[Disease management guidelines in dermatology: implementation, potentials and limitations exemplified by the guidelines for the management of hand eczema]. / Leitlinien in der Dermatologie : Umsetzung, Möglichkeiten und Grenzen am Beispiel der Leitlinie Management von Handekzemen.

In Germany, the "Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften" (AWMF; consortium of scientific medical societies) constitutes the umbrella organisation to conceive, evaluate, and release guidelines. There are 3 stages of development (S1-S3) according to the evidence level and the process of consensus finding. Currently, 59 dermatologic guidelines have been published under the auspices of the Deutsche Dermatologische Gesellschaft (German Dermatological Society). The guideline for the management of hand dermatitis (AWMF-Register-No: 013/053) is an instructive recent example. This guideline clearly demonstrates the benefits of guidelines, i.e. standardized definition of heterogeneous diseases and disease severity as well as standardized therapy algorithms. This is especially important in diseases difficult-to-treat like chronic hand dermatitis. The effective implementation of guidelines with early incorporation of new therapies, for example alitretinoin in the therapy of hand dermatitis, can considerably improve the quality of life of patients.

[Xeroderma pigmentosum (XP) : A genetic disease sheds light on UV-induced skin cancer]. / Xeroderma pigmentosum : Genetische Modellerkrankung bringt Licht ins Dunkel von UV-induziertem Hautkrebs.

The recessively inherited nucleotide excision repair (NER) defect syndrome xeroderma pigmentosum (XP) serves as a model disease for UV-induced skin cancer. XP is characterized by sun-sensitivity, freckling, and poikilodermic skin changes in sun-exposed areas, and a more than 1000-fold increased risk of skin cancer including melanoma as well as basal and squamous cell carcinomas. Seven XP complementation groups (XP-A to XP-G) are known to date representing the defective genes in XP patients. An additional "variant" form (XPV) which is clinically indistinguishable from the complementation groups exhibits defective translesional synthesis. An enhanced understanding of skin cancer development in general can help to identify individuals at an increased risk who should take special precautions, for example to avoid occupational exposures. The position of skin cancer induced by UV-light as an occupational disease in the ordinance on industrial diseases (BKV) is currently a topic of research and discussion in Germany.

Age-specific preterm birth rates after exclusion of risk factors--an analysis of the german perinatal survey.

AIM: A description of preterm birth rates - specified according to maternal age - after the exclusion of anamnestic risk factors. MATERIAL AND METHODS: Data for this study were taken from the German Perinatal Survey of 1998-2000. We analysed data from 492,576 singleton pregnancies and determined preterm birth rates according to maternal age after a stepwise exclusion of anamnestic risk factors. RESULTS: There was a U-shaped dependence of preterm birth rates on maternal age. The lowest preterm birth rate (without excluding women with anamnestic risk factors) was 5.6% at a maternal age of 29 years. The prevalence of some anamnestic risk factors for preterm birth, such as previous stillbirths, spontaneous and induced abortions, and ectopic pregnancies, increased with maternal age. Excluding women with anamnestic risk factors lowered the preterm birth rates substantially. The lowest preterm birth rates were found in women with one previous live birth, without any anamnestic risk factors, and with a body mass index (BMI) of 25.00-29.99. With these restrictions, we found preterm birth rates of under 2% for women aged 24-31 years. CONCLUSIONS: The magnitude and age-dependence of the preterm birth rate can to some extent be explained with the age-dependent prevalence of anamnestic risk factors for preterm birth. Excluding women with anamnestic risk factors from our study population lowered the preterm birth rates substantially.

Previous extrauterine pregnancies and neonatal outcomes in primiparous women--an analysis of the German Perinatal Survey.

