Biological monitoring of experimental human exposure to trimethylbenzene.

Trimethylbenzene (TMB) is a component of numerous commercial preparations of organic solvents (Farbasol, Solvesso, Shellsol) used in the chemical, plastics, printing and other industries. TMB is a mixture of three isomers (pseudocumene-1,2,4-TMB; mesitylene-1,3,5-TMB; hemimellitene-1,2,3-TMB). The proportion of individual isomers in the mixture differs. The aim of this study was to obtain toxicokinetic data on the absorption and elimination of trimethylbenzene and its metabolites in biological fluids and to investigate the relationship between the biological indices of exposure and the absorbed dose. Eight-hour inhalation tests were performed in a toxicological chamber, The subjects were eight volunteers aged 20-39 with no history of exposure to TMB. They were exposed to pseudocumene, mesitylene or hemimellitene at concentrations ranging from 5 to 150 mg/m3 air. Exhaled air, capillary blood and urine samples were collected before, during and after the exposure. The determinations of TMB or its metabolites were performed using gas chromatography (HP 5890 II Plus, MSD, FID). Pulmonary ventilation in the volunteers ranged from 0.56 to 1.0 m3/h. The retention of 1,2,4-TMB; 1,3,5-TMB; 1,2,3-TMB in the lungs was 68%, 67% and 71%, respectively. The elimination of TMB from capillary blood occurred in accordance with the open three-compartment model. Urinary excretion of dimethylbenzoic acids (DMBA) proceeded according to the open two-compartment model. Based on the toxicokinetic data, a simulation model of accretion and excretion of DMBA in urine during a 14-day period was developed. The highest rates of metabolite excretion and the highest quantities of DMBA in urine during 24-h intervals were observed on day 5 of exposure. The relationship between the levels of TMB or DMBA in biological material and TMB air concentration or absorbed dose were determined. To select the urine fraction suitable for determining occupational TMB exposure, linear regression analysis was performed. The biological exposure limit (BEL) for TMB has been proposed, with the current maximum allowable concentration (MAC) value of 100 mg/m3 (Polish standard) baseline value.

[New sources of occupational exposure in modified or new technological processes]. / Nowe zródla narazenia zawodowego, wystepujace w modyfikowanych lub nowych procesach technologicznych.

Mixtures of organic solvents with frequently changing composition are employed in many industries. It is true that dangerous solvents are eliminated from the work environment, but simultaneously new manufacturing techniques are implemented. Glues, varnishes and stains, containing chemicals of unknown toxicity and non-recognized effects on the human body are extensively used in the footwear and furniture industries. The aim of our study was to identify new sources of occupational exposure. The tests were performed in plants of selected industries. Samples of glues, varnishes and wood stains were collected to glass vials (10 ml). The air-tight vials were kept at the temperature of +2 degrees C to +8 degrees C until removed for the analysis. After incubation period (T = 24 degrees C; t = 1 h), 100 microliters of gas phase was removed with gas-tight syringe. Organic solvents were identified by gas chromatography with mass spectrometry detection (GC/MSD). The following classes of organic compounds were detected in glues, varnishes and stains under study: alkanes, cycloalkanes, alcohols, ketones, esters, aromatic hydrocarbons and their numerous alkyl derivatives. The tests confirmed that glues, varnishes and stains contained chemicals with poorly recognized or totally unknown toxicity and toxicokinetics; MAC values were set for only few of them.

[Use of biological monitoring for evaluating occupational exposure in the paint and varnish industry]. / Zastosowanie monitoringu biologicznego do oceny narazenia zawodowego w przemysle farb i lakierów.

Multi-component solvent mixtures are used in the painting and varnishing industry. Trimethylbenzene (TMB approximately 50%) is a main component of these mixtures. Assessment of occupational exxposureto TMB and xylene based on the biological exposure index (capillary blood, urine) was the aim of the study. Gas chromatography with headspace technique (HP 5890/FID) was used to determine unchanged compounds in capillary blood. Gas chromatography (Chrom 5/FID; HP 5890 Series II/FID) was also employed to determine methyl- and dimethylbenzoic acid in urine. The results of the study showed that high exposure to solvents was predominant in the Automative Products Department. The TMB and xylene concentrations in capillary blood accounted for about 120 and 340 micrograms/dm3, respectively, while metabolite levels in urine were 0.65 mg/h and 90 mg/dm3 (the latter value was corrected to specific gravity d = 1.016 g/cm3). The results were remarkably below the proposed values of the biological exposure limit and suggested that the level of occupational exposure was below during the study period. The exposure index used in our study proved to be very sensitive and can be recommended as a monitoring mode to assess exposure to a single solvent or mixtures of solvents.

