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Aims: To evaluate possible differences between men and women in acute health effects after controlled short term chamber exposure to vapours of two common organic solvents. Methods: Fifty six healthy [...]

Events initiated by common-cause-failure (CCF) can significantly affect the availability and reliability of nuclear power plant safety systems. In recognition of this, CCF data are systematically collected and analysed in the International Common-Cause Data Exchange (ICDE) Project, which was initiated in August 1994. Since April 1998, the NEA has formally operated the project. Currently eleven countries participate in the project. The ICDE collects all events where two or more identical, redundant components of a group, fulfilling the same function, have failed or were impaired due to a shared cause (ICDE events). Complete CCFs, i.e. failure of all identical, redundant components in the group due to a shared cause are an important subset of the collected data. Currently, data exchange and analysis covers the following components: centrifugal pumps, diesel generators, motor-operated valves, safety and relief valves, check valves, reactor protection system components (level measurement, control rod drives, etc), circuit breakers, and batteries. The main findings of the ICDE reports issued by 2005 show averaged over all components that about two thirds of all complete CCF events involve faulty actions by plant personnel and contractors. The single largest contribution is from faulty testing and maintenance work due to deficient and/or incomplete procedures. Other important causes are insufficient testing and requalification of components or systems after maintenance, repair, modifications or backfitting work, as well as operator errors of commission. The probability that a reported ICDE event is a complete CCF decreases strongly with increasing number of redundant components, demonstrating the effectiveness of redundancy as a powerful defence against CCFs. However, complete CCFs cannot be completely prevented by high redundancy only.

The aim of the present study was to investigate how the genetic polymorphism in glutathione transferase T1 (GSTT1) affects the metabolism and disposition of methyl chloride in humans in vivo. The 24 volunteers (13 males and 11 females) who participated in the study were recruited from a group of 208 individuals previously phenotyped for GSTT1 by measuring the glutathione transferase activity with methyl chloride in lysed erythrocytes ex vivo. Eight individuals with high (/), eight with medium (/0) and eight with no (0/0) GSTT1 activity were exposed to methyl chloride gas (10 p.p.m.) in an exposure chamber for 2 h. Uptake and disposition was studied by measuring the concentration of methyl chloride in inhaled air, exhaled air and blood. A two-compartment model with two elimination pathways corresponding to exhalation and metabolism was fitted to experimental data. The average net respiratory uptake of methyl chloride was 243, 158, and 44 μmol in individuals with high, intermediate and no GSTT1 activity, respectively. Metabolic clearance was high (4.6 l/min) in the / group, intermediate (2.4 l/min) in the /0 group, and close to zero in 0/0 individuals, while the exhalation clearance was similar in the three groups. No exposure related increase in urinary S-methyl cysteine was detected. However, gender and the GSTT1 phenotype seemed to affect the background levels. In conclusion, GSTT1 appears to be the sole determinant of methyl chloride metabolism in humans. Thus, individuals with nonfunctional GSTT1 entirely lack the capacity to metabolize methyl chloride.

After exposure to methyl tert-butyl ether (MTBE), a gasoline additive, only one metabolite [tert-butyl alcohol (TBA), <1% of dose] has been identified in human urine [Nihlén, A., et al. (1998) Toxicol. Appl. Pharmacol. 148, 274−280]. In the study presented here, metabolites of MTBE were characterized by ¹H-decoupled ¹³C NMR spectroscopy in urine obtained from four volunteers experimentally exposed to 50 ppm ¹³C-labeled MTBE ([1,2-¹³C2]MTBE) vapor (facemask) for 2 h during a light physical work load (50 W). Chemical shifts for the two adjacent ¹³C-labeled carbons in [1,2-¹³C2]MTBE-derived metabolites were consistent with the shifts obtained for spiked standards of α-hydroxyisobutyric acid (HBA) and 2-methyl-1,2-propanediol (MPD). NMR signals were not detected for labeled MTBE, TBA, or possible MTBE-derived conjugates. Quantification of HBA and MPD was performed by NMR for two urine samples (collected 20 h after exposure). One subject had 11% HBA and 1% MPD, and the other individual had 3% HBA and 1% MPD in the urine, expressed as a percentage of MTBE uptake. This indicates that HBA and MPD occur at significantly higher levels in the urine (detected by NMR) than MTBE and TBA (detected by GC). To our knowledge, this is the first characterization of MTBE metabolites, other than TBA, in humans. Further urine, blood, and expired air were collected up to 22 h after exposure, and the toxicokinetics of MTBE, TBA, and acetone were determined by GC. Low relative uptake (39%), a low level of postexposure exhalation of MTBE (17%), and low recovery of TBA in the urine (<1%) were observed. The same subjects had previously been exposed to unlabeled MTBE in a whole-body exposure study [Nihlén, A., et al. (1998) Toxicol. Appl. Pharmacol. 148, 274−280], and the toxicokinetics of MTBE and TBA in this facemask exposure did not differ from the previous whole-body chamber exposure.