AIM: The aim of this study was to compare neonatal outcomes in primiparous women with and without previous extrauterine pregnancies. MATERIAL AND METHODS: We analysed data from 207 171 singleton pregnancies in primiparous women from the German Perinatal Survey of 1998-2000. To minimise confounding factors, we only included women without previous miscarriages or terminations of pregnancy and performed comparisons separately for 3 maternal age groups as well as for all cases together. RESULTS: Women with and without previous extrauterine pregnancies were of comparable height and weight but women with previous extrauterine pregnancies were on average older (29.2 vs. 26.6 years). The preterm birth rate was higher in women with previous extrauterine pregnancies (9.4% vs. 6.8%, odds ratio 1.42 [95% confidence interval 1.18-1.69], p<0.001; analysing all cases together) as was the rate of neonates with a low birth weight ≤ 2 499 g (7.9% vs. 5.7%, odds ratio 1.43 [95% confidence interval 1.17-1.72], p>0.001; analysing all cases together). The proportions of neonates classified as small, appropriate, or large for gestational age were rather similar in women with and without previous extrauterine pregnancies; likewise Apgar scores differed only slightly, although for some comparisons statistical significance was reached in spite of the small magnitude of differences. CONCLUSIONS: Previous extrauterine pregnancies are associated with higher rates of preterm birth and infants of low birth weight in subsequent pregnancies.

Ether oxygenate additives in gasoline reduce toxicity of exhausts.

UNLABELLED: Fuel additives can improve combustion and knock resistance of gasoline engines. Common additives in commercial fuels are "short-chain, oxygen containing hydrocarbons" such as methyl tert-butyl ether (MTBE) and ethyl tert-butyl ether (ETBE). Since these additives change the combustion characteristics, this may as well influence toxic effects of the resulting emissions. Therefore we compared toxicity and BTEX emissions of gasoline engine exhaust regarding addition of MTBE or ETBE. Non-reformulated gasoline served as basic fuel. This fuel was supplemented with 10%, 20%, 25% and 30% ETBE or 15% MTBE. The fuels were combusted in a gasoline engine at idling, part load and rated power. Condensates and particulate matter (PM) were collected and PM samples extracted with dichloromethane. Cytotoxic effects were investigated in murine fibroblasts (L929) using the neutral red uptake assay and mutagenicity using the bacterial reverse mutation assay. BTEX emissions were analyzed by gas chromatography. RESULTS: PM-extracts showed mutagenicity with and without metabolic activation. Mutagenicity was reduced by the addition of MTBE and ETBE, 10% ETBE being most effective. The condensates produced no significant mutagenic response. The cytotoxicity of the condensates from ETBE- and MTBE-reformulated fuels was reduced as well. The BTEX content in the exhaust was lowered by the addition of MTBE and ETBE. This effect was significantly related to the ETBE content at rated power and part load. CONCLUSIONS: Addition of MTBE and ETBE to fuels can improve combustion and leads to decreased toxicity and BTEX content of the exhaust. Reduction of mutagenicity in the PM-extracts is most probably caused by a lower content of polycyclic aromatic hydrocarbons.

Detection of unknown toxic mycotoxins inAspergillus nidulans using a structure-activity approach.

Mycotoxins are secondary metabolites of filamentous fungi that can cause various acute and chronic toxic effects in humans. Previous work by Büngeret al. exhibited that the cytotoxicityof Aspergillus nidulans, one of the most frequent toxigenic moulds in composting plants, could not be explained by its content of identified mycotoxins. The presence of additional mycotoxins or other toxic prinpiples was assumed, which may be detected by a structure-activity approach.An HPLC-diode array detector method was used to separate and characterize the components of theA. nidulans-extract within 50 minutes/analysis. Aliquots of the extract were chromatographed and nine 5-minutes-fractions were collected and lyophilized. Rechromatography of aliquots of the residues confirmed the accuracy of the 5-minutes-cuts.The cytotoxicity of these fractions was estimated in three cell lines (A-549, L-929 and Hep-G2) using the neutral red assay (NRU assay). Ethanol/dichloromethane (1:1, v/v) was proven to be a suitable solvent mixture with a low cytotoxicity. HPLC-fractions were dissolved in this mixture prior to the NRU assay. Three 5-minutes-fractions exhibited a strong cytotoxicity in this screening system and will be further analysed to identify the underlying unknown toxic principles.

