Volatile organic compounds in plasma for the diagnosis of esophageal adenocarcinoma: a pilot study.

BACKGROUND AND AIMS: A noninvasive screening test that can detect esophageal adenocarcinoma (EAC) at an earlier stage could improve the prognosis associated with EAC. The role of plasma volatile organic compounds (VOCs) for the diagnosis of EAC has not been previously studied. METHODS: Plasma samples were collected from subjects with EAC and GERD before endoscopy. Twenty-two preselected VOCs were analyzed with selected ion flow tube mass spectrometry. RESULTS: The headspaces from 39 plasma samples (20 EAC, 19 GERD) were analyzed. The levels of 9 VOCs (acetonitrile, acrylonitrile, carbon disulfide, isoprene, 1-heptene, 3-methylhexane, [E]-2-nonene, hydrogen sulfide, and triethylamine) were significantly altered in EAC patients compared with GERD patients. A multivariable logistic regression analysis was performed to build a model for the prediction of EAC. The model identified patients with EAC with an area under the curve of 0.83 (95% confidence interval, 0.67-0.98). CONCLUSIONS: Plasma VOCs may be useful in diagnosing EAC. Larger studies are needed to confirm our pilot study observations.

A case report of motor neuron disease in a patient showing significant level of DDTs, HCHs and organophosphate metabolites in hair as well as levels of hexane and toluene in blood.

Motor neuron disease is a devastating neurodegenerative condition, with the majority of sporadic, non-familial cases being of unknown etiology. Several epidemiological studies have suggested that occupational exposure to chemicals may be associated with disease pathogenesis. We report the case of a patient developing progressive motor neuron disease, who was chronically exposed to pesticides and organic solvents. The patient presented with leg spasticity and developed gradually clinical signs suggestive of amyotrophic lateral sclerosis, which was supported by the neurophysiologic and radiological findings. Our report is an evidence based case of combined exposure to organochlorine (DDTs), organophosphate pesticides (OPs) and organic solvents as confirmed by laboratory analysis in samples of blood and hair confirming systematic exposure. The concentration of non-specific dialkylphosphates metabolites (DAPs) of OPs in hair (dimethyphopshate (DMP) 1289.4 pg/mg and diethylphosphate (DEP) 709.4 pg/mg) and of DDTs (opDDE 484.0 pg/mg, ppDDE 526.6 pg/mg, opDDD 448.4 pg/mg, ppDDD+opDDT 259.9 pg/mg and ppDDT 573.7 pg/mg) were considerably significant. Toluene and n-hexane were also detected in blood on admission at hospital and quantified (1.23 and 0.87 µg/l, respectively), while 3 months after hospitalization blood testing was found negative for toluene and n-hexane and hair analysis was provided decrease levels of HCHs, DDTs and DAPs.

Quantification of low levels of organochlorine pesticides using small volumes (

A solid phase extraction and gas chromatography with negative chemical ionization mass spectrometry in scan mode (GC-NCI-MS) method was developed to identify and quantify for the first time low levels of organochlorine pesticides (OCs) in plasma samples of less than 100 microl from wild birds. The method detection limits ranged from 0.012 to 0.102 pg/microl and the method reporting limit from 0.036 to 0.307 pg/microl for alpha, gamma, beta and delta-hexachlorocyclohexane (HCH), heptachlor, aldrin, heptachlor epoxide, endosulfan I, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), dieldrin, endrin, endosulfan-II, endrin-aldehyde and endosulfan-sulfate. Pesticide levels in small serum samples from individual Falco sparverius, Sturnella neglecta, Mimus polyglottos and Columbina passerina were quantified. Concentrations ranged from not detected (n/d) to 204.9 pg/microl for some OC pesticides. All levels in the food web in and around cultivated areas showed the presence of pesticides notwithstanding the small areas for agriculture existing in the desert of Baja California peninsula.

Pan-selectin antagonism improves psoriasis manifestation in mice and man.

