Sekkal, Samira MD, PhD; Haddam, Nahida MD, PhD; Scheers, Hans MSc; Poels, Katrien L. PhD; Bouhacina, Linda MD; Nawrot, Tim S. PhD; Veulemans, Hendrik A. PhD; Taleb, Abdesselam MD, PhD; Nemery, Benoit MD, PhD
Workers from the petroleum industry are potentially exposed to hydrocarbons at various operational stages: drilling crude oil (or gas), refining oil for the production of fuels (and other derivatives), or transporting and delivering gasoline and similar petroleum-derived products. Most health studies among petroleum workers have concentrated on their risk of cancer, especially benzene-induced leukemia. Nevertheless, occupational exposure to petroleum-derived hydrocarbons could also lead to other adverse health effects, but these have not been studied much among petroleum industry workers.
Petroleum products consist essentially of aliphatic hydrocarbons, with varying proportions of aromatics, and they may be considered as a particular category of solvents. Admittedly, the exposure of petroleum industry workers cannot be equated quantitatively or qualitatively with that of workers exposed to pure organic solvents, but most of our knowledge of the toxicity of aromatic or aliphatic hydrocarbons is derived from the study of organic solvents, either as pure chemicals or in mixtures. Organic solvents are well known for their potential systemic toxicity: as a category, solvents have a well-established neurotoxicity,1,2 and some specific solvents may also cause injury to the liver, kidney, blood, and other organ systems.3 Organic solvents may also cause local skin damage after prolonged dermal exposure. Nevertheless, unless they are aspirated or inhaled in massive quantities, solvents do not seem to cause substantial toxicity to the respiratory tract.4,5 In general, animal studies do not indicate that the long-term inhalation of solvents causes much damage to the lungs or airways; the few epidemiologic studies that have investigated this in humans have not revealed much incidence of respiratory disease in solvent-exposed workers. This absence of respiratory disorders in relation to solvents is remarkable because occupational exposure to solvents generally occurs via inhalation and because people often report respiratory and ocular irritations when they are exposed to volatile organic compounds, including solvent vapors.6–9 The latter is especially the case among subjects with asthma.
The present cross-sectional study was performed in a large group of employees from a single company handling and distributing refined petroleum products. These exposed subjects were compared with a well-matched group of electricians from another company where there was no significant exposure to solvents. The respiratory assessment of all subjects was done by questionnaire, spirometry, and a measurement of the fractional concentration of exhaled nitric oxide (FENO). The latter index is considered a novel biomarker of (allergic) asthma, because airway inflammation (mainly by eosinophils) is accompanied by an increase in the production of nitric oxide.10,11
This cross-sectional study was performed between November 2006 and May 2007 in the area of Tlemcen, a town in western Algeria. The exposed subjects were workers from a large hydrocarbons distribution company. Of a total of 298 employees of that company, 274 potentially exposed workers were considered for participation in the study. We excluded 14 subjects who had worked less than 1 year in the company, seven subjects with unsatisfactory cooperation in the pulmonary function testing, and three subjects who were unable to perform spirometry for medical reasons. This left 250 exposed subjects, all men between 20 and 60 years who had worked full time for at least 1 year in the company. The control group consisted of 250 electricians from a power company (distribution of electricity and gas) who had no occupational contact with solvents.
The study was considered as part of the occupational medical surveillance offered to the workers. We obtained all the necessary agreements from the relevant authorities of the two companies, as well as from the eligible subjects, who were given detailed information about the study objectives and protocol before the investigation.