Cytokine gene polymorphisms in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders characterized by abnormal cytokine production. From association studies there is evidence that functionally relevant cytokine gene polymorphisms contribute to the genetic basis of psoriasis. Association studies in AD have mostly been limited to polymorphisms of T-helper 2-type cytokines, which dominate in acute AD lesions. Unexpectedly, the results of recent genome scans indicate linkage of AD to psoriasis susceptibility loci. Therefore, AD may also be influenced by genes that modulate cutaneous inflammation independently from atopic mechanisms. OBJECTIVES: To investigate further the role of cytokine gene polymorphisms in AD. METHODS: Polymorphisms in the genes encoding tumour necrosis factor-alpha (TNFA-238 G/A, -308 G/A), interleukin (IL)-1beta (IL1B-511 T/C, +3953 T/C), IL-6 (IL6-174 C/G), IL-10 (IL10-1082 A/G) and the IL-1 receptor antagonist (IL1RN intron 2) were investigated in German patients with AD (n = 94) and in healthy nonatopic individuals (n = 214) by polymerase chain reaction-based methods and direct cycle sequencing. RESULTS: No association was found between AD and any of the polymorphisms analysed. This is in contrast to the recently described association between psoriasis and the TNFA-238 and IL1B-511 polymorphisms. CONCLUSIONS: Our data indicate that cytokine gene polymorphisms may act as specific markers of inflammatory skin diseases rather than contribute to a general disposition towards cutaneous inflammation.

Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal.

We have investigated the interaction of thimerosal, a widely used antiseptic and preservative, with the human erythrocytic GST T1 (glutathione-S-transferase T1). This detoxifying enzyme is expressed in the erythrocytes of solely the human species and it displays a genetic polymorphism. Due to this polymorphism about 25% of the individuals of the caucasian population lack this activity ("non-conjugators"), while 75% show it ("conjugators") (Hallier, E., et al., 1993). Using our newly developed HPLC-fluorescence detection assay (Müller, M., et al., 2001) we have profiled the kinetics of enzyme inhibition in erythrocyte lysates of two individuals previously identified as "normal conjugator" (medium enzyme activity) and "super-conjugator" (very high activity). For the normal conjugator we have determined a 2.77 mM thimerosal concentration to inhibit 50% of the GST T1 activity. In the case of the super-conjugator a 2.3 mM thimerosal concentration causes a 50% inhibition of the enzyme activity. For both phenotypes a 14.8 mM thimerosal concentration results in residual enzyme activities equal to those typically detected in non-conjugator lysates. Thus, sufficiently high doses of thimerosal may be able to change the phenotypic status of an individual--at least in vitro--by inhibition of the GST T1 enzyme.

Genotoxic effects of N-nitrosodicyclohexylamine in isolated human lymphocytes.

Dicyclohexylamine x nitrite is classified as an "experimental equivocal tumorigenic agent" by the National Toxicology Program. Since no genotoxic effects of the substance itself are known, the reported tumorigenic potential of dicyclohexylamine x nitrite could be due to generation of N-nitrosodicyclohexylamine (N-NO-DCHA), which occurs under conditions of use and can be detected in foils that contain dicyclohexylamine x nitrite. Therefore, we investigated possible mutagenic properties of N-NO-DCHA in the Ames test and the cytokinesis-block micronucleus assay with human lymphocytes. Since N-NO-DCHA is not commercially available, the substance was synthesized and purified by thin-layer chromatography. Identity was confirmed by gas chromatography/mass spectroscopy (GC/MS) and 1H- and 13C-NMR. More than 97% purity was achieved. Stability and availability in the solvent were checked by GC/MS. N-NO-DCHA induced micronuclei in isolated human lymphocytes at a dose range of 15-100 micrograms/ml (= 71.4-476.2 microM), exceeding the base rate significantly at one or two nontoxic concentrations in four out of six experiments. For the Ames test, arochlor-1254-, beta-naphthoflavone/phenobarbital- and pyrazole-induced S9-fractions were used with Salmonella typhimurium TA100, TA1535, TA98 and TA104. No effects were seen in the Ames test, with the exception of microcolony induction at doses higher than 250 micrograms (= 1.2 mmol) N-NO-DCHA/plate using TA104 and 20% arochlor-1254 induced S9 at pH 6.5. In conclusion, N-NO-DCHA was negative in the Ames test using TA98, TA100 and TA1535, inconclusive using TA104, and weakly genotoxic in the in vitro micronucleus test with isolated human lymphocytes. With regard to the tumorigenicity of the majority of nitrosamines, our data underline the necessity of further studies on possible genotoxic effects of N-NO-DCHA.

