Azithromycin and clarithromycin inhibition of 50S ribosomal subunit formation in Staphylococcus aureus cells

A mercapturic acid attached to the aromatic ring of toluene was for the first time detected in human urine as a metabolite of toluene. Since the metabolism of toluene is usually considered to take place at the side-chain, this gives, besides the biosynthesis of cresols, a further hint of a metabolic conversion of the aromatic system. We examined a group of 33 workers occupationally exposed to toluene, determining the concentrations of toluene in ambient air and in whole blood, o-cresol and hippuric acid in urine and p-toluylmercapturic acid (p-TMA) in urine. All blood and urine samples were collected post-shift. The renal excretion of S-p-toluylmercapturic acid showed highly significant correlations with established parameters of a biological monitoring of toluene. The median ambient air concentration was 63 ppm, ranging from 13 to 151 ppm, the median concentration of toluene in whole blood was 804 microg/l, corresponding to median urinary concentrations for o-cresol of 2.3 mg/l, hippuric acid of 2.3 g/l and p-TMA of 20.4 microg/l. p-TMA was not detectable in urine samples of a control group of 10 non-exposed persons. Both the German Biological Tolerance Values (BAT-values) for toluene in blood (1000 microg/l) and o-cresol in urine (3 mg/l) correspond to a mean p-TMA elimination of approximately 50 microg/l, and thus are in agreement with each other. According to our results p-TMA reflects internal toluene exposure diagnostically sensitive and specifical. With the developed analytical procedure we determined a median benzylmercapturic acid (BMA) concentration of 190 microg/l in the urine samples of the toluene exposed persons. We also determined a median BMA concentration of 30 microg/l in the control samples of non-exposed persons. However, these results are preliminary and require further confirmation as the reliability of the method was determined only for p-TMA.     

The mouse Cat4 locus maps to chromosome 8 and mutants express lens-corneal adhesion

HYPOTHESIS: Does occupational exposure to solvents in combination with alcohol intake give rise to acquired color vision defects? METHOD: A total of 138 individuals exposed to solvents (toluene, xylene, trichloroethylene, tetrachloroethylene) were examined using Lanthony's D-15 test and compared with 100 nonexposed controls. The extent of color vision loss was quantitatively assessed based on Bowman's color confusion index (CCI). A cumulative exposure index was calculated from the hours of exposure per day and the years of exposure. In 30 persons who were exposed to trichloroethylene and tetrachloroethylene, urinary trichloroacetic acid was assessed as a parameter of exposure. Alcohol intake was calculated as based on interviews of patients in grams of ethyl alcohol per week. RESULTS: Individuals who consumed more than 250 g alcohol/week and were simultaneously exposed to solvents showed a significantly elevated CCI (P = 0.0044). No significant correlation emerged between trichloroacetic acid excretion in the urine or the cumulative exposure index and the CCI. CONCLUSION: The combination of alcohol intake and occupational exposure to solvents discloses the risk of acquired subclinical color vision defects.     

Detection and quantitation of multiple volatile compounds in tissues by GC and GC/MS

Qualitative and quantitative analysis of tissues and body fluids for multiple volatile organic compounds were performed by a combination of packed and open tubular capillary GC and GC/MS. This paper describes methods for such analyses in a case involving the exposure of two persons to methyl ethyl ketone, methyl isobutyl ketone, toluene and the three isomeric xylenes. Tissue and body fluid concentrations of these substances in the two decedents are presented and discussed briefly.     

