine compounds can be found in industry, agriculture and also private households. Environmental analysis in the air, in earth or dust do not allow any evaluation of health risks. Only biological monitoring with qualitative and quantitative determination of the actual concentration of the substance taken up by the organism allows a reliable estimation of the individual health risk. The background exposure of the general population not occupationally exposed to organochlorine compounds can be used for the determination of so-called norm values. For the determination of the chlorophenol spectrum 50 ml urine are necessary. The following values can be given as reference values for the most important chlorophenols: 4-monochlorophenol: 7.5 micrograms/l, 2.4-dichlorophenol and 2.5-dichlorophenol: 33.6 micrograms/l, 2.4.6-trichlorophenol: 4.7 micrograms/l, 2.4.5-trichlorophenol: 4.5 micrograms/l, 2.3.4.6-tetrachlorophenol and 2.3.5.6-tetrachlorophenol: 22.0 micrograms/l, pentachlorophenol 9.0 micrograms/l urine.