Right Atrial Volume is Increased in Corrected Tetralogy of Fallot and Correlates with the Incidence of Supraventricular Arrhythmia: A CMR Study.

The aim of this study was to evaluate right atrial (RA) volume in corrected Tetralogy of Fallot (cTOF) and assess its correlation with the occurrence of supraventricular (SV) arrhythmia. Cardiac magnetic resonance imaging (CMR) and 24-h Holter were performed in n = 67 consecutive cTOF patients (age 30 ± 11.3 years). The CMR protocol included standard HASTE, SSFP cine, and blood flow measurements. Correlations between arrhythmia in ECG, heart volume, and functional parameters were investigated by negative binominal regression. Patients' characteristics (mean ± SD) included mean RA volume of 49 ± 19 ml/m(2) (HASTE sequence), mean right ventricular (RV) end-diastolic volume of 98 ± 27 ml/m(2), mean pulmonary valve regurgitation fraction (PR) of 21 ± 19 %, BMI of 25 kg/m(2), and heart rate of 75/min. Twenty-eight out of 67 patients experienced SV arrhythmia including SV couplets or bigeminus or longer non-sustained SV tachycardia (SVT) episodes. RA volume index was identified as an independent risk factor for different degrees of SV arrhythmia (SV couplets/bigeminus p < 0.001, SVT p < 0.001). Further risk factors for SV arrhythmia were male gender (p = 0.023) and decreased left ventricular (LV) ejection fraction (EF) (LV EF p < 0.001). RA volume is increased in adult patients with cTOF with larger RA volumes relating to higher incidence of SV arrhythmia. SV arrhythmia also appeared more often in male patients and those with decreased LV EF. Risk stratification according to these parameters could help to optimize early prevention and adjusted individual therapy to improve patient outcome and quality of life.

Micronuclei, hemoglobin adducts and respiratory tract irritation in mice after inhalation of toluene diisocyanate (TDI) and 4,4'-methylenediphenyl diisocyanate (MDI).

Toluene diisocyanate (TDI) and 4,4'-methylenediphenyl diisocyanate (MDI), used in the production of polyurethane foam, are well known for their irritating and sensitizing properties. Contradictory results have been obtained on their genotoxicity. We investigated the genotoxicity and protein binding of inhaled TDI and MDI in mice by examining micronucleated polychromatic erythrocytes (PCEs) in bone marrow and peripheral blood and TDI- and MDI-derived adducts in hemoglobin. Male C57Bl/6J mice (8 per group) were exposed head-only to TDI vapour (mean concentrations 1.1, 1.5, and 2.4mg/m(3); the mixture of isomers contained, on the average, 63% 2,4-TDI and 37% 2,6-TDI) or MDI aerosol (mean concentrations 10.7, 20.9 and 23.3mg/m(3)), during 1h/day for 5 consecutive days. Bone marrow and peripheral blood were collected 24h after the last exposure. Inhalation of TDI caused sensory irritation (SI) in the upper respiratory tract, and cumulative effects were observed at the highest exposure level. Inhalation of MDI produced SI and airflow limitation, and influx of inflammatory cells into the lungs. Hemoglobin adducts detected in the exposed mice resulted from direct binding to globin of 2,4- and 2,6-TDI and MDI, and dose-dependent increases were observed especially for 2,4-TDI-derived adducts. Adducts originating from the diamines of TDI (toluene diamine) or MDI (methylene dianiline) were not observed. No significant increase in the frequency of micronucleated PCEs was detected in the bone marrow or peripheral blood of the mice exposed to TDI or MDI. The ratio of PCEs and normochromatic erythrocytes (NCEs) was reduced at the highest concentration of MDI, and a slight reduction of the PCE/NCE ratio, dependent on cumulative inhaled dose, was also seen with TDI. Our results indicate that inhalation of TDI or MDI (1h/day for 5 days), at levels that induce toxic effects and formation of TDI- or MDI-specific adducts in hemoglobin, does not have detectable genotoxic effects in mice, as studied with the micronucleus assay.