Metabolic interferences in subjects occupationally exposed to binary styrene-acetone mixtures

OBJECTIVE: To investigate the excretion of styrene metabolites (mandelic acid, MA, and phenylglyoxylic acid, PGA) in workers employed in plastic manufacturing to verify the possible influence of coexposure to acetone on styrene metabolism. METHODS: This study was carried out on 50 workers employed in 3 factories producing polyester buttons. The workers were divided into three groups according to three different levels of acetone exposure. The trend of excretion for metabolites was examined during and after work shifts. Styrene and acetone were monitored on Thursday during the entire work shift by passive dosimeters placed on the lapel of the workers' uniforms, desorbed by carbon disulfide, and analyzed by gas chromatography. Biological monitoring was performed by determination of the urinary metabolites of styrene in urine samples collected on Thursday at the middle and the end of the work shift. MA and PGA were determined by a high-pressure liquid chromatographic method. RESULTS: The styrene concentrations ranged between 16 and 439 mg/m3, and in ten samples they exceeded the TLV-TWA (213 mg/m3). The acetone concentration ranged between 15 and 700 mg/m3 (TLV-TWA 1780 mg/m3), with the mean value being 208 mg/m3. During cleaning operations higher exposures to acetone demonstrated, with concentrations ranging between 500 and 3400 mg/m3. The amounts of MA and PGA determined at the end of workshifts did not significantly differ between the groups with different levels of acetone coexposure. Analysis of variance (ANOVA) between the groups confirmed that MA and PGA excretion did not significantly differ, although the metabolite values measured on the "morning of the day after" appeared higher in those groups with high levels of acetone exposure and were related to the average airborne concentrations of the solvent. In addition, the range and degree of correlation between styrene in air and biological levels of metabolites were modified by coexposure to acetone. CONCLUSIONS: Our data demonstrate that amounts of MA and PGA did not differ in groups with different levels of acetone exposure, but when the acetone air concentration increased the degree of correlation between styrene and MA and PGA decreased. Furthermore, coexposure to acetone levels similar to those described herein may hamper the use of urinary metabolites for the assessment of exposure to styrene, especially on an individual basis.     

Analysis and evaluation of trans,trans-muconic acid as a biomarker for benzene exposure

Benzene is an important industrial chemical and, due to its occurrence in mineral oil and its formation in many combustion processes, a widespread environmental pollutant. Since benzene is hematoxic and has been classified as a human carcinogen, monitoring and control of benzene exposure is of importance. Although trans,trans-muconic acid (ttMA) was identified as a urinary metabolite of benzene at the beginning of this century, only recently has its application as a biomarker for occupational and environmental benzene exposure been investigated. The range of metabolic conversion of benzene to ttMA is about 2-25% and dependent on the benzene exposure level, simultaneous exposure to toluene, and probably also to genetic factors. For the quantitation of ttMA in urine, HPLC methods using UV and diode array detection as well as GC methods combined with MS or FID detection have been described. Sample pretreatment for both HPLC and GC analysis comprises centrifugation and enrichment by solid-phase extraction on anion-exchange sorbents. Described derivatization procedures prior to GC analysis include reaction with N,O-bis(trimethysilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, pentafluorobenzyl bromide and borontrifluoride-methanol. Reported limits of detection for HPLC methods range from 0.1 to 0.003 mg l(-1), whereas those reported for GC methods are 0.03-0.01 mg l(-1). Due to its higher specificity, GC methods appear to be more suitable for determination of low urinary ttMA levels caused by environmental exposure to benzene. In studies with occupational exposure to benzene (>0.1 ppm), good correlations between urinary ttMA excretion and benzene levels in breathing air are observed. From the reported regressions for these variables, mean excretion rates of ttMA of 1.9 mg g(-1) creatinine or 2.5 mg l(-1) at an exposure dose of 1 ppm over 8 h can be calculated. The smoking-related increase in urinary ttMA excretion reported in twelve studies ranged from 0.022 to 0.2 mg g(-1) creatinine. Only a few studies have investigated the effect of exposure to environmental levels of benzene (<0.01 ppm) on urinary ttMA excretion. A trend for slightly increased ttMA levels in subjects living in areas with high automobile traffic density was observed, whereas exposure to environmental tobacco smoke did not significantly increase the urinary ttMA excretion. It is concluded that urinary ttMA is a suitable biomarker for benzene exposure at occupational levels as low as 0.1 ppm. Biomonitoring of exposure to environmental benzene levels (<0.01 ppm) using urinary ttMA appears to be possible only if the ingestion of dietary sorbic acid, another precursor to urinary ttMA, is taken into account.     

