[Adnexitis and pelvic inflammatory disease]. / Adnexitis und "Pelvic Inflammatory Disease".

Pelvic inflammatory disease and upper genital tract infection describe inflammatory changes in the upper female genital tract of any combination: endometritis, salpingitis, tubo-ovarian abscess, peritonitis in the small pelvis. The International Infectious Disease Society for Obstetrics and Gynecology recommends a revision of the CDC guidelines taking into account the type of germ or the triggering agent and the seriousness of the disease. Infections with Chlamydia trachomatis and Neisseria gonorrhoeae are increasing worldwide. They are one of the main causes of tubal sterility, chronic abdominal pain and ectopic pregnancies. More than 30% of the infections are subclinical and asymptomatic. Therefore it is most recommendable to generally screen young, sexually active women with any of the risks mentioned above. Antibiotic therapy should be started as early as possible, in case of doubt even probatively, and should cover a broad spectrum of germs. C. trachomatis and N. gonorrhoeae should be treated according to resistance testing. In uncomplicated cases, hospitalization is unnecessary, ambulant therapy is sufficient.

Covalent binding of agaritine to DNA in vivo.

14C-Ring-labelled agaritine was administered orally to eight C57BL/6 mice at a chemical dose of 7.5 mg and radioactive dose of 1.2 x 10(9) dpm/kg body weight. After 24 hr, the animals were killed and DNA from stomach, liver and kidneys was purified by a phenol-free method involving proteinase K digestion of chromatin and coprecipitated proteins, followed by hydroxylapatite chromatography, dialysis and precipitation with ethanol. An increase in radioactivity was found in DNA of all three organs examined. Stomach DNA had the highest levels: 160 and 30 dpm/mg DNA in males and females, respectively. Liver and kidney DNA both showed levels of approximately 1 dpm/mg, with no measurable gender differences. Expressed in the units of the covalent binding index (CBI), agaritine has a potency of 42 in mouse stomach in males and 8 in females. The CBI of agaritine in liver and kidney was 0.2-0.3 in both sexes. The genotoxic activity of agaritine is thus very weak. The cumulative lifetime cancer risk of agaritine consumption in mushrooms is estimated to lie at approximately 10(-5).

Pharmacokinetic behavior of 4-nonylphenol in humans.

In this study, the pharmacokinetic behavior of 4-nonylphenol (NP) was investigated in human volunteers. In order to avoid analytical background problems, isotope labeled (13)C(6)-NP was synthesized. Both after intravenous and oral application, the elimination half-life of the parent compound from the blood was 2-3 h. Bioavailability after oral application (determined by oral and intravenous AUCs) was about 20%. NP seems to distribute into the lipid phase of the body within 2 h. Furthermore, levels of NP and 4-octylphenol (OP) in non-occupationally exposed persons were investigated by analyzing human autopsy adipose tissue samples. NP concentrations ranged from 19 to 85 ng/g lipids, OP concentrations from 0.58 to 4.07 ng/g lipids. These values were both in the range of the analytical background contamination. No NP and OP ethoxylates (ethoxylate number 1,2) were found in any of the samples (detection limit of 10 ng/g lipids for NP ethoxylates and 0.5 ng/g lipids for OP ethoxylates). On the basis of the pharmacokinetic data from this study, actual adipose tissue concentrations were estimated to lie a factor of 50 below analytical background values.

Evaluation of the estrogenic potency of nonylphenol in non-occupationally exposed humans.

In this study, the estrogenic potency of 4-nonylphenol (NP) was estimated and a risk calculation for non-occupationally exposed humans was performed. The daily intake of non-occupationally exposed persons was estimated to be less than 0.16 mg/day. Risk estimates were based on this daily intake and the relative potency of NP to 17ß-estradiol. Comparison of this intake with the NOAEL derived from a 90-day subchronic toxicity study in animals, results in a safety factor of about 20 000. A safety margin of 3000 can be derived when comparing the resulting NP blood concentrations (calculated upon pharmacokinetic studies) with 17ß-estradiol levels in the blood of adult males. Risk estimations based on the daily intake of NP and the resulting organ concentrations (calculated upon the lipid content) compared with minimal estrogenic cell effect concentrations result in a safety factor in the range of 5000. In addition, the comparison of NP with genistein in human blood indicate a minor importance of nonylphenol. The results of this study show that the non-occupational exposure to NP does not pose an estrogenic health risk to humans.

