Occupational exposure to veterinary antibiotics: Pharmacokinetics of enrofloxacin in humans after dermal, inhalation and oral uptake - A clinical study.

Occupational exposure to veterinary antibiotics in hen houses at poultry feeding farms was demonstrated by biomonitoring campaigns in the past. The objective of this study was to investigate pharmacokinetics of three uptake routes: dermal, oral and inhaled. In an open-label cross-over study, six healthy volunteers were exposed to single occupational relevant doses of enrofloxacin. Plasma and urine samples were analysed for enrofloxacin and ciprofloxacin. Physiologically based pharmacokinetic (PBPK) modelling based on bioanalysis data showed underestimation for the elimination rate in comparison to experimental data pointing towards a lack of sufficient ADME information and limitations of available physico-chemical properties of the parent drug. The data obtained in this study indicate that oral uptake with its various sources, e.g. airborne enrofloxacin, direct hand-mouth contact, is the major source for occupational exposure to enrofloxacin in hen houses. Dermal exposure was considered negligible.

Occupational Exposure to Antibiotics in Poultry Feeding Farms.

Today, antibiotics are essential for effective treatment of infectious diseases both in human and veterinary medicine. The increasing development and distribution of antibiotic-resistant microorganisms are subject of concern. In some sectors of animal agriculture, such as poultry feeding farms, the application of antibiotics and hence occupational exposure is inevitable. In the past, numerous studies focussed on the occurrence of antibiotic-resistant bacteria in livestock farming, but little attention was paid to the employees. The exposure of workers to antibiotics was the focus of the study detailed in this article. Four biomonitoring campaigns monitoring systemic exposure of workers to antibiotics were run at two farms over four fattening periods. Urine samples of potentially affected employees were sampled and analysed for the antibiotics of interest by liquid chromatography-mass spectrometry. The highest antibiotic concentrations detected in urine samples exceeded the minimum inhibitory concentration of some bacteria strains. In some cases, the amount of antibiotics excreted over a time-period of 24 h indicated the exceedance of the tolerable daily intake.

Relative oral bioavailability of 3-MCPD from 3-MCPD fatty acid esters in rats.

In order to quantify the relative oral bioavailability of 3-chloropropane-1,2-diol (3-MCPD) from 3-MCPD fatty acid diesters in vivo, 1,2-dipalmitoyl-3-chloropropane-1,2-diol (3-MCPD diester) and 3-MCPD were orally applied to rats in equimolar doses. In both cases, the time courses of 3-MCPD concentrations were measured in blood, various organs, tissues and intestinal luminal contents. The results show that 3-MCPD is released by enzymatic hydrolysis from the 3-MCPD diester in the gastrointestinal tract and distributed to blood, organs and tissues. Based on the measurements in blood, the areas under the curve (AUC) for 3-MCPD were calculated. By comparing both AUC, the relative amount of 3-MCPD bioavailable from the 3-MCPD diester was calculated to be 86 % on average of the amount bioavailable following administration of 3-MCPD. In view of limited experimental data, it is justified for the purpose of risk assessment to assume complete hydrolysis of the diesters in the gastro-intestinal tract. Therefore, assessment of the extent of exposure to 3-MCPD released from its fatty acid esters should be performed in the same way as exposure to the same molar quantity of 3-MCPD.

Development and validation of an analytical method for determination of 3-chloropropane-1,2-diol in rat blood and urine by gas chromatography-mass spectrometry in negative chemical ionization mode.

We have developed a highly selective and sensitive method using gas chromatography-mass spectrometry with negative chemical ionization for measuring 3-chloropropane-1,2-diol (3-MCPD) in rat blood and urine. Samples were adsorbed on silica gel, extracted with ethyl acetate, and derivatized by chemical derivatization with heptafluorobutyric acid anhydride. For quantification, matrix-based calibration curves and 3-MCPD-d (5), as an isotope-labeled internal standard, were used. The relative recoveries of 3-MCPD were between 80 and 110% in most cases and the relative standard deviations were typically less than 10%, with some exceptions. The limit of quantification of the method was found to be about 2 ng/mL. In conclusion, a valuable, robust, and sensitive method for detection of 3-MCPD is now available for biokinetics studies.

Use of biocidal products (insect sprays and electro-vaporizer) in indoor areas--exposure scenarios and exposure modeling.