High-performance liquid chromatography/fluorescence detection of S-methylglutathione formed by glutathione-S-transferase T1 in vitro.

Glutathione-S-transferase T1 (GSTT1-1) is a major isoenzyme for the biotransformation of halomethanes. The enzyme activity is located, among other places, in human liver and erythrocytes and is subject to a genetic polymorphism. Metabolism of the halomethanes via GSTT1-1 yields S-methylglutathione (MeSG). A new HPLC assay for the enzymatic formation of MeSG was developed. The glutathione conjugate was derivatized with 9-fluorenylmethyl chloroformate, followed by reverse-phase HPLC with gradient elution and fluorescence detection. The limit of detection was as low as about 39 pmol MeSG on-column. Including derivatization and HPLC analysis, samples could be run at 42-min intervals, thus enabling a high sample throughput. The entire method was validated for analyte recovery (78.2%) and for variations in detector response with replicated injections (11.8%) and with analyses on each of 11 consecutive days (15.2%) with erythrocyte lysate incubations as the matrix. The time-, protein-, and substrate-dependences of the enzymatic catalysis with the model substrates methyl bromide (MeBr) and methyl chloride (MeCl) were studied. Due to its strong electrophilic character, MeBr caused a high level of spontaneous MeSG formation from glutathione in a protein-free medium and a substrate-trapping side reaction in the presence of proteins. Therefore, enzymatic MeSG formation rates may only be determined with MeBr concentrations of at least 3000 ppm in the presence of limited amounts of protein (e.g. 100 microl erythrocyte lysate). In contrast, MeCl showed a lower alkylating potential allowing enzymatic catalysis to be the dominant reaction in incubations with 10,000 ppm MeCl and 2 ml erythrocyte lysate.

Genotoxicity of N-nitrosodicyclohexylamine in V79 cells in the sister chromatid exchange test and the single cell gel assay.

Dicyclohexylaminexnitrite is used in chemical formulations as an anti-corrosion agent. N-Nitrosodicyclohexylamine (N-NO-DCHA) can be formed by nitrosation from dicyclohexylamine during the application of these formulations. As most of the nitrosamines are genotoxic carcinogens, the genotoxic potential of N-NO-DCHA was investigated in V79 Chinese hamster cells in the single cell gel assay and the sister chromatid exchange (SCE) test. In addition, N-NO-DCHA cytotoxicity was determined in the neutral red assay. Neutral red uptake was suppressed up to 50% after 24 h incubation at a concentration of approximately 135 microM. In the single cell gel assay, a significantly elevated and dose-dependent induction of DNA lesions was detected in a concentration range from 5 microM to 100 microM (P<0.001). The use of proteinase K (1 mg/ml) in the lysing solution did not influence these results. In the SCE analysis, a significant induction of SCE was found at a minimum concentration of 5 microM N-NO-DCHA as well. A dose-dependent SCE induction could be detected up to the maximum concentration tested in the assay (100 microM). In conclusion, N-NO-DCHA is genotoxic in V79 cells in the single cell gel assay and the SCE test. With respect to human health hazard prevention, a substitution of dicyclohexylaminexnitrite in chemical formulations used to prevent corrosion is recommended.