Distribution and pharmacokinetics of alkylphenolic compounds in primary mouse hepatocyte cultures.

In order to allow an interpretation of in vitro results on the estrogenic potency of 4-nonylphenol (NP) and 4-octylphenol (OP), their distribution and pharmacokinetics were investigated in primary mouse hepatocyte cultures. 10(-5) M NP and 10(-6)M OP were added to the hepatocyte cultures and incubated up to 48 h. The time course of parent NP and OP concentrations was followed with GC-MS both in the medium and in the cell fraction. Both NP and OP concentrations decreased rapidly in the cell cultures, indicating that the alkylphenols underwent a rapid metabolism. The concentrations in the cell fractions were 100 ng NP and 2-6 ng OP/mg cell protein after 2 h, declining to about 20 ng NP and 1-4 ng OP/mg cell protein, respectively, after 48 h.

Biological monitoring of the fungicide epoxiconazol during application.

A method was developed for the biological monitoring of the fungicide epoxiconazol (Opus; BASF). Comparison of the urine levels of a hydroxylated metabolite after dermal application to the levels after oral intake revealed a dermal absorption of 1-2.5% of the dose. In a field study with 10 applicators a dermal exposure ranging between 60 and 10,000 microgram/person/day was determined from the urine levels of a hydroxylated metabolite; the contribution of the inhalation exposure was found to be negligible. From these data an incorporation of 1 to 100 microgram epoxiconazol/person/day could be derived. The measured exposure was compared to two commonly used exposure models. The model calculation resulted in a dermal exposure of 555 microgram/person/day (German BBA model) and 2115 microgram/person/day (British POEM), respectively, which is in accordance with the actually measured exposure.

Organophosphates in the zebra mussel Dreissena polymorpha: subacute exposure, body burdens, and organ concentrations.

Subacute exposures (10 d) of the freshwater mollusc Dreissena polymorpha to disulfoton (10 mg/L), thiometon (6 mg/L), and its activated oxygen analogue demeton-S-methyl (6 mg/L) corroborate earlier findings of organophosphate resistance and accumulation in the organism. Mortality occurred not before the ninth day of exposure. Mortality was induced at high ambient water concentrations and must be due to unknown specific organophosphate effects. Body burdens reached saturation levels within one week being around 40 mg/kg wet weight for thiometon and 60 mg/kg for disulfoton. Mussels dying during the tests showed lower tissue concentrations. Elimination of accumulated organophosphates was so low in the mussel, that an efficient metabolism of these compounds in the mussel was unlikely. Different organs of Dreissena previously acutely exposed (96 h) to the organophosphate thiometon (6, 12, 25, 50 mg/L) were analyzed for their thiometon content. Thiometon could be found in all organs, but were highest in the anterior part of the viscera (230 mg/kg), where it was accumulated either in the digestive gland and/or in the gonadal tissue.

Screening of European coffee final products for occurrence of ochratoxin A (OTA).

Samples (633) of final coffee products were drawn from the markets of different European countries relative to the market share of each product type and brand. These samples were analysed in a cooperative action with nine different laboratories. With low limits of detection (mean detection limit approximately 0.5 ng/g) no OTA was found in over half of the samples (334 negatives). In the remaining samples occurrence of OTA at a rather low level was seen. Only four samples (all instants) exceeded a level of 10 ng/g, whereas for both instants, and roast and grounds (R & G), over three-quarters of the samples were in the range from nondetectable to 1 ng/g. The overall mean for all R & Gs was 0.8 ng/g and for all instant 1.3 ng/g (for samples in which no OTA was detected, half of the detection limit was included in this calculation). In the brewing methods frequently used in Europe the OTA is essentially fully extracted. Consumption of four cups of coffee per day (approximately 24 g R & G or approximately 8 g instant coffee) contributes on average 19 or 10 ng/day respectively. Four cups/day is above the per caput consumption level in most European contries. Compared with the Provisional Tolerable Weekly Intake (PTWI) recently set by the Joint FAO/WHO Expert Committee on Food Additives at 100 ng/kg bodyweight/week, consumption of 28 cups/week contributes up to 2% to the PTWI.