The selectin family of vascular cell adhesion molecules is comprised of structurally related carbohydrate binding proteins, which mediate the initial rolling of leukocytes on the activated vascular endothelium. Because this process is one of the crucial events in initiating and maintaining inflammation, selectins are proposed to be an attractive target for the development of new antiinflammatory therapeutics. Here, we demonstrate that the synthetic pan-selectin antagonist bimosiamose is effective in pre-clinical models of psoriasis as well as in psoriatic patients. In vitro bimosiamose proved to be inhibitory to E- or P-selectin dependent lymphocyte adhesion under flow conditions. Using xenogeneic transplantation models, bimosiamose reduced disease severity as well as development of psoriatic plaques in symptomless psoriatic skin. The administration of bimosiamose in patients suffering from psoriasis resulted in a reduction of epidermal thickness and lymphocyte infiltration. The clinical improvement was statistically significant (P=0.02) as analyzed by comparison of psoriasis area and severity index before and after treatment. Assessment of safety parameters showed no abnormal findings. These data suggest that pan-selectin antagonism may be a promising strategy for the treatment of psoriasis and other inflammatory diseases.

Development of a physiologically based pharmacokinetic model for volatile fractions of gasoline using chemical lumping analysis.

Physiologically based pharmacokinetic (PBPK) models have often been used to describe the absorption, distribution, metabolism, and excretion of chemicals in animals but have been limited to single chemicals and simple mixtures due to the numerous parameters required in the models. To overcome the barrier to modeling more complex mixtures, we used a chemical lumping approach, used in the past in chemical engineering but not in pharmacokinetic modeling, in a rat PBPK model for gasoline hydrocarbons. Our previous gasoline model consisted of five individual components (benzene, toluene, ethylbenzene, xylene, and hexane) and a lumped chemical that included all remaining components of whole gasoline. Despite being comprised of hundreds of components, the lumped component could be described using a single set of chemical parameters that depended on the blend of gasoline. In the present study, we extend this approach to evaporative fractions of gasoline. The PBPK model described the pharmacokinetics of all of the volatility-weighted fractions of gasoline when differences in partitioning and metabolism between fractions were taken into account. Adjusting the ventilation rate parameter to account for respiratory depression at high exposures also allowed a much improved description of the data. At high exposure levels, gasoline components competitively inhibit each other's metabolism, and the model successfully accounted for binary interactions of this type, including between the lumped component and the five other chemicals. The model serves as a first example of how the engineering concept of chemical lumping can be used in pharmacokinetics.

Poor metabolization of n-hexane in Parkinson's disease.

Although genomic screening studies have identified several genes associated with Parkinson's disease (PD), there is evidence that environmental factors are also involved in the pathogenesis of the disease and that hydrocarbon-solvents may be one of them. The genetic component is less evident in late-onset PD. To assess whether age and PD may affect the catabolism of the hydrocarbon n-hexane, a two-part study was performed. In the first part the urinary levels of its main metabolites, 2,5-hexanedione and 2,5-dimethylpyrroles, were measured in 108 patients and 108 healthy controls, matched by age and sex. Metabolite urinary excretion was significantly reduced in PD patients as compared with controls and was inversely related to age in both groups. In the second part the same comparison was made between 24 non-smoking and 10 smoking patients, matched to controls, after smoking of a hydrocarbon-rich cigarette. In these subjects also n-hexane and 2,5-hexanedione blood levels were measured. There was no appreciable difference in n-hexane blood levels between patients and controls in non-smokers, whereas there was a significant increase in patients over controls in smokers (p < 0.01). 2,5-hexanedione blood levels were significantly lower in patients than in healthy controls, both in non-smokers and in smokers, but the reduction was more pronounced in smokers (-46.3 % versus -10.7 %). The same was true for 2,5-hexanedione and 2,5-dimethylpyrrole urinary levels. This study suggests that aging and PD may be associated with a reduction in the capacity to eliminate the hydrocarbon n-hexane. This metabolic alteration may play a role in the pathogenesis of PD.

Changes in n-hexane toxicokinetics in short-term single exposure due to co-exposure to methyl ethyl ketone in volunteers.