The exposure measurements were made in April to June 2009 and January to March 2010. In a first stage, samples of the various products (gasoline, diesel, paints, thinners, etc) handled by the exposed workers were analyzed in the laboratory of Occupational Hygiene and Toxicology of the K.U. Leuven to identify their composition. Later, the degree of exposure was assessed by personal air sampling during the different tasks: a total of 45 workers wore sampling pumps for about 4 hours during their normal work. The pumps (Gillian LFS 113, Sensidyne Inc., Clearwater, FL) were calibrated before and after each sampling by means of a Gilibrator airflow calibrator. The inlet of the sampling tube was placed in the worker's breathing zone and air was sampled (100 mL/min) through SKC 226–01 tubes (lot 2000), containing activated charcoal (100 mg front section and 50 mg backup section). At the end of the sampling, the tubes were sealed, labeled, and kept frozen at −18°C. On arrival at the laboratory, the two sections of the activated charcoal tubes were individually desorbed using 1 mL of carbon disulfide. Samples were shaken for 30 minutes on an automatic shaker. The analyses were carried out on an Agilent 4890 gas chromatograph with flame ionization detection and equipped with an autosampler. A 2-μL aliquot of each sample was simultaneously injected onto two capillary columns (60 m) with different polarity (SPB-1 and WAX10, Supelco Inc., Bellefonte, PA) using split injection. A constant high-purity helium flow was applied through the columns. The gas chromatograph separation was obtained using a program with an initial oven temperature of 55°C that was gradually increased to a final temperature of 233°C. The oven was held at the final temperature for 3 minutes. The injector was maintained at a temperature of 230°C, while the flame ionization detector was at 250°C.
The questionnaires were administered by the same investigator (SS) during a face-to-face interview in the morning before any work or testing. A first general questionnaire concerned administrative and other general characteristics: age, sex, marital status, educational level, medical and surgical history, current job, seniority at work, occupational history, smoking habits, alcohol and drug consumption, and exposures outside work. Then the following specific questionnaires were administered: (1) the International Union Against Tuberculosis and Respiratory Diseases (IUATLD) Bronchial Symptoms Questionnaire (1986),12 to obtain information about respiratory symptoms in the past 12 months; (2) the questionnaire on allergic rhinitis by Annesi-Maesano et al,13 which gives a Score for Allergic Rhinitis (SFAR, positive if 7 or higher); and (3) sleep questionnaires (these results will be presented elsewhere).
Spirometry was performed in the sitting position using an electronic spirometer (Essilor HI 801, distributed by LABOPTIC, Algiers, Algeria) according to recommendations by the European Respiratory Society.14 At least three satisfactory forced expiratory maneuvers were obtained in each subject, and the best flow-volume curve was retained for calculation of the following parameters: forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1:FVC ratio, maximal mid-expiratory flow (MMEF), peak expiratory flow, and maximal expiratory flows (MEFs) at 75%, 50%, and 25% of FVC (MEF75, MEF50, and MEF25). Pulmonary function parameters were also expressed as percent of predicted according to the equations of the European Respiratory Society.15 All flow-volume curves were available in print and (a random) half of them were later checked for quality by an experienced technician of the lung function laboratory of the Leuven university hospital. Standing height and weight were measured and used to calculate body mass index (BMI).
Maximal inspiratory and expiratory pressures were also measured, but these results will be presented elsewhere.
The FENO, expressed as parts per billion (ppb), was measured using the NioxMino® analyzer (Aerocrine AB, Solna, Sweden), a hand-held device with which a flow of 50 mL/s at a pressure of 10 cm of H2O is obtained for at least 10 seconds, according to recommendations.16
We used Epi-info (version 6.04) from the Centers for Disease Control and Prevention (Atlanta, GA) for preliminary analyses and SAS software version 9.2 (SAS Institute Inc, Cary, NC) for the final statistical analysis. For comparison of means and proportions, we applied t test and the chi-square statistic, respectively. Nonnormally distributed data (FENO) were logarithmically transformed. We used a general linear model and a logistic regression model to study group differences for continuous and dichotomous variables, respectively, with adjustments being made for various variables, as indicated. The level of significance was set at P < 0.05 (two-sided).
General Characteristics and Exposure Data
The characteristics of the two groups of workers are presented in Table 1. The exposed and control populations were well matched with respect to age and duration of employment, BMI, and smoking habits. In general, ex-smokers were significantly older (44.2 [SD, 9.5] years) than nonsmokers (40.5 [SD, 10.0] years) and smokers (40.9 [SD, 8.8] years) (P = 0.001); smokers had a significantly lower BMI (23.7 [SD, 3.7] kg/m2) than nonsmokers (25.6 [SD, 4.5] kg/m2) and ex-smokers (25.1 [SD, 3.7] kg/m2) (P < 0.001).
Among the workers from the petroleum company, there were 61 operators, who were involved mainly in loading and unloading fuels; 64 mechanics, who were involved in the maintenance of tanks and trucks; 25 petroleum truck drivers; 57 spray painters (for tanks and vehicles); 14 brush or roller painters (for buildings); and 29 security workers. These groups did not differ significantly with regard to age, years of employment, BMI, or smoking.