The transfer of polychlorinated dibenzo-p-dioxins and dibenzofurans from soil into eggs of foraging chicken.

The levels of the 2,3,7,8-chlorosubstituted PCDD/Fs (polychlorinated dibenzo-p-dioxins and dibenzofurans) were determined in eggs of foraging chicken and in the corresponding soils. Compared to eggs from hens kept without soil contact the determined levels were clearly elevated. These increased levels were attributed to soil related PCDD/F uptake and were used to deduce congener specific factors describing the transfer from soil into the eggs by the foraging. Based on these transfer factors an calculation method allowing the prediction of the 2,3,7,8-TCDD toxic equivalent (I-TEq) levels in eggs based on the PCDD/F concentrations in soil was developed. The comparison of predicted and determined PCDD/F levels was used to discuss limitations and uncertainties of the model. Based on a given soil contamination, this approach allows a conservative prediction of the I-Teq levels in eggs of foraging chicken.

Occurrence of nitro and non-nitro benzenoid musk compounds in human adipose tissue.

Nitro benzenoid musk compounds (Musk tibetene [CAS no. 145-39-1], Musk ambrette [83-66-9], Musk moskene [116-66-5], Musk ketone [81-14-1] and Musk xylene [81-15-2]) and non-nitro benzenoid musks (Celestolide [13171-00-1], Galaxolide [1222-05-5]) and Fixolide [1506-02-1] [21445-77-7] were analysed in 15 human adipose tissue samples from Switzerland by gas chromatography/high resolution mass spectrometry. The levels of Musk xylene and Galaxolide ranged up to 288 ng/g lipids and 171 ng/g lipids, respectively. The concentrations of non-nitro benzenoid musks found in human adipose tissue raise concern since very few toxicological data are available.

Airborne exposure to polycyclic aromatic hydrocarbons (PAHs) and urinary excretion of 1-hydroxypyrene of carbon anode plant workers.

Workers in plants producing carbon anodes for aluminium electrolysis are exposed to PAHs containing coal tar pitch volatiles, pitch and coke. The aim of this study was to evaluate the suitability of urinary 1-hydroxypyrene to characterize respiratory exposure to PAH, which is most relevant for assessing individual health risks. Six workers in a carbon anode plant volunteered to take part in a personal air sampling and a biological monitoring programme lasting five consecutive 8-h shifts to determine occupational exposure to airborne PAHs and urinary excretion of 1-hydroxypyrene. Exposure to total PAH for all worksites varied from 3.99 to 120.6 micrograms PAH m-3 and for benzo(a)pyrene (BaP) from 0.17 to 4.88 micrograms BaP m-3. The concentration of 1-hydroxypyrene in post- and pre-shift urine samples was in the range (0.5- 61.8 mumol 1-OHP per mol creatinine) and depended on the worksite. The Spearman rank correlation test showed a low but significant (P<0.005) correlation of urinary 1-hydroxypyrene in the post-and pre-shift samples with respiratory pyrene exposure. The quantitative aspects of biological monitoring for the evaluation of respiratory PAH exposure were tested with a pharmacokinetic model. On the basis of individual pyrene exposure, excretion of urinary 1-hydroxypyrene during the working week was calculated for each worker. The results presented in this investigation indicate that biological monitoring of the pyrene metabolite 1-hydroxypyrene is a useful indicator of a general PAH exposure, but cannot replace personal air sampling for assessing the lung cancer risk of individuals.

The use of toxic equivalency factors in assessing occupational and environmental health risk associated with exposure to airborne mixtures of polycyclic aromatic hydrocarbons (PAHs).