[Micromethods for determining organic solvents in blood by headspace analysis]. / Mikrometody oznaczania rozpuszczalników organicznych w krwi technika headspace.

The evaluation in industrial exposure to volatile organic compounds based on assessing concentrations of unchanged substances in blood of exposed workers seems to gain increasing interest. The main obstacle to a wide application of this method is the difficulty in collecting venous blood samples. Many authors suggest determining volatiles in capillary blood samples because they display the same concentrations as the arterial blood samples. The collection of capillary blood samples is much more convenient in occupational setting than the collection of venous blood samples. The aim of this study was to develop micromethod for determining organic solvents in small blood samples (100 mm3) by gas chromatography with headspace technique. 1.8 cm3 glass vessels (Sapelco) with screw caps, silicone rubber membranes and aluminium foil pads were used. After addition of 0.1 cm3 of blood and 2.0 cm3 of aqueous solution of internal standard, the vessels were closed tightly and shaken for 30 min. at 70 degrees C in water bath. Then about 1 cm3 of the gas phase was sampled with a gastight syringe (Hamilton) injected into the gas chromatograph. The parameters of the recently developed methods for determining organic solvents in blood samples, including linearity, precision, reproducibility, stability and sensitivity, are fully compatible with the principles of biological monitoring.

[Compartment simulation models and physiologic use in pharmaco- and toxicokinetics]. / Symulacyjne modele kompartmentowe i fizjologiczne stosowane w farmako-i toksykokinetyce.

The pharmaco- and toxicokinetic studies describe the process of absorption, distribution, metabolism and elimination of drugs or chemical compounds in animals and humans. In simple compartmental models, the body is divided into basic compartments, central and peripheral. The central compartment is an equilibrium of arterial and venous blood flows, and the peripheral one is connected to the central compartment through a series of flow rate constants that describe the flow of chemicals in both directions. For instance, we can use the PH/EDSIM software for calculating the constants. The flow of the material from one to the other reflected by vectorial connections of two types of kinetics: linear and Michaelis-Menten (nonlinear). At present, the PB-PK models (physiologically-based pharmacokinetic models), which rely on actual physiological (breath rates, blood flow rates and tissue volumes), biochemical and metabolic parameters, tend to be more commonly used. Tissue groups or compartments that are frequently applied in PB-TK model include organs, muscle, fat tissue and the liver. Tissue compartments are connected by arterial and venous blood flows, and each compartment is characterised by a unique set of differential equations. The flow rate constants that describe that flow of materials from and to the compartments, and the rate of change in the amount of chemical in each compartments are directly proportional to the blood flow rate, tissue solubility and organ value.

[Determining trichloroacetic acid in the urine by the gas chromatography method]. / Oznaczanie kwasu trichlorooctowego w moczu metoda chromatografii gazowej.

It has been found that the method of determination of trichloroacetic acid in urine after Monster and Boersma due to high detectability and specificity may be used for determination of trichloroacetic acid (TCA) in urine particularly when aimed at evaluation of exposure to tetrachloroethylene (PERC) or to trichloroethylene (TRI) et low concentrations range. The improvement of determinations precision has been obtained by introduction of internal standard. In case of application of full procedure for trichloroacetic acid solutions in urine ranging from 1.0 to 15.0 mg/1, the relative standard deviation amounted to: sr = 0.063 (n = 21).

[Use of the ACSL simulation language for physiologic toxicokinetic models]. / Zastosowanie symulacyjnego jezyka ACSL w fizjologicznych modelach toksykokinetycznych.