The qualitative analysis of the various products revealed the expected compositions of short- and long-chain aliphatic hydrocarbons with varying amounts of aromatic hydrocarbons (up to 60% in unleaded gasoline). The paints and thinners contained the expected mixtures of various solvents. The paints used by the spray painters included two-component paints, with di-isocyanate–based hardeners. The personal monitoring data are presented in Table 2. Results for each compound are obtained by summation of the concentrations found on front and backup sections of the charcoal tubes. Samples taken in summer had somewhat higher concentrations than those taken in spring (not shown). Overall, the concentrations measured were well below the American Conference of Governmental Industrial Hygienists Threshold Limit Values (TLVs) for all compounds.17 Excursions above the TLVs were found for benzene, toluene, and chlorobenzene. Values above the TLV for benzene were found in one air sample from fuel loaders and three samples from brush painters. For toluene and chlorobenzene, air concentrations above the TLV were observed only in 1 of the 11 samples from spray painters. Although no exposure measurements were made for security workers and truck drivers, we considered it reasonable to include them in the exposed group because they worked on the plant premises or were exposed to petroleum products during loading and unloading of the trucks. No detectable amounts of hydrocarbons were found among the control subjects.
In general, the prevalences of all respiratory and nasal symptoms were substantially and significantly higher among the exposed subjects than among the control subjects (Table 3). In the exposed group, more subjects reported at least one respiratory symptom from the IUATLD questionnaire (n = 92, 37%) than in the control group (n = 37, 15%) (P < 0.01). Similarly, the proportion of subjects reporting nasal symptoms was higher in the exposed group than in the control group, and the prevalence of subjects reporting personal allergy was also significantly higher (P = 0.001) among exposed subjects (n = 36, 14.4%) than among controls (n = 14, 5.6%), although the prevalence of reported allergies among family members did not differ between the two groups (13.6% among exposed; 9.6% among controls). Consequently, on the basis of the SFAR, 32 exposed subjects (13%) had (allergic) rhinitis (SFAR ≥ 7), against 16 subjects (6%) among controls (P = 0.023). Among the exposed subjects, 6 of the 18 asthmatic subjects also had a positive SFAR score.
After adjustments for age, BMI, and smoking category, the odds ratios (ORs) for reporting respiratory symptoms among exposed subjects compared with control subjects ranged from 2 to more than 10 (Table 3). In general, the ORs were higher for the respiratory questionnaire of the IUATLD, where the highest ORs were obtained for positive replies to the questions relative to “troubled breathing” and “being breathless at rest,” than for the nasal questionnaire. On the basis of the IUATLD questionnaire, 17% of the exposed subjects had chronic bronchitis (phlegm for 3 months per year), compared with 5% among controls, and 7% of exposed subjects had asthma compared with less than 2% among controls; only two subjects had both asthma and chronic bronchitis.
Additional adjustment for reported personal allergy (Table 3, right columns) led to slight decreases in the magnitude of the ORs for lower respiratory symptoms without affecting statistical significances. Nevertheless, such adjustment abolished the differences regarding most nasal symptoms (except those reported to occur throughout the year) and not the eye symptoms. Adjustment for reported family allergy did not have such effect (not shown).
Excluding the 57 spray painters—who were also exposed to asthmogenic isocyanates—from the exposed subjects did not modify either the prevalences or the OR (Supplemental Table 1, http://links.lww.com/JOM/A112). Equally, excluding the 29 security workers and 25 truck drivers—for whom no exposure measurements were available—did not substantially modify the results for the respiratory symptoms, although the OR for nasal symptoms and SFAR decreased somewhat (Supplemental Table 1, http://links.lww.com/JOM/A112).
Overall, smoking per se did not affect spirometric indices markedly but lung function was affected in the expected direction in that the FEV1:FVC ratio was significantly higher in nonsmokers than in ex-smokers and smokers, and MEF50 and MEF25 were significantly lower in ex-smokers than in nonsmokers (data not shown). After adjustment for age, height, and exposure class, there were no significant differences between smoking categories, except for FEV1:FVC ratio, which was significantly higher in nonsmokers than in ex-smokers and smokers.