OBJECTIVES: Animal studies demonstrate that the formation of the neurotoxic metabolite, 2,5-hexanedione (HD) decreases during co-exposure to methyl ethyl ketone (MEK). The aim of the present study was to describe the influence of co-exposure to MEK on n-hexane toxicokinetics in humans. METHODS: Four healthy male volunteers were exposed, on different occasions, to three different combinations of vapor of these solvents, namely: 50 ppm n-hexane alone, and in combination with 100 and 200 ppm MEK, for 2 h during light physical exercise (50 W). Arterialized capillary blood, venous blood, and urine were sampled at scheduled intervals before, during, and up to 24 h after the onset of the exposure. HD in venous blood and urine was analyzed by gas chromatography with electron capture detector after derivatization with O-(pentafluorobenzyl) hydroxylamine. RESULTS: Serum HD decreased with increasing exposure to MEK at 2 h after the onset of the exposure, from an average concentration of 2.2 micromol/l in the n-hexane-alone condition to 1.2 and 0.44 micromol/l in the 100 and 200-ppm MEK conditions, respectively. The area under the concentration-time curve of HD in venous blood and the concentration of HD at 2 and 4 h after the end of exposure decreased with increasing MEK. These results suggest that combined exposure to MEK and n-hexane at occupationally realistic levels depresses the metabolism of n-hexane in a dose-dependent fashion. CONCLUSION: The internal exposure to the toxic metabolite of n-hexane decreased with co-exposure to MEK in a dose-dependent fashion. Estimation of external exposure by HD in serum or urine could be confounded by the co-exposure to MEK.

Sensitive determination of n-hexane and cyclohexane in human body fluids by capillary gas chromatography with cryogenic oven trapping.

A sensitive method was developed for determination of n-hexane and cyclohexane in human body fluids by headspace capillary gas chromatography (GC) with cryogenic oven trapping. Whole blood and urine samples containing n-hexane and cyclohexane were heated in a 7.5 mL vial at 70 degrees C for 15 min, and 5 mL of the headspace vapor was drawn into a glass syringe. All vapor was introduced through an injection port of a GC instrument in the splitless mode into an Rtx-Volatiles middle-bore capillary column at an oven temperature of -40 degrees C for trapping volatile compounds. The oven temperature was programmed to 180 degrees C for GC with flame ionization detection. These conditions gave sharp peaks for both n-hexane and cyclohexane, a good separation of each peak, and low background impurities for whole blood and urine. The extraction efficiencies of n-hexane and cyclohexane were 13.2-30.3% for whole blood and 12.7-20.7% for urine. The coefficients of within-day variation in terms of extraction efficiency of both compounds were 5.0-9.5% for whole blood and 3.8-10.8% for urine; those of day-to-day variation for the compounds were not greater than 16.6%. The regression equations for n-hexane and cyclohexane showed good linearity in the range of 5-500 ng/0.5 mL for whole blood and urine. The detection limits (signal-to-noise ratio = 3) for both compounds were 1.2 and 0.5 ng/0.5 mL for whole blood and urine, respectively. The data on n-hexane or cyclohexane in rat blood after inhalation of each compound are also presented.

Some immunological parameters in workers occupationally exposed to n-hexane.

1. To estimate the quantitative relation between exposure to airborne n-hexane and various markers of immune function, 35 male workers were examined and compared with unexposed controls. 2. Urinary 2,5-hexanedione concentrations were significantly higher in the exposed group than in the unexposed. 3. A significant suppression was observed in the serum immunoglobulin (IgG, IgM and IgA) levels between two populations. Also, a significant correlation was found between urinary 2,5-hexanedione concentrations and serum Ig level of the exposed group. 4. No significant difference between white blood cell counts was found in the two groups.

Blood and urine concentrations of chemical pollutants in the general population.