A physiologically based toxicokinetic model was developed for inhalation exposure of 1,2,4-trimethylbenzene (TMB) in man. The model consists of six compartments for TMB and one compartment for the metabolite 3,4-dimethylhippuric acid (DMHA). Based on previous experimental findings from human exposures to TMB, liver metabolism was divided in two pathways, one of the first order and one of the Michaelis–Menten type. Muscle tissue was split in two compartments to account for working and resting muscle tissues during bicycle exercise. The model was used to investigate how various factors influence potential biomarkers of exposure, i.e., TMB in blood and exhaled air and DMHA in urine. Increasing the work load from rest to moderate exercise (100 W) more than doubled all biomarker levels end of shift. The effect on next morning levels was even more pronounced, illustrated by a fivefold increase in the DMHA excretion rate. Simulations of five daily 8-h exposures suggest that biomarker levels end of shift remain fairly constant whereas the levels prior to shift increase gradually during the week. This suggests that end of shift levels reflect the exposure of the same day whereas levels Friday morning reflect exposure during the entire working week. Simulations with randomly generated exposures show that the variability due to fluctuating exposure is lower next morning than end of shift. End of shift exhalation rate of TMB is more sensitive to fluctuation than TMB in venous blood and DMHA in urine. Biomarker levels for 25 ppm exposure at different sampling times are given.

The Swedish Fire Research Board and the U.S. Federal Emergency Management Agency are sponsoring a project to further the understanding of the basic mechanisms involved, as well as to support the development of standards for and to seek ways of improving the performance of portable fire suppression systems used by fire departments.

The material comprised 222 assault victims whose injuries required attention at the Departments of Oral Surgery and Ear, Nose, and Throat diseases, the Central Hospital in Falun or corresponding departments at the Karolinska Institutet, Stockholm or the University Hospital in Huddinge. Information was obtained from patient records.One hundred and thirty-eight patients had fractures and the remainder had flesh-wounds, haematomas or swellings. The most frequent fracture site was the nasal bone followed by the jaws.Forty-one per cent of the patients in Falun and 28 per cent in Stockholm reported the assaults to the police: in Falun the proportion of women victims who reported the assault was significantly higher than those who did not. The willingness to notify the police of the violence was not influenced by the use of drugs or the seriousness of the injuries.The study showed that violence in suburban Stockholm was aggravated: one-third of the patients in the study required hospitalization compared to a quarter in a rural area.

The objective of this study was to determine the uptake and disposition of inhaled trimethylbenzenes (TMBs) in man. The toxicokinetics were studied in 10 male, healthy volunteers exposed to TMB vapor in an exposure chamber for 2 hr during a work load of 50 W. The subjects were exposed on four occasions to 25 ppm of 1,2,4-TMB, 1,2,3-TMB, and 1,3,5-TMB, and to 2 ppm of 1,2,4-TMB. The TMB isomers were analyzed in blood, urine, and exhaled air by gas chromatography. The relative respiratory uptake was in the range 56–64%. The elimination of TMBs was moderate compared to other aromatic solvents, with a total blood clearance of 0.6–1.0 liter hr−1kg−1. Large volumes of distribution (30–39 liters/kg) and long terminal half-lives of the TMBs in blood (78–120 hr) imply extensive accumulation in adipose tissue. Exhalation during and postexposure accounted for 20–37% of the absorbed amount, whereas the urinary excretion of unchanged TMBs was low (≤0.002%). The kinetics of 1,2,4-TMB seemed linear up to 25 ppm. In addition, the occurrence of symptoms of acute effects was studied by means of a questionnaire. The subjects rated the degree of irritation and central nervous system symptoms on a 100-mm visual analog scale. No discomfort was reported at these exposure conditions.

Abstract: This study compares the toxicokinetics of inhaled 1,2,4-trimethylbenzene (124TMB) in men exposed to white spirit with that previously observed in the same individuals exposed to 124TMB alone. The appropriateness of using dimethylhippuric acid (DMHA) metabolites of 124-, 123- and 135TMB in urine as biomarkers of exposure is also addressed and the kinetics of n-decane, n-undecane and 123TMB is investigated. The toxicokinetics of 124TMB was studied in nine male, healthy volunteers exposed to solvent vapours in an exposure chamber for 2 h during a work load of 50 W. The subjects were exposed to 2 ppm (11 mg/m3) of 124TMB during exposure to 300 mg/m3 of white spirit. The 124TMB isomer was analysed in blood, urine and exhaled air by gas chromatography. The DMHA metabolites of all three TMB isomers were analysed in urine by high-performance liquid chromatography. The results were compared with previously published exposures to 2 and 25 ppm (120 mg/m3) of 124TMB vapour alone. In addition, the occurrence of acute effects was studied by means of a questionnaire. Irritation and central nervous system (CNS) symptoms were recorded by ratings on a 100 mm visual analogue scale. Blood levels of 124TMB and excretion rates of 3,4-DMHA in urine were markedly elevated both during and after exposure to white spirit compared to the same exposure level of 124TMB alone. No irritation or CNS effects were reported in the questionnaire at any exposure condition. It appears that components in white spirit interfere with the metabolic elimination of 124TMB. This should be considered in biological exposure monitoring as well as in risk assessment.