Exposure to flame retardants in electronics recycling sites.

Waste electrical and electronic equipment (WEEE) contains various hazardous substances such as flame retardants (FRs). Inhalation exposures to many FRs simultaneously among WEEE recycling site workers have been little studied previously. The breathing zone airborne concentrations of five brominated FR compounds tetrabromobisphenol-A (TBBP-A), decabromodiphenylethane (DBDPE), hexabromocyclododecane, 1,2-bis(2,4,6-tribromophenoxy)ethane, hexabromobenzene, and one chlorinated FR (Dechlorane Plus®) were measured at four electronics recycling sites in two consecutive years. In addition, concentrations of polybrominated diphenyl ethers (PBDEs) and polybrominated biphenyls were measured. The three most abundant FRs in personal air samples were PBDEs (comprising mostly of deca-BDE), TBBP-A, and DBDPE, with mean concentrations ranging from 21 to 2320 ng m(-)(3), from 8.7 to 430 ng m(-3), and from 3.5 to 360 ng m(-3), respectively. At two of the sites, the emission control actions (such as improvements in ventilation and its maintenance and changes in cleaning habits) proved successful, the mean levels of FRs in personal samples being 10-68 and 14-79% of those from the previous year or alternatively below the limit of quantification. At the two remaining sites, the reductions in FR exposures were less consistent. The concentrations reported may pose a health hazard to the workers, although evaluation of the association between FR exposure and adverse health effects is hampered by lacking occupational exposure limits. Therefore, the exposures should be minimized by adequate control measures and maintaining good occupational hygiene practice.

Protein adducts as biomarkers of exposure to aromatic diisocyanates in workers manufacturing polyurethane (PUR) foam.

This work was undertaken to investigate the usefulness of diisocyanate-related protein adducts in blood samples as biomarkers of occupational exposure to toluene diisocyanate (TDI; 2,4- and 2,6-isomers) and 4,4'-methylenediphenyl diisocyanate (MDI). Quantification of adducts as toluene diamines (TDAs) and methylenedianiline (MDA) was performed on perfluoroacylated derivatives by gas chromatography-mass spectrometry (GC-MS/MS) in negative chemical ionisation mode. TDI-derived adducts were found in 77% of plasma and in 59% of globin samples from exposed workers manufacturing flexible polyurethane foam. The plasma levels ranged from 0.003 to 0.58 nmol mL(-1) and those in globin from 0.012 to 0.33 nmol g(-1). The 2,6-isomer amounted to about two-thirds of the sum concentration of TDA isomers. MDI-derived adducts were detected in 3.5% of plasma and in 7% of globin samples from exposed workers manufacturing rigid polyurethane foam. A good correlation was found between the sum of TDA isomers in urine and that in plasma. The relationship between globin adducts and urinary metabolites was ambiguous. Monitoring TDI-derived TDA in plasma thus appears to be an appropriate method for assessing occupational exposure. Contrary to TDI exposure, adducts in plasma or globin were not useful in assessing workers' exposure to MDI. An important outcome of the study was that no amine-related adducts were detected in globin samples from TDI- or MDI-exposed workers, alleviating concerns that TDI or MDI might pose a carcinogenic hazard. Further studies are nevertheless required to judge whether diisocyanates per se could be such a hazard.

Non-invasive estimation of pulmonary outflow tract obstruction: A comparative study of cardiovascular phase contrast magnetic resonance and Doppler echocardiography versus cardiac catheterization.