The concentration of 9 environmental chemical pollutants in the general population was measured in blood and urine. For the 9 different pollutants, the blood samples tested varied from 88 for acetone to 431 for benzene. Urine samples varied from 48 for styrene to 213 for n-hexane. Six of these agents (benzene, toluene, styrene, n-hexane, acetone and carbon disulphide) were present in all or almost all (100-94%) blood samples. The three chlorides (chloroform, trichloroethylene and tetrachloroethylene) were present only in 60-85% of samples. After acetone, with blood concentrations in microgram/1 (mean 840 microgram/l), the highest mean blood levels were those of toluene (1097 ng/l), chloroform (955 ng/l) and n-hexane (642 ng/l). Trichloroethylene and free carbon disulphide showed similar values (458 and 438 ng/l, respectively). Finally, benzene, styrene and tetrachloroethylene showed the lowest values (262, 217 and 149 ng/l, respectively). There was generally a significant difference between rural and urban workers in terms of blood benzene (200 ng/l vs 264 ng/l), trichloroethylene (180 ng/l vs 763 ng/l) and tetrachloroethylene (62 ng/l vs 263 ng/l). In a group of subjects potentially exposed to industrial solvents, classed as chemical workers, blood benzene, toluene, chloroform and n-hexane were significantly higher than in rural and urban workers. Smokers showed a significantly higher blood concentration than non-smokers for benzene (381 ng/l vs 205 ng/1), toluene (1431 ng/l vs 977 ng/l), and n-hexane (838 ng/l vs 532 ng/l). All or almost all urine samples (100-92%) contained all the compounds except trichloroethylene and tetrachloroethylene, present in 79% and 76% of samples, respectively (table 2). Urinary concentrations of all compounds did not differ significantly between rural and urban workers. Benzene and toluene were significantly higher in in urine of smokers than of non-smokers. Chloroform and n-hexane showed significantly higher urinary than blood values. Excluding acetone, with urinary and blood concentrations in pg/l, chloroform, toluene and n-hexane showed the highest mean concentrations both in blood and in urine.

[Blood interface in environmental and occupational exposure to industrial chemical pollutants]. / L'interfaccia ematica nell'esposizione ambientale e professionale a inquinanti chimici industriali.

The concentration of 12 environmental chemical pollutants was measured in the blood of the general population. With reference to the 12 different pollutants, the blood samples tested varied from 88 for acetone to 431 for benzene. Nine of these agents (benzene, toluene, styrene, cumene, xilene, n-hexane, nitrous oxide (N20), acetone and carbon disulphide) were present in all or almost all (100-94%) blood samples. The three chlorides (chloroform, trichloroethylene and tetrachloroethylene) were present only in 60-85% of samples. After acetone and carbon disulphide, with blood concentrations in microgram/l (mean 840 micrograms/l and 2.4 micrograms/l respectively), the highest mean blood levels were those of toluene (1097 ng/l), chloroform (955 ng/l), N2O (915 ng/l), and n-hexane (642 ng/l). Trichloroethylene and free carbon disulphide had similar values (458 and 438 ng/l, respectively). Finally, benzene, styrene and tetrachloroethylene had the lowest values (262, 217 and 149 ng/l, respectively). There was generally a significant difference between rural and urban workers in terms of blood benzene (200 ng/l vs. 264 ng/l), trichloroethylene (180 ng/l vs 763 ng/l) and tetrachloroethylene (62 ng/l vs. 263 ng/l). In a group of subjects potentially exposed to industrial solvents, classed as chemical workers, blood benzene, toluene, chloroform and n-hexane were significantly higher than in rural and urban workers. Smokers showed a significantly higher blood concentration than non-smokers for benzene (381 ng/l vs. 205 ng/l), toluene (1431 ng/l vs. 976 ng/l) and n-hexane (803 ng/l vs. 505 ng/l).

Comparative evaluation of blood and urine analysis as a tool for biological monitoring of n-hexane and toluene.