The health risk associated with inhalatory exposure to PAHs either in the occupational atmosphere or in outdoor air is commonly assessed on the basis of benzo(a)pyrene (BaP) concentrations in air. The PAH-related health risk is calculated with the help of epidemiological data from coke oven workers. The proportion of individual carcinogenic PAHs to BaP has been shown to vary in different environments by one to two orders of magnitude. Despite this, the unit risk value for BaP derived from epidemiological studies of coke oven workers is used for risk estimation of these environments. Toxic equivalency factors (TEFs) for individual PAHs were used to estimate human health risk associated with inhalatory exposure to PAHs. Given the uncertainties involved in risk assessment in general, a variability of risk estimation for PAH mixtures based on the toxic equivalency factor concept by a factor 2.6 is low and rather unreasonably precise. This underlines the importance of BaP as a surrogate compound of a PAH mixture.

The occurrence of ochratoxin A in coffee.

Ochratoxin A (OA) is a nephrotoxic and nephrocarcinogenic mycotoxin which is predominantly produced by the two ubiquitous fungal genera, Aspergillus and Penicillium. OA is found in foodstuffs, predominantly in cereals but also in coffee beans. Inconsistent results have been published regarding the influence of roasting on the OA content in roasted beans and the transfer into the coffee brew. In the present study an HPLC method was used for the detection of OA in green and roasted coffee beans as well as in the coffee brew. For qualitative confirmation and quantification of low OA levels in roasted coffee beans and coffee brew an additional clean-up step by immunoaffinity column was applied before HPLC analysis. In green coffee beans OA was detected in 13 out of 25 commercial samples analysed (detection limit, 0.5 micrograms OA/kg). Roasting (250 degrees C, 150 sec) of naturally contaminated green beans or beans inoculated with A. ochraceus resulted only in a small reduction in the OA level. OA was also found to be eluted into the brew. Of 40 coffee brews prepared from commercially available samples OA was detected in 18 brews by HPLC and/or additional immunoaffinity column clean-up in the range of 0.4 to 7.8 micrograms OA/kg equivalent ground coffee. Our preliminary results suggest, therefore, that regular coffee consumption may contribute to exposure of humans to OA.

Genotoxicity of agaritine in the lacI transgenic mouse mutation assay: evaluation of the health risk of mushroom consumption.

The mutagenic potency of the common mushroom Agaricus bisporus and crude agaritine extracted from mushrooms was determined in vivo using a new mutagenesis assay with lacI transgenic mice (Big Blue mice). Pairs of female lacI mice were fed one of three diets for 15 wk: (1) fresh mushrooms 3 days/wk followed by normal lab chow for 4 days/wk; (2) freeze-dried mushrooms mixed at 25% (w/w) into powdered chow; or (3) a mushroom extract containing 30% agaritine (w/w) mixed into powdered chow. The corresponding daily doses of agaritine were 30 (averaged over the whole week), 80 and 120 mg/kg body weight, respectively. Positive control animals received N-nitrosodimethylamine, N-nitrosomethylurea or urethane, mixed into powdered chow at concentrations corresponding to daily doses of 0.3, 3 and 130 mg/kg body weight, respectively. DNA of the forestomach, kidney, liver, lung and glandular stomach of the lacI mice was examined for increases in mutant frequency (MF). Control MFs ranged from 5 x 10(-5) to 10 x 10(-5). Positive control substances induced a two- to seven-fold increase in MF in their respective target organs. Of the mushroom diets, significant effects were seen only with the crude agaritine extract: it induced an increase in MF of 100% in the kidney and 50% in the forestomach. The other two A. bisporus diets, with lower agaritine doses, showed slightly but not significantly, raised MF values in the kidney alone. Thus, agaritine was weakly genotoxic in vivo; no genotoxic activity other than that attributable to agaritine was detected in A. bisporus. Substances or processes that might influence carcinogenicity by means of non-genotoxic mechanisms (e.g. increase in fibre, or decrease in calorie intake) are not detected in the lacI assay. Using a previously derived quantitative correlation between mutagenicity in the lacI test and carcinogenic potency, the carcinogenicity of agaritine in mushrooms was estimated: the average Swiss mushroom consumption of 4 g/day would be expected to contribute a lifetime cumulative cancer risk of about two cases per 100,000 lives.