For the description of the processes of absorption, excretion or elimination of chemicals, the open one- or two-compartment models have been used thus far. The latter consist mainly of the fast (central) and slow (peripheral) compartments. The toxicological studies were based on an assumption that the organic processes develop according to is the first order kinetic reaction. However, the absorption, elimination or excretion of toxic chemicals are in fact much more complicated processes that should be explained using, e.g. the physiologically-based toxicokinetic (PBTK) models, covering physiological, biochemical and metabolic parameters, as well as the allometric calibration of selected parameters for interspecies extrapolations, and in vitro/in vivo extrapolations of metabolic parameters. Simulation languages, e.g. ACSL (Advanced Continuous Simulation Language) are indispensable application tools to be operated with PBTK models. They have been developed for modelling systems described by time-dependent non-linear differential equations and/or transfer functions. ACSL with its interfaces (ACSL Builder, ACSL Graphic Modeller, ACSL Math) ensures data input and communication inside the model by the control, transfer and computed parameters. The physiologically-based toxicokinetic models employ a large number of different parameters, which enables, e.g. forecasting the dose/effect or dose/response relationship absorption rate, metabolic pathways, excretion or elimination according to the absorbed dose of xenobiotic; evaluation of risk assessment; extrapolation from high to low doses characteristic of environmental exposure or setting biological exposure limits.

[Specific nature of the software used to construct simulations: physiologically-based toxicokinetic models]. / Specyfika stosowanego oprogramowania w konstruowaniu symulacyjnych, fizjologicznych modeli toksykokinetycznych (PBTK).

Building of the physiologically-based toxicokinetic (PBTK) models is based on the application of simulation languages, such as advanced continuous simulation language (ACSL). The aim of this study was to develop the principles of constructing the fundamental model and the models dedicated to chemicals found in the work environment (e.g. trimethylbenzene (TMB) isomers present in the petrochemical, paint and lacquer and related industries). The fundamental model is based on four main compartments (fat tissues, richly perfused tissue, slowly perfused tissue and liver) and six auxiliary compartments (lungs, venous blood, arterial blood, body weight, inhaled air and exhaled air). The basic element of the PBTK model comprises blocks containing definitions of variables and constants supplemented by the following parameters: command, calculated, transferred and resulted. The models dedicated to various chemicals and organisms are built by a suitable modification of the fundamental model. All sets of command parameters values for the organism, chemical and simulation are written in the text files and loaded before or during the simulation. The empirical data obtained in experiments with volunteers are used in a similar way. The specimen dedicated model was built for 1,2,3-TMB (hemimellitene). 2,3-Dimethylbenzoic acid (2,3,-DMBA) (a hemimelitene metabolite) excretion rate data obtained from an experiment during which volunteers were exposed to hemimellitene at 25 at 100 mg/m3 were compared with the results of the computer simulation. A high convergence of the comparable values was obtained. Simulations were also made for exposure periods of one week and one month. The results confirmed the experiment-based recommendations on the assessment of the occupational exposure. The application of the new physiologically-based toxicokinetic models renders it possible to forecast toxic chemical (or it metabolite) concentrations corresponding to the concentrations of those chemicals in the workplace atmosphere.

[Alkyl derivatives of benzene, indene, naphthalene, diphenyl and fluorene as a potential source of occupational and environmental exposure]. / Alkilowe pochodne benzenu, indenu, naftalenu, difenylu oraz fluorenu jako potencjalne zródla narazenia zawodowego i srodowiskowego.

Mixtures of organic solvents are used extensively in industry. The aim of this study was to develop a method for the determination of components of commercial multi-component solvent mixtures, and to perform qualitative and quantitative analyses of the mixtures. Farbasol, Solvesso and Shellsol mixtures were analysed by gas chromatography with a mass spectrometry detector (GC/MS). The composition of mixtures was determined using the mass spectrum computer analysis. Fractions of alkyl benzene, naphthalene and diphenyl derivatives were isolated. The proportions of the individual fractions in the mixtures differed. A predominant fraction was present in each mixture. Solvents (trimethylbenzene, tetramethylbenzene, ethyltoluene, diethylbenzene, isopropylotoulene) which significantly increase health risk due to their suspected neurotoxicity, were identified in each mixture.

[Comparison of standard methods for determination of pseudocumene in urine using gas chromatography with the headspace technique and a new method using a headspace automatic sampler]. / Porównanie metody standardowej oznaczania pseudokumenu w moczu z zastosowaniem chromatografii gazowej oraz techniki headspace z metoda, w której wykorzystano automatyczna przystawke headspace.