In general, subjects reporting respiratory symptoms (except for chronic phlegm) had consistently poorer values than asymptomatic subjects for all or most pulmonary function tests, except FVC, both before and after adjustments for smoking category (data not shown). After adjustments for smoking category, age, height, and exposure class, only subjects reporting asthma, wheezing, or chronic coughing still had poorer values for most pulmonary function tests, except FVC. Subjects with rhinitis (SFAR ≥ 7) did not have lower pulmonary function indices than those without (data not shown).
The results of the pulmonary function testing according to exposure category are presented in Table 4. Mean FVC was almost identical in exposed and control subjects. Forced expiratory volume in 1 second tended to be slightly lower (P < 0.2), peak expiratory flow and MEF75 were borderline significantly lower, and FEV1: FVC ratio as well as MEFs at low volumes (MEF50 and MEF25) were significantly lower in exposed than in control subjects, both when absolute values were taken with adjustments made for age, height, and smoking category, and when values were expressed as percent predicted with adjustment made for smoking. An additional adjustment for reported personal allergy slightly reduced the levels of significance. Excluding subjects with rhinitis (ie, with SFAR ≥ 7) from these comparisons hardly modified the findings (Table 4, italics). Also, excluding either the spray painters or the security workers and truck drivers did not abolish the observed differences or their significance (not shown).
In the exposed group, 24 subjects (9.6%) had an FEV1 below 80% predicted, against 15 subjects (6.0%) in the control group (P = 0.13; OR, 1.68 with adjustment for age, BMI, and smoking); correspondingly, 21 exposed subjects (8.4%) had an FEV1:FVC ratio below 70% against five control subjects (2%) (P < 0.01; OR, 4.51 with adjustment for age, BMI, and smoking; OR, 4.39 [P < 0.01] with an additional adjustment made for the presence of rhinitis). The same significant differences were obtained when considering the numbers of subjects with either a low FEV1 or a low FEV1:FVC ratio (34 exposed, 18 controls), and those with both a low FEV1 and a low FEV1:FVC ratio (11 exposed and 2 controls).
No significant differences in pulmonary function were apparent between the different job categories within the exposed group, both with and without adjustment for age, BMI, and smoking category. The only exception was FVC, where spray painters and workers involved in loading and unloading had lower values than security workers. Nevertheless, when values were expressed as percent predicted, no significant differences were found (Table 5).
In general, FENO was not related to age or BMI. Nevertheless, FENO was significantly affected by smoking, being lower (P < 0.001) in smokers (22.2 [SD, 14.5] ppb) than in nonsmokers (27.5 [SD, 21.4] ppb) and ex-smokers (31.0 [SD, 22.3] ppb). Values of FENO were also higher in subjects reporting asthma (60.6 [SD, 44.6] ppb vs 24.2 [SD, 15.2] ppb; P < 0.001), chronic cough (30.8 [SD, 25.2] ppb vs 24.5 [SD, 16.6] ppb; P = 0.009), dyspnea after exercise (30.4 [SD, 23.9] ppb vs 24.3 [SD, 16.8] ppb, P = 0.010), personal allergy (36.3 [SD, 27.8] ppb vs 24.7 [SD, 17.4] ppb; P < 0.001) or rhinitis (34.8 [SD, 26.7] ppb vs 24.9 [SD, 17.7] ppb; P = 0.002).
Values of FENO were significantly (P < 0.0001) higher among exposed workers (30.1 [SD, 23.4] ppb) than among controls (21.6 [SD, 11.6] ppb), both with and without adjustment for age, height, and smoking category (Table 4). Additional adjustments for personal allergy or exclusion of subjects with rhinitis did not alter the FENO data substantially. Although FeNO was inversely related to FEV1:FVC ratio, peak expiratory flow, and MEF75, the corresponding coefficients were close to zero (not shown).
Table 5 also shows that mean FENO varied according to job title, with the highest values being found among the spray painters, followed by truck drivers and mechanics. Even after exclusion of the spray painters, the exposed subjects still had higher FENO than the controls.
In this cross-sectional study of a large and fairly homogeneous group of workers exposed to low levels of hydrocarbons in the petroleum industry, we found evidence for mild respiratory effects, as assessed by questionnaire, spirometry, and FENO, when compared with a well matched group of workers without substantial exposure to solvents or other inhaled chemicals.