Urinary excretion of phenols as an indicator of occupational exposure in the coke-plant industry

OBJECTIVE: In the present study the relationship between the level of exposure to o-cresol and of 2,4- +2,5-, 3,4-, and 3,5-xylenols and the urinary excretion of their metabolites was examined. The mixed exposure to phenolic derivatives of exposed workers during their work shift was monitored by personal air sampling of the breathing-zone air and by measurements of phenol, o-cresol, and xylenol isomer concentrations in shift-end urine. METHODS: The study subjects were 76 men working at a coke plant who were 22-58 years old and 34 nonexposed subjects. Concentrations of phenolic compounds were determined in the breathing-zone air during the work shift, whereas concentrations of phenol, cresol, and xylenol isomers were measured in urine collected after the work shift. Concentrations of phenols in air and urine were determined by gas chromatography with flame-ionization detection. Urine samples were extracted after acid hydrolysis of glucuronides and sulfates by solid-phase extraction. The gas chromatography-mass spectrometry method was applied to identify metabolites in urine samples. RESULTS: The time-weighted average concentrations of phenol, cresol, and xylenol isomers detected in breathing-zone air showed that the exposure level of the workers was relatively low. The geometric mean values were as follows: 0.26 mg/m3 for phenol, 0.09 mg/m3 for o-cresol, 0.13 mg/m3 for p- and m-cresol, and 0.02-0.04 mg/m3 for xylenols at the tar-distillation process. Corresponding urinary concentrations were 10.39, 0.53, and 0.25-0.88 mg/g creatinine for phenol, o-cresol, and xylenol isomers, respectively. The correlation coefficients between the o-cresol and 2,4-, 2,5-, 3,4-, and 3,5-xylenol concentrations measured in urine and in the breathing-zone air were statistically significant, varying in the range of 0.54-0.74 for xylenol isomers and being 0.69 for o-cresol. CONCLUSION: We have found that the presence of o-cresol and xylenol isomers in urine can be used as a biomarker for phenol exposure. Analysis performed on workers at the tar-distillation process showed that they were exposed to relatively low concentrations of phenolic compounds.     

Specifity and sensitivity of the inhibition of drug metabolism following inhalation of carbon disulphide-air mixtures

A single 8-h exposure of adult female Wistar rats to 20 ppm carbon disulphide (CS2), the threshold limit value (TLV) in several countries, was sufficient to cause inhibition of the following drug-metabolizing reactions: formation of trichloroethanol and trichloroacetic acid from trichloroethylene (aliphatic C-hydroxylation), formation of 4-hydroxyantipyrine from antipyrine (quasi-aromatic C-hydroxylation), formation of acetaminophenol from acetanilid (aromatic C-hydroxylation) and phenacetin (oxidative odealkylation), respectively, and formation of 4-aminoantipyrine from aminopyrine (oxidative N-demethylation). The behaviour of these effects was dependent on the dose of CS2 administered in that the inhibitory process was enhanced when increasing the concentration to (50), 100, 200, and 400 ppm. The respective changes could be demonstrated by a short-duration (6-h) reduction in the urinary excretion of the metabolites. In the case of trichloroethylene the limitation in metabolite formation persisted for as long as 36 h due to the varying rate of formation of trichloroethanol and trichloroacetic acid. This deficiency in excretion was compensated in part during the subsequent elimination phase (up to 24 and 36 h, respectively), an observation which suggests the rapid reversibility of the alteration. As shown by the respective prolongation of the hexobarbital sleeping time in the rat, the side-chain oxidation of hexobarbital to ketohexobarbital was increasingly inhibited by rising concentrations of CS2 in the range of 20 to 400 ppm/8 h. On the basis of the present results it is concluded that CS2 also inhibits various oxygenases of the microsomal enzyme system. In adult female NMRI mice a significant inhibition of the microsomal procaine-hydrolyzing esterase of the liver was observed only after 400 ppm/8 h; however, this limitation did not affect the LD50 of procaine-HCl, particularly as the corresponding serum esterase activity also remained uninfluenced. The aromatic N-acetylation of sulphisomidine and the quasi-aromatic N-acetylation of 4-aminoantipyrine in rats failed to be significantly reduced by CS2 even after 400 ppm/8 h, nor did the same dose of CS2 affect the glucuronidation of 4-hydroxyantipyrine in the same animal species. It is concluded from the above results that the specificity and sensitivity of the inhibition of drug metabolism observed in small laboratory animals is probably similar to that prevailing in man. This assumption has already been substantiated for the oxidative N-demethylation of aminopyrine.     