Blood and urine samples were collected from 57 male Japanese solvent workers [exposed to n-hexane (Hex-A), ethyl acetate, and toluene (Tol-A) at 1.5, 2.3, and 2.3 ppm as GM-TWA, respectively] and also from 20 male nonexposed workers at the end of a 8-h shift, and analyzed for n-hexane (Hex-B) and toluene (Tol-B) in blood, and n-hexane (Hex-U), toluene (Tol-U), 2,5-hexanedione [both with (HD-U/cHYD) and without hydrolysis (HD-U/sHYD)] and hippuric acid (HA-U) in urine. Regression analysis showed that both Hex-B and Tol-B correlated significantly with corresponding exposure to the solvents. Solvents in urine (Hex-U and Tol-U) also correlated with solvents in air but with smaller correlation coefficients than the solvents in blood. Both HD-U/cHYD and HD-U/sHYD showed significant correlation with Hex-A, but HA-U failed to do so with Tol-A. Based on the correlation among biological exposure indicators and solvent concentration in air, sensitivity as an exposure indicator was compared between the solvent in blood and the metabolite in urine in terms of the lowest solvent concentration at which the exposed can be separated (with statistical significance) from the nonexposed (the lowest separation concentration; LSC). The LSC was 3.9 ppm for Hex-B, 1 to 2 ppm for HD-U/sHYD and 10 to 30 ppm for HD-U/cHYD, suggesting that HD-U/sHYD is superior even to Hex-B in detecting low n-hexane exposure; this high sensitivity of HD-U/sHYD is due to the absence of HD-U/sHYD in the urine from the nonexposed.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinalysis vs. blood analysis, as a tool for biological monitoring of solvent exposure.

Blood and urine samples were collected at the end of an 8-h workshift from 30 male workers exposed to a mixture of n-hexane, ethyl acetate and toluene (each being about 2 ppm as geometric means) and also from 20 nonexposed male workers. Blood samples were analyzed for n-hexane and toluene, and urine samples were analyzed for n-hexane, toluene, 2,5-hexanedione (both with and without hydrolysis) and hippuric acid. Based on the correlation between biological exposure indicators and solvent concentrations in air, sensitivity as an exposure indicator was compared between solvents in blood and solvents or metabolites in urine in terms of the lowest solvent concentration at which the exposed subjects can be statistically separated from the nonexposed. Both n-hexane and toluene in blood were sensitive enough to detect the exposure at 6.1 ppm and 1.4 ppm, respectively. n-Hexane exposure below 2 ppm was detectable also by urinalysis for 2,5-hexadione without hydrolysis. Urinary hippuric acid, however, failed to detect low toluene exposure under the conditions studied. Of additional interest is the fact that toluene in urine correlated significantly with toluene in air, which apparently deserves further study for confirmation.

Mechanism of transport and distribution of organic solvents in blood.

Little is known about the mechanism of transport and distribution of volatile organic compounds in blood. Studies were conducted on five typical organic solvents to investigate how these compounds are transported and distributed in blood. Groups of four to five rats were exposed for 2 hr to 500 ppm of n-hexane, toluene, chloroform, methyl isobutyl ketone (MIBK), or diethyl ether vapor; 94, 66, 90, 51, or 49%, respectively, of these solvents in the blood were found in the red blood cells (RBCs). Very similar results were obtained in vitro when aqueous solutions of these solvents were added to rat blood. In vitro studies were also conducted on human blood with these solvents; 66, 43, 65, 49, or 46%, respectively, of the added solvent was taken up by the RBCs. These results indicate that RBCs from humans and rats exhibited substantial differences in affinity for the three more hydrophobic solvents studied. When solutions of these solvents were added to human plasma and RBC samples, large fractions (51-96%) of the solvents were recovered from ammonium sulfate-precipitated plasma proteins and hemoglobin. Smaller fractions were recovered from plasma water and red cell water. Less than 10% of each of the added solvents in RBC samples was found in the red cell membrane ghosts. These results indicate that RBCs play an important role in the uptake and transport of these solvents. Proteins, chiefly hemoglobin, are the major carriers of these compounds in blood. It can be inferred from the results of the present study that volatile lipophilic organic solvents are probably taken up by the hydrophobic sites of blood proteins.

Effects of MEK on kinetics of n-hexane metabolites in serum.