The petroleum industry can be divided into the upstream industry, which encompasses exploration, drilling, processing, and transport of crude oil (or gas), and the downstream industry, which involves refining (to produce gasoline, diesel, and other petroleum-derived products) and distribution from the refinery to various points of retail and then to consumers.18,19 Here, we studied workers from the downstream industry, more specifically those involved in the storage and distribution of various fuels, and related maintenance and ancillary activities, including painting. In other words, these petroleum workers were neither exposed to crude oil nor were they involved in oil refining. The control workers were electricians and they had no exposure to solvents, except perhaps for very occasional duties.
The type and degree of exposure to hydrocarbons were well characterized by personal air sampling and state-of-the-art analysis by gas chromatography. The compounds identified in the personal samples were those normally expected in handlers of petroleum products and they also generally corresponded to the composition of the products analyzed. The levels of exposure to individual compounds were generally low when compared with accepted standards, such as the TLVs of the American Conference of Governmental Industrial Hygienists,17 even though some samples were close to the TLV for benzene, which has a low TLV because of its carcinogenicity. The generally low level of exposure by inhalation is not unexpected based on the fact that these were largely outdoor jobs; the higher values in summer than in spring reflect the higher evaporation with higher ambient temperature. Nevertheless, these low average levels of hydrocarbons in the air do not exclude occasional overexposures resulting from spills or incidents, nor do they exclude exposure via the skin, because opportunities for dermal exposure were clearly present. The highest measured exposures occurred among spray painters, who were most exposed to toluene and other aromatic solvents. In the spray painters, there was also exposure to isocyanates because some of the hardeners of two-component paints used were confirmed to contain isocyanates. Nevertheless, we did not attempt to measure isocyanates in the air.
Using two validated questionnaires,12,13 we found substantial differences in the prevalences of reported respiratory symptoms between the two groups of workers. The prevalence of lower respiratory symptoms proved to be consistently higher among the petroleum workers than among the controls and, with ORs ranging from 2 to more than 10, the contrasts between the two groups were also quite marked. Thus, on the basis of the IUATLD questionnaire, the prevalence of asthma was 7% among the exposed subjects against less than 2% among the controls, whereas the prevalences of chronic bronchitis were 17% and 5%, respectively. Nasal symptoms were also more frequently reported by the petroleum workers, in whom, according to the SFAR questionnaire, the prevalence of (allergic) rhinitis was 13%, that is, twice the prevalence among controls. These differences in symptom reporting could not be attributed to technical factors or to differences in age, obesity, or smoking habits, because the groups were well matched for these factors and because we corrected for these potential confounding factors in the statistical analysis.
The two groups did, however, differ with regard to reported personal history of allergy. In the absence of any objective assessment of allergy (by skin testing or serologic results), this finding is not easy to interpret. Questionnaire-derived personal allergy could either reflect a non–work-related individual risk factor or, on the contrary, represent an outcome parameter. We favor the latter possibility because subjects were likely to attribute their nasal symptoms to “allergy,” especially with the use of the SFAR questionnaire in which the question on personal allergy follows those on nasal symptoms. The fact that the proportions of subjects reporting a positive family history of allergy did not differ between the groups is compatible with this interpretation. Whatever the exact explanation, the close relationship between reported allergy and nasal symptoms explains why after adjustments for personal allergy, the ORs for nasal symptoms (except—interestingly—perennial nasal symptoms and also eye symptoms) became close to unity; because the SFAR index is partly determined by a positive reply to the question on personal allergy, it is not surprising that differences for this index also disappeared. Self-reported personal allergy, however, did not affect the lower airway symptoms, nor pulmonary function or FENO.
Although the correlation between reported symptoms and objective parameters was not perfect, there was a good internal consistency between the (subjective) reporting of symptoms and more objective pulmonary function tests or FENO. Upper and lower respiratory symptoms are often reported to be caused by exposure to solvents, especially by persons with asthma, and others have also found higher prevalences of chronic bronchitis or dyspnea in solvent-exposed subjects.5,6
Although the differences in symptom reporting were quite marked, the differences in lung function appeared, at first sight, much less pronounced. The mean values of FVC were remarkably similar in the two groups, but there was a trend for FEV1 to be lower (by about 110 mL) and the FEV1:FVC ratio was significantly lower (by 2 percentage points) among the hydrocarbon-exposed subjects than among the controls. The MEFs were also significantly lower, not only at low volumes but even at high volumes. All these differences were present whether or not smoking category and the presence of rhinitis were taken into account.