AIM: To compare estimated pressure gradients from routine follow-up cardiovascular phase-contrast magnetic resonance (PC-MR) with those from Doppler echocardiography and invasive catheterization in patients with congenital heart disease (CHD) and pulmonary outflow tract obstruction. METHODS: In 75 patients with pulmonary outflow tract obstruction maximal and mean PC-MR gradients were compared to maximal and mean Doppler gradients. Additionally, in a subgroup of 31 patients maximal and mean PC-MR and Doppler pressure gradients were compared to catheter peak-to-peak pressure gradients (PPG). RESULTS: Maximal and mean PC-MR gradients underestimated pulmonary outflow tract obstruction as compared to Doppler (max gradient: bias = + 8.4 mm Hg (+ 47.6%), r = 0.89, p < 0.001; mean gradient: + 4.3 mm Hg (+ 49.0%), r = 0.88, p < 0.001). However, in comparison to catheter PPG, maximal PC-MR gradients (bias = + 1.8 mm Hg (+ 8.8%), r = 0.90, p = 0.14) and mean Doppler gradients (bias = - 2.3 mm Hg (- 11.2%), r = 0.87, p = 0.17) revealed best agreement. Mean PC-MR gradients underestimated (bias = - 7.7 mm Hg (- 55.6%), r = 0.90, p < 0.001) while maximal Doppler gradients systematically overestimated catheter PPG (bias = + 13.9 mm Hg (+ 56.5%), r = 0.88, p < 0.001). CONCLUSIONS: Estimated maximal PC-MR pressure gradients from routine CHD follow-up agree well with invasively assessed peak-to-peak pressure gradients. Estimated maximal Doppler pressure gradients tend to overestimate, while Doppler mean gradients agree better with catheter PPG. Therefore, our data provide reasonable arguments to either apply maximal PC-MR gradients or mean Doppler gradients to non-invasively evaluate the severity of pulmonary outflow tract obstruction in the follow-up of CHD.

N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk.

We observed previously that polymorphisms in glutathione S-transferase (GST) genes modified allergic responses to diisocyanate exposure. Here, we extended the study to examine the possible role of N-acetyltransferase (NAT) genotypes in the development of diisocyanate-induced ill effects, both separately and in combination with the previously examined GSTM1, GSTM3, GSTP1 and GSTT1 genotypes. The study population comprised 182 diisocyanate-exposed workers, 109 of whom were diagnosed with diisocyanate-induced asthma and 73 of whom had no symptoms of asthma. The diisocyanates to which the workers had been exposed to were diphenylmethane diisocyanate (MDI), hexamethylene diisocyanate (HDI) and toluene diisocyanate (TDI). The NAT2 genotype did not have any significant effect on the risk of developing asthma, but the putative slow acetylator NAT1 genotypes posed a 2.54-fold risk of diisocyanate-induced asthma (95% confidence interval [CI] 1.32 to 4.91). The effect of the NAT1 genotype was especially marked for workers exposed to TDI, among whom the NAT1 slow acetylator genotypes posed a 7.77-fold risk of asthma (95% CI 1.18 to 51.6). Statistically significant increases in asthma risk were also observed among the whole study population for the concurrent presence of the GSTM1 null genotype and either NAT1 (odds ratio [OR] 4.53, 95% CI 1.76 to 11.6) or NAT2 (OR 3.12, 95% CI 1.11 to 8.78) slow acetylator genotypes, and of NAT1 and NAT2 slow acetylator genotypes (OR 4.20, 95% CI 1.51 to 11.6). The results suggest for the first time that in addition to GSTs, the NATs play an important role in inception of asthmatic reactions related to occupational exposure to diisocyanates.

The total right/left-volume index: a new and simplified cardiac magnetic resonance measure to evaluate the severity of Ebstein anomaly of the tricuspid valve: a comparison with heart failure markers from various modalities.