The neurotoxicity of n-hexane is thought to be caused ultimately by 2,5-hexanedione (2,5-HD), one of the n-hexane metabolites. The potentiation of n-hexane neurotoxicity by co-exposure with MEK, therefore, is suspected to be related to kinetics of 2,5-HD in blood. To clarify the kinetics of n-hexane metabolites in the mixed exposure of n-hexane and MEK, rats were exposed to 2000 ppm n-hexane or a mixture of 2000 ppm n-hexane and 2000 ppm MEK, and the time courses of serum n-hexane metabolites were determined. 2,5-HD in serum increased until 2 h after the end of exposure, when serum 2,5-HD concentration reached a peak of 16.35 micrograms/ml in the n-hexane-alone group. In contrast, 2,5-HD in the mixed exposure group increased much more slowly during and after exposure than in the n-hexane-alone group. It reached a peak of 2.12 micrograms/ml at 8 h after the end of exposure. Serum MBK, a precursor of 2,5-HD in the co-exposure group, was about half in the n-hexane-alone group during exposure. However, MBK decreased more slowly in the co-exposure group than in the n-hexane-alone group after the end of the exposure. The results suggest that co-exposed MEK might inhibit oxidation of n-hexane and decrease clearance of n-hexane metabolites. Co-exposed MEK did not increase serum 2,5-HD, which was considered a main neurotoxic metabolite. Therefore the enhancement of neurotoxicity could not be attributed to increased serum 2,5-HD in the co-exposed group.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood n-hexane concentration following acute inhalation exposure in rats.

Blood n-hexane concentrations in rats is reported. Groups of four rats were exposed to a n-hexane vapor/air mixture, in a glass chamber. At the end of the exposure, the animals were sacrificed by decapitation, blood was collected, and the concentration of n-hexane in blood was determined by headspace gas chromatography. Results indicate that blood becomes saturated with n-hexane in 10 minutes or less and persisted in the other exposure periods, up to and including 30 minutes.

Experimental human exposure to n-Hexane. Study of the respiratory uptake and elimination, and of n-Hexane concentrations in peripheral venous blood.

The respiratory uptake rate of n-hexane showed considerable differences in six healthy male persons, exposed at rest to 360 mg/m3 and 720 mg/m3 of n-hexane in inspired air and to 360 mg/m3 under different levels of physical exercise. These differences could partly be explained by a positive correlation with the amount of body fat. At rest also a strong influence of the respiratory minute volume and respiratory frequency on the uptake rate could be proven. The average uptake rate remained virtually constant over a range of 20 to 60 W of continuous external physical load, indicating that under these circumstances the inspired n-hexane concentration alone predominantly determines the uptake rate. The respiratory elimination during the first hours after an exposure was also subject to important inter- and intraindividual fluctuations. The pulmonary ventilation rate at the moment of breath sampling had a pronounced influence on the measured exhaled concentration. On the other hand, there was no apparent effect of the amount of body fat. Generally, the correlation between the amount of n-hexane taken up and breath concentrations at different time intervals was rather poor. n-Hexane concentrations in peripheral venous blood reacted rapidly to changes in exposure conditions, but not in the same proportion as the uptake rate. The blood concentration proved more closely related to respiratory n-hexane retention than to the uptake rate, reflecting the state of saturation of different body tissues. At rest this parameter was clearly influenced by the amount of body fat. A decrease in relative blood perfusion of fatty tissue could explain why such relation was not found during exposure combined with physical effort.

Biotransformation of n-hexane and methyl n-butyl ketone in guinea pigs and mice.

Peripheral neuropathies caused by exposures to the industrial solvents n-hexane and MBK exhibit strinkingly similar characteristics. In in vivo studies, the metabolites of MBK and n-hexane identified in blood and urine of guinea pigs were 2-hexanol (partly as glucuronide in urine); and 2,5-hexanedione which was detected only in MBK treated groups. Phenobarbital pretreatment increased 2-hexanol urinary excretion in both solvent treatment groups. In in vitro studies, hepatic reduction of MBK required the cytosol fraction to form 2-hexanol; whereas the oxidation of MBK and n-hexane required the microsomal fraction to form 2,5-hexanedione and 2-hexanol, respectively. The in vivo and in vitro biotransformation of MBK and n-hexane to a common metabolite (2-hexanol) suggests that the neurotoxic action of these solvents may be metabolite related.