What is the relevance of finding these somewhat lower—but still “normal”—average pulmonary function values in the exposed subjects? One consideration is that there were twice as many subjects (about 8%) with obstructive impairment (FEV1 < 80% predicted or FEV1:FVC ratio < 70%) among the exposed subjects than among the controls. Moreover, if we assume, for the sake of simplicity, that our two groups had a similar pulmonary function when they started working (at 26 years on average) and that FEV1 decreases linearly with age, then a 110-mL lower FEV1 after 15 years of work represents an average extra loss of about 7 mL per year for the hydrocarbon-exposed workers. This may seem trivial, but it is not so trivial when compared with, for instance, the effects of smoking. Indeed, it should be remembered that even for a well established and “strong” risk factor such as cigarette smoking, the mean group differences in pulmonary function between exposed subjects (ie, smokers) and nonexposed subjects (ie, nonsmokers) are not large, especially in young populations, in neither cross-sectional studies nor longitudinal studies.20 Thus, in an analysis of eight large cross-sectional studies in the United States, Vollmer et al21 determined estimated excess declines in FEV1 of −4 and −10 mL per year for men smoking less and more than 10 cigarettes per day, respectively; the excess decline was −6 mL per year for each pack-year smoked. In a longitudinal study,22 young adult smokers lost “only” an extra 65 mL of FEV1 over 8 years, that is, −8.4 mL per year for each pack of cigarettes smoked per day, compared with nonsmokers. In our study of relatively young adults, smoking had not yet affected FEV1 significantly, neither among exposed subjects nor among the control group, although FEV1:FVC ratio and MEFs at low volumes were decreased as expected.
Measuring FENO as an endpoint in epidemiological studies of occupational exposures has not yet been widely applied. Fractional concentration of exhaled NO has mainly been investigated as a diagnostic tool in studies of occupational asthma,23,24 but on the basis of a prospective study among apprentices,25 FENO has also been proposed as a possible indicator of bronchial hyperresponsiveness and, hence, an early marker of occupational asthma. In the present study, we found, in general accordance with the literature,10 that FENO was lower in smokers and higher in subjects with asthma (as well as other respiratory symptoms). We also found that the exposed subjects had higher values of FENO than the control subjects. This suggests that the exposed subjects had more (eosinophilic) inflammation in the airways than the control workers, but this remains to be verified. Interestingly, the higher FENO among the exposed subjects was independent of the reported presence of (allergic) rhinitis. In a previous cross-sectional study of an Algerian workforce,26 solvent-exposed workers also exhibited a poorer pulmonary function and more bronchial hyperresponsiveness (as assessed by a histamine test). To our knowledge, no other study has investigated whether exposure to petroleum hydrocarbons or solvents is associated with changes in FENO.
Only few studies have reported adverse effects of occupational exposure to solvents on the respiratory tract.4,5 The present study is compatible with our previous findings26 and indicates that even at low exposure levels, those who were exposed to petroleum-derived hydrocarbons had more respiratory symptoms, lower pulmonary function (with an obstructive pattern of impairment), and also more signs of airway inflammation based on FENO. These findings among petroleum workers were not due to or influenced by the presence of spray painters in the group. The latter workers were also exposed to isocyanate-containing paints and this constitutes a well-known risk of occupational asthma. Nevertheless, exclusion of the spray painters did not modify the differences found between the exposed group and the control group. One could also object that the levels of exposure to hydrocarbons were too low to be held responsible for the observed differences between the exposed and control subjects. Nevertheless, it cannot be excluded that the real exposures were higher than those measured in the present study, for example, as a result of brief peak exposures, incidental spills, or both.
The mechanisms for the respiratory effects of such low hydrocarbon exposure remain unclear. In this study, we also found evidence of sleep disturbances and decreased maximal inspiratory and expiratory forces among the exposed subjects (unpublished observations).
Within the limits of cross-sectional studies with regard to attributing causality, this study indicates that long-term low exposure to hydrocarbons in the petroleum industry may affect respiratory health.
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