Inhibition of rat lung mixed-function oxidase activity following repeated low-level toluene inhalation: possible role of toluene metabolites

Toluene is a commonly used solvent that has been shown to alter mixed-function oxidase (MFO) activity, in an organ- and isozyme-specific pattern, following intraperitoneal administration. The purpose of this study was to determine whether similar changes occurred following repeated, low-level inhalation exposure, and to investigate the role of toluene metabolites in these alterations. Exposure to 375 ppm toluene, 6 h/d for up to 5 d, resulted in significant inhibition of the activity of pulmonary arylhydrocarbon hydroxylase (AHH), cytochrome P-4502B1 (CYP2B1), and CYP4B1, but not CYP1A1. After exposure to lower toluene levels (125 ppm, 6 h/d, 3 d), the activities of lung AHH, CYP2B1, and CYP4B1 were also significantly decreased, but in a dose-related manner. MFO activity was not consistently altered in liver. Control pulmonary or liver microsomes were incubated with various concentrations (0.01-10 mM) of toluene or its metabolites and CYP2B1, CYP1A1, and/or CYP4B1 activities were subsequently determined. Benzaldehyde produced a significant dose-related inhibition in the activity of all three lung P-450s examined (IC50 10(-3) M). Toluene was found to be a more potent inhibitor of lung CYP2B1 and CYP1A1 (IC50, 10(-4) M) than benzaldehyde, but neither toluene nor benzyl alcohol was an effective inhibitor of lung CYP4B1. Toluene and its metabolites were weaker inhibitors of CYP1A1 than of CYP2B1. For CYP2B1 and CYP1A1, the order of inhibitory potency was toluene > benzaldehyde > benzyl alcohol and suggests that both the parent molecule and its metabolites may act in concert to inhibit catalytic activity of these cytochromes. The MFO inhibition seen after repeated low-level toluene inhalation exposure could result in altered metabolic profiles of other xenobiotics in an organ-specific fashion.     

Biological monitoring during exposure to the anesthetics isoflurane and sevoflurane

Exposure to traces of inhaled anaesthetic agents may impair the health of the operating theatre personnel. Although no cause-effect relationship has been found, most public health authorities recommend various occupational exposure standards to minimize possible health risks. If metabolites of the substances are known, biological monitoring is an alternative to the monitoring of the operating theatre's air. The new anaesthetic agent Sevoflurane is considerably more transformed to fluoride than Isoflurane. Concerning fluoride there exist Biological Tolerance Values of 4.0-7.0 mg fluoride (F-) per gram creatinine (Crea). The aim of our study was to compare the fluoride excretion under the occupational exposure to sevoflurane and isoflurane. By the means of a direct-reading instrument trace concentrations of sevoflurane, isoflurane, and nitrous oxide were measured during 40 anaesthetic procedures. Urine samples were collected before (Z1) and after the workshift (Z2), and in the morning of the next day (Z3). The analysis was done by the means of an ionselective electrode. The personnel-related concentrations (median, range) were 0.50 (0.16-7.04) ppm isoflurance and 27.36 (5.87-467.10) ppm nitrous oxide, and 0.79 (0.15-1.95) ppm sevoflurane and 17.74 (2.45-84.20) ppm nitrous oxide. The resulting fluoride values presented at Z1, Z2, and Z3 as median (range) during exposure to isoflurane were 0.15 (0.11-0.53), 0.19 (0.11-0.53), 0.20 (0.11-0.31) mg F-/g Crea, and 0.15 (0.10-0.46), 0.22 (0.13-0.44), 0.23 (0.15-0.69) mg F-/g Crea during exposure to sevoflurance, respectively. The trace concentrations were clearly under 10 ppm for the volatile substances and 100 ppm for nitrous oxide. The values are comparable to data recorded under similar working conditions. The measured fluoride values were low and remained under the legal tolerance values. Under the described conditions potential health risks were low.     