BACKGROUND: The classification of clinical severity of Ebstein anomaly still remains a challenge. The aim of this study was to focus on the interaction of the pathologically altered right heart with the anatomically-supposedly-normal left heart and to derive from cardiac magnetic resonance (CMR) a simple imaging measure for the clinical severity of Ebstein anomaly. METHODS AND RESULTS: Twenty-five patients at a mean age of 26±14 years with unrepaired Ebstein anomaly were examined in a prospective study. Disease severity was classified using CMR volumes and functional measurements in comparison with heart failure markers from clinical data, ECG, laboratory and cardiopulmonary exercise testing, and echocardiography. All examinations were completed within 24 hours. A total right/left-volume index was defined from end-diastolic volume measurements in CMR: total right/left-volume index=(RA+aRV+fRV)/(LA+LV). Mean total right/left-volume index was 2.6±1.7 (normal values: 1.1±0.1). This new total right/left-volume index correlated with almost all clinically used biomarkers of heart failure: brain natriuretic peptide (r=0.691; P=0.0003), QRS (r=0.432; P=0.039), peak oxygen consumption/kg (r=-0.479; P=0.024), ventilatory response to carbon dioxide production at anaerobic threshold (r=0.426; P=0.048), the severity of tricuspid regurgitation (r=0.692; P=0.009), tricuspid valve offset (r=0.583; P=0.004), and tricuspid annular plane systolic excursion (r=0.554; P=0.006). Previously described severity indices ([RA+aRV]/[fRV+LA+LV]) and fRV/LV end-diastolic volume corresponded only to some parameters. CONCLUSIONS: In patients with Ebstein anomaly, the easily acquired index of right-sided to left-sided heart volumes from CMR correlated well with established heart failure markers. Our data suggest that the total right/left-volume index should be used as a new and simplified CMR measure, allowing more accurate assessment of disease severity than previously described scoring systems.

Biological monitoring of aromatic diisocyanates in workers exposed to thermal degradation products of polyurethanes.

Exposure to diisocyanates was assessed by biological monitoring among workers exposed to the thermal degradation products of polyurethanes (PURs) in five PUR-processing environments. The processes included grinding and welding in car repair shops, milling and turning of PUR-coated metal cylinders, injection moulding of thermoplastic PUR, welding and cutting of PUR-insulated district heating pipes during installation and joint welding, and heat-flexing of PUR floor covering. Isocyanate-derived amines in acid-hydrolysed urine samples were analysed as perfluoroacylated derivatives by gas chromatography mass spectrometry in negative chemical ionisation mode. The limits of quantification (LOQs) for the aromatic diamines 2,4- and 2,6-toluenediamine (2,4- and 2,6-TDA) and 4,4'-methylenedianiline (4,4'-MDA) were 0.25 nmol l(-1), 0.25 nmol l(-1) and 0.15 nmol l(-1), respectively. The LOQ for the aliphatic diamines hexamethylenediamine (HDA), isophoronediamine (IpDA) and 4,4'-diaminodicyclohexyl methane (4,4'-DDHM) was 5 nmol l(-1). TDA and MDA were detected in urine samples from workers in car repair shops and MDA in samples from workers welding district heating pipes. The 2,4-TDA isomer accounted for about 80% of the total TDA detected. No 2.6-TDA was found in the urine of non-exposed workers. The highest measured urinary TDA and MDA concentrations were 0.79 nmol mmol(-1) creatinine and 3.1 nmol mmol(-1) creatinine, respectively. The concentrations found among non-exposed workers were 0.08 nmol mmol(-1) creatinine for TDA and 0.05 nmol mmol(-1) creatinine for MDA (arithmetic means). Exposure to diisocyanates originating from the thermal degradation of PURs are often intermittent and of short duration. Nevertheless, exposure to aromatic diisocyanates can be identified by monitoring diisocyanate-derived amines in acid-hydrolysed urine samples.

Exposure to airborne isocyanates and other thermal degradation products at polyurethane-processing workplaces.