Cytotoxic and mutagenic effects, particle size and concentration analysis of diesel engine emissions using biodiesel and petrol diesel as fuel.

Diesel engine exhaust particles (DEP) contribute substantially to ambient air pollution. They cause acute and chronic adverse health effects in humans. Biodiesel (rapeseed oil methyl ester. RME) is used as a "green fuel" in several countries. For a preliminary assessment of environmental and health effects of RME, the particulate-associated emissions from the DEP of RME and common fossil diesel fuel (DF) and their in vitro cytotoxic and mutagenic effects were compared. A test tractor was fuelled with RME and DF and driven in a European standard test cycle (ECE R49) on an engine dynamometer. Particle numbers and size distributions of the exhausts were determined at the load modes "idling" and "rated power". Filter-sampled particles were extracted and their cytotoxic properties tested using the neutral red assay. Mutagenicity was tested using the Salmonella typhimurium/microsome assay. Despite higher total particle emissions, solid particulate matter (soot) in the emissions from RME was lower than in the emissions from DF. While the size distributions and the numbers of emitted particles at "rated power" were nearly identical for the two fuels, at "idling" DF emitted substantially higher numbers of smaller particles than RME. The RME extracts caused fourfold stronger toxic effects on mouse fibroblasts at "idling" but not at "rated power" than DF extracts. The extracts at both load modes were significantly mutagenic in TA98 and TA100. However, extracts of DF showed a fourfold higher mutagenic effect in TA98 (and twofold in TA100) than extracts of RME. These results indicate benefits as well as disadvantages for humans and the environment from the use of RME as a fuel for tractors. The lower mutagenic potency of DEP from RME compared to DEP from DF is probably due to lower emissions of polycyclic aromatic compounds. The higher toxicity is probably caused by carbonyl compounds and unburned fuel, and reduces the benefits of the lower emissions of solid particulate matter and mutagens from RME.

Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization.

OBJECTIVE: Thimerosal is an important preservative in vaccines and ophthalmologic preparations. The substance is known to be a type IV sensitizing agent. High sensitization rates were observed in contact-allergic patients and in health care workers who had been exposed to thimerosal-preserved vaccines. There is evidence for the involvement of the glutathione system in the metabolism of thimerosal or its decomposition products (organomercury alkyl compounds). Thus detoxification by polymorphically expressed glutathione S-transferases such as GSTT1 and GSTM1 might have a protective effect against sensitization by these substances. METHODS: To address this question, a case control study was conducted, including 91 Central European individuals with a positive patch-test reaction to thimerosal. This population was compared with 169 healthy controls and additionally with 114 individuals affected by an allergy against para-substituted aryl compounds. The latter population was included in order to test whether possible associations were due to substance-specific effects, or were a general feature connected with type IV immunological diseases. Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase chain reaction. RESULTS: Glutathione S-transferase M1 deficiency was significantly more frequent among patients sensitized to thimerosal (65.9%, P = 0.013) compared with the healthy control group (49.1%) and the "para-compound" group (48%, P = 0.034). Glutathione S-transferase T1 deficiency in the thimerosal/mercury group (19.8%) was barely elevated versus healthy controls (16.0%) and the "para-compound" group (14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more frequent among thimerosal-sensitized patients than in healthy controls (17.6% vs. 6.5%, P = 0.0093) and in the "para-compound" group (17.6% vs. 6.1%, P =0.014), revealing a synergistic effect of these enzyme deficiencies (healthy controls vs. thimerosal GSTM1 negative individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1.2 [CI = 0.70-2.1], GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]). CONCLUSIONS: Since the glutathione-dependent system was repeatedly shown to be involved in the metabolism of thimerosal decomposition products, the observed association may be of functional relevance.

Mutagenicity of diesel exhaust particles from two fossil and two plant oil fuels.