Cell density-dependent changes in the insulin action pathway: evidence for involvement of protein-tyrosine phosphatases

Three gas chromatographic procedures for the determination of ethanol in postmortem blood using alternative internal standards to n-propanol are presented: a direct injection procedure using t-butanol, and two headspace methods using t-butanol and methyl ethyl ketone. t-Butanol and methyl ethyl ketone were well resolved from ethanol, acetone, methanol and other commonly observed putrefactive volatiles using direct injection or headspace analysis. CVs for the direct injection method were below 5% for ethanol and below 10% for the other volatiles. The lower limits of detection (LOD) were 25-50 mg/L. The CVs for the headspace methods were below 5% for ethanol and below 6% for the other volatiles. The LODs were 10 mg/L using either t-butanol or methyl ethyl ketone as internal standards. The use of t-butanol or methyl ethyl ketone as alternatives to n-propanol avoids the possibility of error in the quantitation of ethanol due to the presence of n-propanol and allows for the identification of other volatiles that may aid in distinguishing antemortem ingestion from postmortem production of ethanol.     

The management of unexplained infertility

Since allyl alcohol and ethanol are both metabolized by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), ethanol could affect allyl-alcohol induced toxicity under in vivo coexposure conditions. Male Sprague-Dawley rats were treated with ethanol (2 g/kg, i.p.) simultaneously or 2 h before with allyl alcohol (40 mg/kg, i.p.). Coexposure to allyl alcohol and ethanol resulted in neither enhancement nor protection in allyl alcohol-induced hepatotoxicity at 24 h. However, markedly increased lethality was observed under our coexposure conditions. Pretreatment with 4-methylpyrazole (4-MP) to inhibit ADH did not result in increased lethality to allyl alcohol or ethanol alone, but significantly reduced the lethality of the combined treatment. In contrast, ALDH inhibition increased the lethality of allyl alcohol alone as well as that of the combined allyl alcohol and ethanol treatment. Kinetic studies revealed that combined treatment with allyl alcohol and ethanol resulted in higher blood allyl alcohol levels compared to allyl alcohol alone, and these were accompanied by greater lethality. ADH inhibition increased allyl alcohol blood levels significantly when rats were treated with allyl alcohol alone or allyl alcohol plus ethanol, leading to protection against lethality. In contrast, ALDH inhibition did not affect blood allyl alcohol levels, but resulted in increased lethality. These data suggest a possible role for a metabolite of allyl alcohol, acrolein, in the increased lethality of allyl alcohol and ethanol coexposure in rats.     

The activity of ENU, iPMS and MMS in male mouse germ cells using the Muta Mouse positive selection transgenic mutation assay

The alkylating agents ethyl nitrosourea (ENU), isopropyl methanesulphonate (iPMS) and methyl methanesulphonate (MMS) are potent male rodent germ cell mutagens. The mutagenic activity of these compounds in male mouse germ cells has been evaluated using the Muta Mouse positive selection transgenic mutation assay. Both ENU (150 mg/kg) and iPMS (100 mg/kg) gave increased mutant frequencies in testicular DNA recovered 50 days after dosing. During the course of the mutation assays on iPMS its activity as a dominant lethal mutagen was confirmed by mating the treated animals with virgin (non-transgenic) females on day 10 post-dosing. Ova analysis on animals exposed to iPMS confirmed earlier reports that the dose level used caused sterility in mice 40 days after dosing. This sterility was shown to be due to aspermia in the treated mice at day 50 post-dosing. These collected findings indicate that at day 50 post-dosing with iPMS, mutations in testicular DNA can be observed in sterile animals. MMS (100 mg/kg) was not mutagenic to either testicular DNA or epididymal sperm DNA, 10 or 50 days, respectively, after dosing.     