The biological indicators that have been proposed for monitoring occupational exposure are: concentration of the solvent or metabolized compounds in alveolar or expired air samples, in venous or arterial capillary blood samples and in urine samples. Recently, many researches have reported significant relationships between the time-weighted average exposure and the urinary concentrations for various solvents. The aim of our study was to compare two methods in which urinary concentrations of pseudocumene were determined by gas chromatography using headspace technique. The standard method was based on determining concentration of organic solvents in 100 mm3 or 1 cm3 samples of urine. The incubation conditions were as follows: equilibration temperature and time: 70 degrees C, 30 min., respectively. 1 cm3 of gas phase was sampled with a gas-tight syringe and injected into a gas chromatograph. The new method using Headspace Sampler was based on determining concentrations of solvents in 10 cm3 samples of urine. The operating conditions were: equilibration time 30 min.; equlibration temperature 80 degrees C; pressurization time 0.1 min.; loop fill time 0.1 min.; loop equilibration 0.1 min.; loop equilibration time 0.05 min.; inject time 1 min.; loop temperature 150 degrees C, transfer line temperature 150 degrees C. HP 7694 Headspace Sampler minimizes sample degradation with a chemically inert pathway extending from the sample loop to the column head. The analytical parameters of both methods (linearity, precision, reproducibility, stability and sensitivity) are fully compatible with the principles of biological monitoring. Application of the headspace autosampler eliminated interference from the biological matrix and made it possible to achieve very low detection limit.

[Determination of dimethylbenzoic acid isomers in urine by gas chromatography]. / Oznaczanie izomerów kwasów dimetylobenzoesowych w moczu metoda chromatografii gazowej.

Trimethylobenzene (TMB) is a main ingredient of many organic solvents used in industry. In Farbasol (Polish trade name of the solvent) TMB occurs as a mixture of three isomers: pseudocumene (1, 2, 4-TMB) 30%; mesitylene (1, 3, 5-TMB) 15%; hemimellitene (1,2,3-TMB) 5%. As it is known in human organism, TMB is metabolized mainly to dimethylbenzoic (DMBA) and dimethylhippuric (DMHA) acids, and some authors suggest, that the acids excreted in urine can be biological indicators of exposure to TMB. This study was aimed at developing the method of determination of DMBA isomers in urine. Biological material was hydrolyzed with sodium hydroxide and next extracted with diethyl ether. DMBA concentration in urine was determined by gas chromatography using a variant of quantitative analysis with internal standard (5-methyl-2-isopropylphenol, thymol). Analytical parameters of the developed method of determination of DMBA isomers in urine such as linearity, precision, reproducibility, stability (192 days, when urine samples stored at-18 degrees C), detectability limit (400 micrograms/dm3) have been fully compatible with the requirements of biological monitoring. In order to confirm the presence of DMBA isomers in urine, four volunteers were exposed (8 hours) to Farbasol in toxicological chamber. The TMB concentration in the air, determined by means of gas chromatograph (HP 5890), amounted to 100 mg/m3 (MAC value in Poland). In urine samples collected 2,3-; 2,4-; 2,5-; 2,6-; 3,4-; 3,5-dimethylbenzoic acids were identified by means of GC/MSD.(ABSTRACT TRUNCATED AT 250 WORDS)

Excretion of methylbenzoic acid in urine as a result of single and combined exposure to m-xylene.

Influence of combined exposure to solvent vapours on the metabolism of m-xylene and the kinetics of excretion of methylbenzoic acid (MBA) in urine was investigated. The volunteers were exposed in groups of four or five. Each experiment consisted of two parts. During the first part, the same test group was exposed to m-xylene for a period of 4 hours, whereas during the second part, the group was exposed to m-xylene in combination with other solvents. No significant differences in the excretion of MBA in urine were observed after exposure to m-xylene in concentrations of about 45 and 70 ppm and exposure to m-xylene together with n-hexane, toluene, methyl isobutyl ketone or n-butyl alcohol in combined concentrations of about 90 and 140 ppm. Only in the case of combined exposure to m-xylene and n-butyl acetate was a significant increase in the excretion of MBA in urine found. For both the single and combined exposure to kinetics of excretion of MBA was similar with t1/2 values in the first phase of excretion ranging between 1-1.3 h.