Particulate matter of diesel engine exhaust from four different fuels was studied for content of polynuclear aromatic compounds and mutagenic effects. Two so-called biodiesel fuels, rapeseed oil methylesters (RME) and soybean oil methylesters (SME), were compared directly with two fossil diesel fuels with the normal (DF) and a low sulfur content (LS-DF). Diesel exhaust particles were sampled on filters from the diluted and cooled exhaust of a test engine at five different speeds and loads. Filters were weighed for total particulate matter, Soxhlet extracted with dichloromethane and the content of insoluble material determined. The soluble organic fraction was analysed for polynuclear aromatic compounds. Mutagenicity was determined using the Salmonella typhimurium/mammalian microsome assay with strains TA98 and TA100. Compared with DF, the exhaust particles of LS-DF, RME and SME contained less insoluble material, which consisted mainly of the carbon cores of diesel exhaust particles. The concentrations of individual polynuclear aromatic compounds varied widely among the different exhaust extracts, but total concentrations of the compounds were approximately double for DF and SME compared with LS-DF and RME. In TA98 significant increases in mutation rates were obtained for the soluble organic fractions of all fuels for engines running at full speed (load modes A and D), but for DF revertants were 2- to 10-fold more frequent as compared with LS-DF, RME and SME. Revertant frequencies for DF and partly for LS-DF were also elevated in TA100, while RME and SME gave no significant increase in mutations. The results indicate that diesel exhaust particles from RME, SME and LS-DF contain less black carbon and total polynuclear aromatic compounds and are significantly less mutagenic in comparison with DF. A high sulfur content of the fuel and high engine speeds (rated power) and loads are associated with an increase in mutagenicity of diesel exhaust particles.

N-acetyltransferase 1 and 2 polymorphisms in para-substituted arylamine-induced contact allergy.

Sensitization to arylamines such as p-phenylenediamine is frequently diagnosed in patients with allergic contact dermatitis. Reactive metabolites of p-phenylenediamine might be produced in the skin by O-acetylation of N-hydroxylamines catalysed by local N-acetyltransferases (NATs). In this study, we tested whether genetic polymorphisms of NATs, which are known to affect enzyme activity, may influence the susceptibility to para-substituted arylamine-induced contact eczema. Using polymerase chain reaction and restriction enzyme analysis, the distribution of polymorphisms of NAT1 and NAT2 was investigated in 88 patients sensitized to para-substituted aryl compounds and 123 healthy controls. NAT2 rapid acetylators, i.e. carriers of the NAT2*4 wild-type allele, were more common in the contact allergy (44%) than in the healthy control group [30%; P = 0.042, odds ratio 1.9 (95% confidence interval, CI 1. 05-3.27)]. Slow acetylators carrying the NAT2*5b/2*6a genotype were significantly less frequent among patients [13% vs. 38% in controls; P = 0.009, odds ratio 0.39 (95% CI 0.19-0.78)]. The carriage rate of the NAT1*10 allele, which is supposed to encode for a rapid NAT1 phenotype, was not significantly different between patients and controls [43% vs. 36%; odds ratio 1.5 (95% CI 0.88-2.68)]. Interactions between NAT2*4 and NAT1*10 were suggested by the increased frequency of the NAT2*4/NAT1*10 haplotype in patients (27%) compared with controls [15%; P = 0.039, odds ratio 2.1 (95% CI 1.04-4.04)]. As the NAT1 and NAT2 encoding genes are located in close proximity on chromosome 8p22, the latter finding could at least partly be due to genetic linkage. In fact, a linkage disequilibrium between NAT2*4 and NAT1*10 was observed in the contact allergy (P = 0.0025) and in the control group (P = 0.042). Our data indicate an association between the NAT2*4/NAT1*10 haplotype and contact sensitization to para-substituted aryl compounds. Therefore, acetylation may either enhance contact sensitization or NAT2*4 and NAT1*10 might be linked to an unknown susceptibility factor.

Health complaints and immunological markers of exposure to bioaerosols among biowaste collectors and compost workers.