[Narcotic gas burden of personnel in pediatric anesthesia]. / Narkosegasbelastung des Personals in der Kinderanästhesie.

METHODS: To assess the occupational exposure of the anaesthetist to anaesthetic gases, a total of 1 German and 25 Swiss hospitals were investigated. A Brüel & Kjaer Type 1302 multi-gas monitor was used to measure concentrations of nitrous oxide and halogenated anaesthetic agents in the anaesthetist's breathing zone. Measurements were performed during 114 general anaesthetic, 55 of which were in patients under 11 years of age. In these 55 patients, the influence of various factors on the exposure (time-weighted average concentrations) was estimated by comparing different data groups. The efficiency of the applied scavenging equipment was examined by surveying the exhalation valve with a leak detector (type TIF 5600, TIF Instruments, Miami). RESULTS: Sessions with patients under 11 years of age revealed much higher anaesthetic gas exposures compared to older patients. The concentrations of nitrous oxide were on average threefold (Fig. 1), those of the halogenated anaesthetics fivefold higher (Fig. 2) for the younger patients. In 11- to 16-year-old patients the exposure level was the same as in adult patients. The measurements showed a reduction of 85% in exposure if an efficient scavenging system (i.e., no waste gas discharge to room air through the exhalation valve) or lower fresh gas flow were used (Fig. 4); 42% of the inspected scavengers were inefficient, and reduced the exposure on average by only 30%. In operating theatres with a ventilation rate of at least ten air changes per h, the measured concentrations of anaesthetic gases in the inhalation zone of the anaesthetists were reduced more than 50% compared to poorly ventilated rooms (Figs. 4 and 5). The use of tracheal intubation or laryngeal mask airway (LMA) anaesthesia resulted in a reduction of 80% in exposure compared to standard face masks if efficient scavenging was used. The exposures during sessions with inefficiently scavenged Bain coaxial systems or unscavenged semi-open delivery systems of the Jackson-Rees type were tenfold higher than with scavenged rebreathing circuit systems (Fig. 6). During anaesthesia with IV or double-mask induction, the average levels of inhalation anaesthetics were reduced by about 80% compared to inhalational induction with standard masks (Fig. 7). The anaesthetist's working technique is a very important factor that strongly influences the concentrations. Poor work practices, like lifting off the face mask with anaesthetic gas flow turned on, increased the exposure of the anaesthetist and other operating room personnel drastically, even if the other conditions (scavenger and room ventilation) were good. DISCUSSION: The exposure levels of anaesthetic gases are generally higher during anaesthesia in children up to 10 years of age than in older patients. Nevertheless, the measurements showed that exposure during paediatric anaesthesia can be kept below the recommended limit (8-h TWA in Switzerland) of 100 ppm nitrous oxide and 5 ppm halothane or 10 ppm enflurane or isoflurane. Causes of high exposures were particularly high fresh gas flows often applied without scavenging or together with inefficient scavenging devices and the high part of mask anaesthesia and inhalation induction with a loosely held mask. To achieve an effective reduction of occupational exposure, well-adjusted and maintained scavenging systems and low-leakage work practices are of primary importance. As leakage can never be completely avoided, a ventilation rate of at least ten air changes per h should be maintained in operating rooms and rooms where anaesthesia is induced to keep down concentrations of waste anaesthetic gases. High exposure during mask anaesthesia and inhalation induction can be prevented by further measures. Using a LMA instead of a standard mask reduces the exposure to the same level as endotracheal intubation.

[Sputum examination in the diagnosis of Pneumocystis carinii pneumonia in HIV-infected patients]. / Sputumuntersuchung zur Diagnostik der Pneumocystis-carinii-Pneumonie bei HIV-Infizierten.