Toluene determination in capillary blood as a biological indicator of exposure to low levels of toluene.

The possibility of evaluating occupational exposure to toluene at low levels (50-150 mg/m3), based on the determination of unchanged substances in capillary blood, was investigated. The volunteers were exposed in a toxicological chamber; during and after exposure venous and capillary blood samples were analysed by gas chromatography using the headspace technique. Toxicokinetic data point out that determination of toluene should be performed in blood samples collected 15-20 min after termination of exposure. The toluene concentration in capillary blood may reflect the toluene dose absorbed during the workshift only in the case of constant exposure. Otherwise, this measurement refers to the rate of toluene absorption, mainly in the last 2 hours of daily exposure.

Kinetics of trichloroethylene elimination from venous blood after acute inhalation poisoning.

The kinetics of trichloroethylene were examined in three men, 28-36 years old, hospitalized after an acute occupational exposure. The trichloroethylene concentration of venous blood was determined by gas chromatography with headspace analysis; urinary trichloroacetic acid was assayed by the colorimetric method of Fujiwara. The kinetics of blood trichlorethylene (t1/2 21.7 h) and the urinary elimination of trichloracetic acid over six days were used to calculate the total inhalation exposures. Blood trichlorethylene was diagnostically more relevant than urinary trichloracetic acid.

Neurobehavioral effects of experimental exposure to toluene, xylene and their mixture.

The effects of experimental exposure to toluene (100 ppm), xylene (100 ppm) and their mixture (50 ppm of toluene and 50 ppm of xylene) on CNS functions were studied in 10 male volunteers aged 22-35. Changes in CNS functions were measured by means of nine psychological tests. Acute exposure to xylene produced the most adverse effect on simple reaction time SRT and choice reaction time ChRT. Exposure to toluene affected only the memory test performance. The effect of combined exposure appeared to be weaker than the effect of exposure to xylene alone but stronger than the effect of exposure to toluene.

Metabolic disposal of antipyrine and lipid peroxidation indices in volunteers jointly exposed to industrial organic solvents and ethanol.

Each of twelve volunteers, at 2 week intervals, received 1 g of antipyrine, a test drug, and were exposed for 4 h either to toluene (375 mg/m3) or xylene (435 mg/m3) singly or in combination with ethanol (0.45 g/kg body wt. before the onset of exposure and 0.15 g/kg thrice every 1 h during exposure to maintain a steady level of ethanol in blood approximately 11 mmol/dm3). No significant differences were found in salivary antipyrine half-life (T1/2 approximately 12 h); and clearance (ClAP approximately 0.83 cm3/s) between control and groups exposed to solvents and/or ethanol. Nevertheless, a tendency to increase the metabolic rate of antipyrine in xylene-exposed group (T1/2 approximately 6.8 h; ClAP approximately 1.40 cm3/s) and counteraction of ethanol (T1/2 approximately 15 h; ClAP approximately 0.63 cm3/s) should be noted. The stimulation of lipid peroxidation in the serum as a biological effect of combined exposure to ethanol and toluene/xylene was observed.

Acute potassium dichromate poisoning: a toxicokinetic case study.

CASE REPORT: A 48-year-old man drank 150 mL of an aqueous solution containing potassium dichromate 22.5 g in a suicidal attempt and was admitted 7 hours after the ingestion. Hemodialysis was promptly undertaken and chromium concentrations in serum, erythrocytes, and dialysate were determined during the treatment. Chromium elimination in urine was monitored during hemodialysis and the subsequent 400 hours. The total chromium eliminated via hemodialysis and urine was calculated as 36.7 mg or 0.16% of the ingested dose. Spontaneous urinary elimination proceeded according to an open one-compartment model. The elimination half-life was 71.37 hours +/- 17.13 hours (95% CI). Chromium elimination from serum followed an open two-compartment model, with the half-lives of 3.16 hours +/- 2.63 hours for phase 1 and 50 hours +/- 27 hours (95% CI) for phase 2. Calcium-EDTA therapy had no influence on erythrocyte, serum, or urine chromium level. It contributed, however, to a significant increase in chromium elimination rate in the dialysate. Serum zinc was very low at admission and serum zinc, copper, and magnesium were controlled during the initial 30 hours.