Effects of a new topic amikacin formulation on chemotaxis and release of profibrotic factors by human monocytes

OBJECTIVE: The aim of the present study was to develop valid methods for monitoring of occupational exposure to dichloromethane (DCM). METHODS: Carbon cloth as an adsorbent in diffusive sampling was tested for its capacity to adsorb DCM vapor and to retain adsorbed DCM after termination of the exposure. Urine samples collected from DCM-exposed workers were analyzed for DCM by the head-space technique. After extraction with carbon disulfide, DCM in the cloth was analyzed on a DB-WAX capillary column by flame-ionization detection gas chromatography (FID-GC) and DCM in urine was analyzed by electron-capture detection (ECD)-GC. RESULTS: The diffusive sampling with carbon cloth as an adsorbent is applicable to 4-h monitoring of exposure to up to 100 ppm DCM vapor. DCM concentrations detected in end-of-shift urine samples correlated linearly with time-weighted average DCM concentrations measured in the breathing-zone air of the exposed workers; essentially the same exposure-excretion relationship was obtained by vapor monitoring for the afternoon 4-h period as compared with a whole day (8-h) of vapor monitoring. There was no sex difference in the exposure-excretion relation. CONCLUSIONS: Both personal diffusive sampling (at up to 100 ppm DCM and for up to 4 h) and biological exposure monitoring by urinalysis for DCM are applicable in occupational health as reliable measures of exposure to this chlorinated hydrocarbon solvent.     

Body distribution of free, liposomal and nanoparticle-associated mitoxantrone in B16-melanoma-bearing mice

BACKGROUND & AIMS: Ethyl propionate and isopropyl acetate were identified as gallstone solvents with more favorable physicochemical properties than the currently used solvent methyl tert-butyl ether (MTBE). In this study, their efficacy and toxicity were compared. METHODS: To compare efficacy, matched stones from 33 patients were subjected to dissolution with each solvent. To evaluate cytotoxicity, jejunal segments of the anesthetized rat were exposed to each solvent or saline; the segments were then perfused with markers for active absorption and passive permeability. RESULTS: For 23 gallstone sets that dissolved completely with all three solvents, the average dissolution time was shorter with ethyl propionate (38 +/- 8 minutes) than with MTBE (60 +/- 13 minutes) (P = 0.03) or isopropyl acetate (55 +/- 12 minutes) (P < 0.001). Four stones did not dissolve with ethyl propionate, seven with MTBE, and eight with isopropyl acetate. After 2 minutes of exposure to the solvents, the dry weight of the segments decreased by 36% after MTBE but was unchanged after the other two solvents (P < 0.001). MTBE caused more inhibition of active absorption than the other solvents (P < 0.001) and a greater increase in passive permeation (P < 0.03). CONCLUSIONS: Ethyl propionate and isopropyl acetate are less toxic to the intestinal mucosa than MTBE, and ethyl propionate is more effective for gallstone dissolution.     