Five commercially available insect sprays were applied in a model room. Spraying was performed in accordance with the manufacturers' instructions and in an overdosed manner in order to simulate worst-case conditions or an unforeseeable misuse. In addition, we examined electro-vaporizers. The Respicon aerosol monitoring system was applied to determine inhalation exposure. During normal spraying (10 seconds) and during the following 2-3 minutes, exposure concentrations ranged from 70 to 590 microg/m3 for the pyrethroids tetramethrin, d-phenothrin, cyfluthrin, bioallethrin, and the pyrethrins. Calculated inhalable doses were 2-16 microg. A concentration of approximately 850 microg chlorpyrifos/m(3) (inhalable dose: approximately 20 microg) was determined when the "Contra insect fly spray" was applied. Highest exposure concentrations (1100-2100 microg/m3) were measured for piperonyl butoxide (PBO), corresponding to an inhalation intake of 30-60microg. When simulating worst-case conditions, exposure concentrations of 200-3400microg/m3 and inhalable doses of 10-210microg were determined for the various active substances. Highest concentrations (4800-8000 microg/m3) were measured for PBO (inhalable: 290-480 microg). By applying the electro-vaporizer "Nexa Lotte" plug-in mosquito killer concentrations for d-allethrin were in the range of 5-12microg/m3 and 0.5-2 microg/m3 for PBO while with the "Paral" plug-in mosquito killer concentrations of 0.4-5microg/m3 for pyrethrins and 1-7 microg/m3 for PBO were measured. Potential dermal exposures were determined using exposure pads. Between 80 and 1000microg active substance (tetramethrin, phenothrin, cyfluthrin, bioallethrin, pyrethrins, chlorpyrifos) were deposited on the clothing of the total body surface area of the spray user. Highest levels (up to 3000 microg) were determined for PBO. Worst-case uses of the sprays led to 5-9 times higher concentrations. Also a 2-hour stay nearby an operating electro-vaporizer led to a contamination of the clothing (total amounts on the whole body were 450 microg d-allethrin and 50 microg PBO for "Nexa Lotte" plug-in mosquito killer and 80 microg pyrethrins and 190 microg PBO for "Paral" plug-in mosquito killer). Human biomonitoring data revealed urine concentrations of the metabolite (E)-trans-chrysanthemum dicarboxylic acid ((E)-trans-CDCA) between 1.7 microg/l and 7.1 microg/l after 5 minutes of exposure to the different sprays. Also the use of electro-vaporizers led to (E)-trans-CDCA concentrations in the urine in the range of 1.0 microg/l to 6.2 microg/l (1-3 hours exposure period). The exposure data presented can be used for performing human risk assessment when these biocidal products were applied indoors. The airborne concentrations of the non-volatile active chemical compounds could be predicted from first principles using a deterministic exposure model (SprayExpo).

Identification of highly polar nitroaromatic compounds in leachate and ground water samples from a TNT-contaminated waste site by LC-MS, LC-NMR, and off-line NMR and MS investigations.

Leachate and ground water samples from a trinitrotoluene-contaminated waste disposal site near a former ammunitions plant in Stadtallendorf, Germany, were analyzed by liquid chromatography (LC)-mass spectrometry (MS) and LC-NMR hyphenated techniques to comprehensively characterize the range of highly polar nitroaromatic compounds. Wherever unknown components could not be identified by comparison with a multistandard, the spectroscopic data obtained on-line were used to make initial structure proposals, which were later confirmed by comparison with authentic reference materials. In those cases where reference materials were not commercially available, unknown compounds were isolated by HPLC cuts and their structures were elucidated by off-line NMR and MS investigations. A variety of previously unknown compounds, including nitrophenols, nitrobenzyl alcohols, methylnitrobenzoic acids, and hydroxynitrobenzoic acids, could be identified. The NMR and MS data are presented here. The main polar compounds were additionally quantified.

Cross validation of multiple methods for measuring pyrethroid and pyrethrum insecticide metabolites in human urine.