To assess the sensitivity and negative predictive value of sputum examination for Pneumocystis carinii in HIV-positive patients, follow-ups were performed in HIV-infected patients who had been investigated for the presence of Pneumocystis carinii (376 examinations of sputum and 71 bronchoalveolar lavages). Pneumocystis carinii pneumonia was diagnosed 65 times in 64 patients (57 male and 7 female, median age 35 [23-67]years). In 52% of the cases (n = 34) the pathogen was identified in the sputum, in 48% (n = 31) by means of the bronchoalveolar lavage. Of 342 negative findings in sputum examination, five were definitely false negative since the subsequent lavage yielded pneumocysts. In nine further cases Pneumocystis carinii pneumonia could not be excluded because of the course of the disease. In patients from whom sputum samples were available the sensitivity of pathogen identification was at least 70.8% and the negative predictive value at least 95.9%. Since preceding prophylaxis did not render identification in the sputum more difficult, examination of spontaneous or provoked sputum is indicated as a first hand measure in all patients infected with HIV in whom Pneumocystis carinii pneumonia is suspected.

The trace analysis of musk xylene in biological samples: problems associated with its ubiquitous occurrence.

Musk xylene (1-tert-butyl-3,5-dimethyl-2,4,6-trinitrobenzene) (MX), a synthetic musk often used in fragrances has previously been described to occur in human tissue. In this article a specific and sensitive method for the determination of MX in blood is described. It includes a simple clean-up by silica gel adsorption chromatography followed by GC/MS detection with negative chemical ionisation (NCI) and multiple ion detection of the molecular ion and M-30. The absolute detection limit in the MID-mode was 50 fg of MX. 11 human blood samples of 3 individuals were analysed to elucidate the suitability of this method. The MX concentrations ranged from 66 to 270 pg/g plasma or 12 to 49 ng/g blood lipids, respectively. In the course of the method evaluation the hazard of sample contamination during the clean-up procedure was investigated and MX was found to be present in several materials in the laboratory. Some of these contamination sources could be eliminated.

Chlorinated dibenzo-p-dioxins and -furans: problems in analysis of biomarkers.

Although dioxin concentrations in adipose tissue or blood lipids can suitably be used for toxicological evaluation, such data usually are not yet asked for in the risk assessment process, which is still based mainly on theoretical calculations of possible environmental exposure instead of measured concentrations in humans. The latter is necessary because the substantial kinetic differences between experimental animals and humans observed for dioxins lead to different organ concentrations and distribution patterns. Hence the classical extrapolation method for assessing toxicity on the basis of the administered oral dose is inappropriate. Also, the applied models and theoretical assumptions that often predicted a considerable human exposure by the oral, dermal, or inhalatory route in the case of contaminated soil and dust have not proved to be pertinent, since the actual burdens determined by biomonitoring in people living at heavily contaminated sites did not show markedly increased concentrations.

The lacI transgenic mouse mutagenicity assay: quantitative evaluation in comparison to tests for carcinogenicity and cytogenetic damage in vivo.

The detection limit of the lacI transgenic mouse mutagenicity assay lies, in practice, at approximately a 50-100% increase in mutant frequency in treated animals over controls. The sensitivity of this assay in detecting genotoxins can be markedly improved by subchronic rather than acute application of the test compound. The lacI transgenic mouse mutagenicity assay was compared quantitatively to rodent carcinogenicity tests and to presently used in vivo mutagenicity assays. With the genotoxic carcinogens tested thus far, a rough correlation between mutagenic potency and carcinogenic potency was observed: on average, to obtain a doubling in lacI mutant frequency the mice had to be treated with a total dose equal to 50 times the TD50 daily dose level. This total dose could be administered either at a high dose rate within a few days or, preferably, at a low dose rate over several weeks. This analysis also indicated that a lacI experiment using a 250-day exposure period would give a detection limit approximately equal to that of a long-term carcinogenicity study. In comparison to the micronucleus test or the chromosome aberration assay, acute studies with the presently available lacI system offered no increase in sensitivity. However, subchronic lacI studies (3-4-month exposure) resulted in an increase in sensitivity over the established tests by 1-2 orders of magnitude (shown with 2-acetylaminofluorene, N-nitrosomethylamine, N-nitrosomethylurea and urethane). It is concluded that a positive result in the lacI test can be highly predictive of carcinogenicity but that a negative result does not provide a large margin of safety.