Catalytic Oxidation of Volatile Organic Liquids

Metal oxide and supported-Pt catalysts were developed for complete oxidation of volatile organic compounds (VOCs) and other solvent-derived organic vapors (OVs) in air at relatively low temperatures. The goal for this work is to produce a simple, cost-effective technology for reducing the concentration of organic contaminants in air to acceptable levels before the air is released into the atmosphere or recirculated. Specific applications include ventilated work spaces for spray painting and engine maintenance, indoor air decontamination, dry cleaning, food processing, fume hoods, residential use, and solvent-intensive industrial processes. Catalyst powders and monolith-supported catalysts were screened for conversion of 1-butanol, toluene, and methyl ethyl ketone to carbon dioxide and water. The concentration of OVs in the feedstream was maintained at approximately 100 ppmv, and the space velocity was between 6,000 and 18,000 h?1. Metal oxide catalysts without Pt generated complete conversion of 1-butanol to CO2 at 150°C, 69% conversion at 100°C, and 15% conversion at 80°C. For toluene, complete conversion was achieved at 200°C, and greater than 75% conversion at 150°C. Addition of Pt to the metal oxide compositions typically lowered the temperature for a given OV oxidation rate by at least 20–50°C. Catalysts deposited onto standard commercial cordierite monoliths retained their composition and activity, and were stable in humid air, as well as nitrogen- and chlorine-containing OVs. However, the catalysts quickly deactivated in the presence of sulfur and phosphorus.     

Carbon tetrachloride toxicity potentiated by isopropyl alcohol. Investigation of an industrial outbreak

Fourteen workers in an isopropyl alcohol packaging plant became ill after accidental exposure to carbon tetrachloride. In four, renal failure or hepatitis developed. Isopropyl alcohol potentiation of carbon tetrachloride toxicity has been shown previously only in rats. Acetone, a product of isopropyl alcohol metabolism, is a major potentiator of carbon tetrachloride toxicity. Workers had elevated levels of acetone in samples of expired alveolar gas and thus were metabolically predisposed to carbon tetrachloride injury. Stricter limits for industrial carbon tetrachloride exposure should be established where concomitant isopropyl alcohol use occurs.     

Developmental regulation of the 3-methylcholanthrene- and dioxin-inducible CYP1A5 gene in chick embryo liver in vivo

Measurement of specific adducts to hemoglobin can be used to establish the dosimetry of electrophilic compounds and metabolites in experimental animals and in humans. The purpose of this study was to investigate the dose response for adduct formation and persistence in rats and mice during long-term low-level exposure to butadiene by inhalation. Adducts of 3,4-epoxy-1-butene, the primary metabolite of butadiene, with N-terminal valine in hemoglobin were determined in male B6C3F1 mice and male Sprague-Dawley rats following exposure to 0, 2, 10, or 100 ppm of 1,3-butadiene, 6 h/day, 5 days/week for 1, 2, 3, or 4 weeks. Blood samples were collected from groups of five mice and three rats at the end of each week during the 4 weeks of exposure and weekly for 3 weeks following the end of the 4-week exposure period. The increase and decrease, respectively, of the adduct levels during and following the end of the 4-week exposure followed closely the theoretical curve for adduct accumulation and removal for rats and mice, thereby demonstrating that the adducts are chemically stable in vivo and that the elimination follows the turnover of the red blood cells. The adduct level increased linearly with butadiene exposure concentration in the mice, whereas a deviation from linearity was observed in the rats. For example, after exposure to 100 ppm butadiene, the epoxybutene-hemoglobin adduct levels were about four times higher in mice than in rats; at lower concentrations of butadiene, the species difference was less pronounced. Blood concentrations of epoxybutene, estimated from hemoglobin adduct levels, were in general agreement with reported concentrations in mice and rats exposed by inhalation to 62.5 ppm. These studies show that adducts of epoxybutene with N-terminal valine in hemoglobin can be used to predict blood concentration of epoxybutene in experimental animals.     