OBJECTIVES: In a cross sectional study, work related health complaints and diseases of 58 compost workers and 53 biowaste collectors were investigated and compared with 40 control subjects. Levels of specific IgG antibodies to moulds and bacteria were measured as immunological markers of exposure to bioaerosols. METHODS: With a standardised protocol, the participants of the study were interviewed for work related symptoms, conditions of exposure to bioaerosols at their workplaces, exposure to bioaerosols from other sources, atopic diseases, and smoking habits. They were clinically examined by physicians specialised in occupational medicine. Also, concentrations of specific IgG antibodies against antigens of moulds and actinomycetes occurring regularly at these workplaces were measured and compared with the health complaints of the workers. RESULTS: Compost workers had significantly more symptoms and diseases of the airways (p=0.003) and the skin (p=0.02) than the control subjects. Health complaints of biowaste collectors did not differ significantly from those of the control group. Subjects with atopic diseases were underrepresented in the compost workers (p=0.003). Significantly increased antibody concentrations against fungi and actinomycetes were measured in workers at composting plants. The concentrations in biowaste collectors did not differ significantly from those in the control subjects. A significant association between the diseases and increased antibody concentrations were found in the compost workers. CONCLUSION: The high exposure to bioaerosols of compost workers is significantly associated with a higher frequency of health complaints and diseases as well as higher concentrations of specific antibodies against moulds and actinomycetes. A healthy worker effect is indicated by the underrepresentation of atopic diseases among the compost workers compared with biowaste collectors and the control group.

Psychological effects upon exposure to polyhalogenated dibenzodioxins and dibenzofurans.

Thirty workers who had been exposed to combustion products for several years due to testing of flame retarding qualities of building materials and 30 controls from the same facility were investigated. Concentrations found in samples taken from different places of the facility were up to 14,660 microg/kg for polybrominated dibenzofurans and up to 67.1 microg/kg for polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs). Physical examination, routine laboratory parameters, and blood fat concentrations of PCDDs and PCDFs revealed normal findings. Neurotoxic symptoms showed a weak tendency of overrepresentation among the exposed workers. The frequency of neurobehavioural symptoms increased significantly with trait anxiety independent of exposure to combustion products.

Mutagenicity of N-nitrosodiethylamine in the Ames test with S. typhimurium TA1535 is due to volatile metabolites and is not dependent on cytochrome P4502E1 induction.

N-Nitrosodiethylamine (NDEA) is carcinogenic in all investigated animal species at relatively low dosages. No threshold has been detected for these carcinogenic effects. The substance has been extensively investigated in various in vitro systems, revealing only weak mutagenicity at relatively high dosages. We reinvestigated NDEA in the Ames test with Salmonella typhimurium TA1535 to establish appropriate modifications of the standard Ames test protocol, to achieve a dose-dependent mutagenic response at a reasonably low dose range. Two main modifications were evaluated. Since the metabolism of dialkylnitrosamines is postulated to be mainly dependent on cytochrome P4502E1, a pyrazole-induced rat liver S9 was applied. The second modification involved a gastight preincubation, since metabolites of NDEA might evaporate from the incubation mixture. Cytochrome P4502E1 induction in Wistar rats was achieved by pyrazole treatment. For comparison, a rat liver S9-fraction produced by beta-naphtoflavone/phenobarbital induction was used. N-Nitrosopyrrolidine served as positive control for pyrazole-induced S9-mix with TA1535. NDEA showed no mutagenic response under all test conditions in the presence of pyrazole-induced S9-mix. A strong mutagenic response, exceeding the base rate up to 15-fold at a dose range of 25-1000 microg/plate, was observed using beta-naphtoflavone/phenobarbital-induced S9-mix, gastight preincubation and TA1535. In conclusion the Ames test with gastight preincubation can be useful for the testing of volatile compounds or substances leading to gaseous metabolites. The weak response of NDEA in the Ames test observed previously seems mainly to be due to the volatile character of its mutagenic metabolites. Our results do not support the hypothesis that cytochrome P4502E1 is a major toxifying enzyme for the formation of Ames-test-positive metabolites from NDEA.