The objective of our study was to compare three vastly different analytical methods for measuring urinary metabolites of pyrethroid and pyrethrum insecticides to determine whether they could produce comparable data and to determine if similar analytical characteristics of the methods could be obtained by a secondary laboratory. This study was conducted as a part of a series of validation studies undertaken by the German Research Foundation's Committee on the Standardization of Analytical Methods for Occupational and Environmental Medicine. We compared methods using different sample preparation methods (liquid-liquid extraction and solid-phase extraction with and without chemical derivatization) and different analytical detection methods (gas chromatography-mass spectrometry (single quadrupole), gas chromatography-high resolution mass spectrometry (magnetic sector) in both electron impact ionization and negative chemical ionization modes, and high-performance liquid chromatography-tandem mass spectrometry (triple quadrupole) with electrospray ionization). Our cross validation proved that similar analytical characteristics could be obtained with any combination of sample preparation/analytical detection method and that all methods produced comparable analytical results on unknown urine samples.

Aircraft disinsection: exposure assessment and evaluation of a new pre-embarkation method.

A new "pre-embarkation" method for aircraft disinsection was investigated using two different 2% d-phenothrin containing aerosols. Five experiments in aircrafts of the type Airbus 310 (4x) and Boeing 747-400 (1x) were performed. In the absence of passengers and crew the d-phenothrin aerosol was sprayed under the seat rows and in a second step at the height of approximately 1.60 m by moving from one end of the cabin to the other. Concentration levels of d-phenothrin were determined at different time periods after application of the aerosol spray. In a B 747-400 with the air conditioning system operating the concentrations ranged between 853 and 1753 microg/m3 during and till 5 min after the beginning of spraying at different locations in the cabin. Within 5-20min after the end of the spraying concentrations of 36-205 microg/m3 and 20-40 min thereafter only ca. 1 microg d-phenothrin/m3 were detectable (average values in relation to each period of measurement). On cabin interior surfaces the median values for mainly horizontal areas ranged from 100 to 1160 ng d-phenothrin/cm2. d-Phenothrin concentrations in the air were sufficient to kill flying insects like house flies and mosquitoes within 20 min. Horizontal surfaces were 100% effective against insects up to 24 h after spraying. Doses inhaled by sprayers determined by personal measurements were calculated to be 30-235 microg d-phenothrin per 100 g spray applied (30% in the respirable fraction for Arrow Aircraft Disinsectant; 10% for Aircraft Disinsectant Denka). If passengers will board, e.g., 20 min after the end of the disinsection operation, inhalation exposure is estimated to be practically negligible. Also possible dermal exposure from residues in seats and headrests is very low for passengers during the flight. Therefore any health effects for passengers and crew members are very unlikely.

Analysis of highly polar compounds in groundwater samples from ammunition waste sites. Part I-Characterization of the pollutant spectrum.

Five groundwater samples from the former ammunition production site at Elsnig, Germany, were analyzed for highly polar components by LC-NMR and LC-MS. A variety of unknown pollutants could be identified. Possibilities and limitations of the combined use of LC-NMR and LC-MS techniques for on-line identification are discussed. Further unknown components were identified through isolation by HPLC cuts and off-line NMR and MS investigations. Most of the polar compounds in the investigated samples could also be quantified.

In-flight spraying in aircrafts: determination of the exposure scenario.

Exposure measurements were carried out in parked aircrafts during and after application of a biocide aerosol spray (simulated in-flight spraying). The aerosol product SRA spray (Standard Reference Aerosol Spray) was used for spraying. Concentrations of the pyrethrins--the active ingredients--in the air of the passenger cabin (airborne particles, measured during spray application and 40 minutes afterwards) varied from 11 to 65 microg/m3; those of the synergist piperonyl butoxide were 200-485 microg/m3. The concentrations on surfaces of the cabin furniture differed widely. Low concentrations were determined on surfaces in vertical positions (median values: pyrethrins < or =2 ng/cm2; piperonyl butoxide < or =17 ng/cm2), while under seats, on seats and on headrests the concentrations were up to 55.5 ng/cm2 for pyrethrins and 1162.5 ng/cm2 for piperonyl butoxide (median values). The inhaled doses for sprayers (using 100 g of spray) and persons sitting in the passenger cabin were calculated to be 17 microg for pyrethrins and 200 microg for piperonyl butoxide (maximum values). Maximum total external body doses for the applicators during spraying were 830 microg for pyrethrins and 8840 microg for piperonyl butoxide. The potential dermal dose for persons sitting in the passenger cabin was about a factor of two lower.