Formic acid excretion in rats exposed to trichloroethylene: a possible explanation for renal toxicity in long-term studies

Rats exposed to trichloroethylene, either by gavage or by inhalation, excreted large amounts of formic acid in urine which was accompanied by a change in urinary pH, increased excretion of ammonia, and slight increases in the excretion of calcium. Following a single 6-h exposure to 500 ppm trichloroethylene, the excretion of formic acid was comparable to that seen after a 500 mg/kg dose of formic acid itself, yet the half-life was markedly different. Formate excretion in trichloroethylene treated rats reached a maximum on day 2 and had a half-life of 4-5 days, whereas urinary excretion was complete within 24 h following a single dose of formic acid itself. Formic acid was shown not to be a metabolite of trichloroethylene. When rats were exposed to 250 or 500 ppm trichloroethylene, 6 h/day, for 28 days, the only significant effects were increased formic acid and ammonia excretion, and a change in urinary pH. There was no evidence of morphological liver or kidney damage. Long-term exposure to formic acid is known to cause kidney damage suggesting that excretion of this acid may contribute to the kidney damage seen in the long-term studies with trichloroethylene.     

Diagnosis and differential therapy of mitral stenosis

The aim of this study was to investigate the role of metabolic activation in the olfactory toxicity of methyl iodide (MeI). Adult male rats were exposed via nose-only inhalation to 100 ppm MeI for 0-6 h, and non-protein sulphydryl (NP-SH) concentrations determined in selected tissues. Depletion of NP-SH occurred in all tissues, but was most marked and rapid in the respiratory epithelium of the nasal cavity and the kidney. Olfactory, lung and liver NP-SH levels were affected to a lesser extent, and those of the brain declined by only 20-30% over the whole time course. In order to modulate glutathione (GSH) status, animals were pre-treated with (1) phorone plus L-buthionine sulphoximine (BSO), which depleted NP-SH levels in all the tissues examined, or (2) the isopropyl ester of GSH (IP-GSH), which was shown to replenish NP-SH concentrations in all tissues except the liver of animals previously administered phorone. When animals were pre-treated with phorone plus BSO and then exposed to 100 ppm MeI for 2 h, there was a potentiation of the toxicity of MeI as judged by the clinical observations on the animals. In contrast, treatment with IP-GSH prior to and during exposure to MeI for 4 h afforded a marked protection to the olfactory epithelium. In order to inhibit cytochromes P450, animals were pre-treated with cobalt protoporphyrin IX. This decreased hepatic cytochrome P450 concentrations by > 90%, but when animals were then exposed to 100 ppm MeI for 4 h there was no effect on the severity of the olfactory lesion. These results indicate that conjugation of MeI with GSH is a detoxification rather than an activation pathway. Also, there is no major role for cytochrome P450-dependent oxidation in the development of the olfactory lesion.     

Regulation of tumour cell fatty acid oxidation by n-6 polyunsaturated fatty acids

The aim of this study was to evaluate acute effects of ethyl tert-butyl ether (ETBE) in man after short-term exposure. ETBE may in the future replace methyl tert-butyl ether, a widely used oxygenate in unleaded gasoline. Eight healthy male volunteers were exposed to ETBE vapor for 2 h at four levels (0, 5, 25, and 50 ppm) during light physical exercise. The subjects rated irritative symptoms, discomfort, and central nervous system effects in a questionnaire. Ocular (eye redness, tear film break-up time, conjunctival epithelial damage, and blinking frequency), nasal (acoustic rhinometry and analysis of inflammatory markers and cells in nasal lavage fluid), and pulmonary (peak expiratory flow, forced expiratory volume in 1 s, forced vital capacity, vital capacity, and transfer factor) measurements were performed. Significantly increased ratings of solvent smell (p = 0.001, repeated-measures ANOVA) were seen during exposures and correlated to exposure levels. Furthermore, significantly elevated ratings of discomfort in throat and airways were seen during and after 50 ppm compared to the control exposure (p = 0.02). Increased nasal swelling (p = 0.001) and blinking frequency (p = 0.01) were noted at all exposure levels, but their magnitudes were not related to exposure levels. A slightly impaired pulmonary function was seen at 25 and 50 ppm, since forced vital capacity (p = 0.02) and vital capacity (p = 0.04) differed significantly from the clean air exposure. Although the impairments seemed to fall within normal inter- and intraindividual variation and have no clinical relevance as such, it cannot be excluded that other individuals may react more severely than eight healthy male volunteers in this study.