The thermal degradation products of polyurethanes (PURs) and exposure to isocyanates were studied by stationary and personal measurements in five different occupational environments. Isocyanates were collected on glass fibre filters impregnated with 1-(2-methoxyphenyl)piperazine (2MP) and in impingers containing n-dibutylamine (DBA) in toluene. connected to a glass fibre postfilter. The derivatives formed were analysed by liquid chromatography: 2MP derivatives with UV and electrochemical detection and DBA derivatives with mass spectrometric detection. The release of aldehydes and other volatile organic compounds into the air was also studied. In a comparison of the two sampling methods, the 2MP method yielded about 20% lower concentrations for 4,4'-methylenediphenyl diisocyanate (MDI) than did the DBA method. In car repair shops, the median concentration of diisocyanates (given as NCO groups) in the breathing zone was 1.1 microg NCO m(-3) during grinding and 0.3 microg NCO m(-3) during welding, with highest concentrations of 1.7 and 16 pg NCO m(-3), respectively. High concentrations of MDI, up to 25 and 19 microg NCO m(-3), respectively, were also measured in the breathing zone during welding of district heating pipes and turning of a PUR-coated metal cylinder. During installation of PUR-coated floor covering, small amounts of aliphatic diisocyanates were detected in the air. A small-molecular monoisocyanate, methyl isocyanate, and isocyanic acid were detected only during welding and turning operations. The diisocyanate concentrations were in general higher near the emission source than in the workers' breathing zone. A sampling strategy to evaluate the risk of exposure to isocyanates is presented.

Monoterpene and wood dust exposures: work-related symptoms among Finnish sawmill workers.

BACKGROUND: Monoterpenes and wood dust are released into the work environment during sawing of fresh wood. Symptoms related to exposure to monoterpenes and wood dust include irritation of the eyes, mucous membrane, and skin. METHODS: We studied 22 sawhouse workers who process pine and spruce in 1997-99. Exposure to monoterpenes was assessed by determining monoterpenes in air and verbenols in urine by gas chromatography using flame ionization detection. Wood dust was determined gravimetrically. A questionnaire was used to evaluate work-related subjective symptoms. RESULTS: Exposures to monoterpenes (geometric mean, GM) among sawhouse workers were 61-138 mg/m(3) and 2.0-13 mg/m(3) during processing of pine and spruce, respectively. Urinary verbenol correlated well with worker exposure to the alpha-pinene fraction of monoterpenes. The inhalable dust concentration in the breathing zone was 0.5- 2.2 mg/m(3) during pine processing and 0.4-1.9 mg/m(3) during spruce processing. The prevalence of symptoms, in the eyes or respiratory tract, was high during both seasons and in connection with either tree species. CONCLUSIONS: The highest monoterpene concentration (GM), in the breathing zone, measured during processing of pine, was less than one-fourth of the Finnish occupational exposure limit (OEL, 570 mg/m(3)). Verbenol concentrations in postshift urine samples reflected accurately the exposure to monoterpenes. The concentrations of inhalable dust (GM) were less than one-half the Finnish OEL (5 mg/m(3)). No significant differences in dust exposure were observed among tree species processed. Work-related symptoms appeared to correlate with monoterpene exposure during processing of pine and with wood dust exposure during processing of spruce.

Harmonized Nordic strategies for isocyanate monitoring in workroom atmospheres.

The Nordic Network on Isocyanates (NORDNI) is financed by the Nordic Council of Ministers and is under the administration of Prof. Yngvar Thomassen and co-workers. National Institute of Occupational Health, Norway. The aim of NORDNI is to establish a broad network between the Nordic National Institutes of Occupational Health working within the field of isocyanate exposure and strategies for sampling and determination of isocyanates in workroom atmospheres. This viewpoint article summarizes the resolutions that were established at the 1st NORDNI consensus meeting arranged in Frøya, Norway, 31st August-2nd September, 2001. The consensus platform from the 1st NORDNI meeting was presented at the 4th International Symposium on Modern Principles of Air Monitoring, Lillehammer, Norway, 3-7 February, 2002.