Annals of Occupational Hygiene Advance Access originally published online on June 17, 2005
Annals of Occupational Hygiene 2005 49(6):521-527; doi:10.1093/annhyg/mei022
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© 2005 British Occupational Hygiene Society Published by Oxford University Press
Original Article |
Long-Term Effects of Elemental Mercury on Renal Function in Miners of the Idrija Mercury Mine
1 Ljubljana University Medical Centre, Clinical Institute of Occupational Medicine, Poljanski nasip 58, 1000 Ljubljana, Slovenia; 2 Faculty of Medicine, Department of Pharmacology and Experimental Toxicology, Korytkova 2, 1000 Ljubljana, Slovenia
* Author to whom correspondence should be addressed. E-mail: alenka.franko{at}siol.net
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Background: The kidneys are one of the main target organs for elemental mercury (Hg0). The influence of Hg0 on kidneys has been extensively studied but the long-term effects on this organ have not yet been determined with certainty. The basic aim of this research was to study the effects of a long-term exposure to Hg0 vapours on the renal function in miners in the post-exposure period.
Methods: The population studied comprised 53 miners (33 active and 20 retired) from the Idrija Mercury Mine as the exposed miners group and 53 unexposed workers as the control group. On the basis of mine exposure records (air and biological monitoring), the environmental and biological indicators of the past exposure to Hg0 were calculated for each miner. Kidney function was determined in both groups, i.e. in the exposed miners as well as in the controls. Glomerular kidney function was evaluated by a quantitative analysis of albumin and IgG in urine. Tubular kidney function, however, was determined by a quantitative analysis of 
1-microglobulin in urine and by the enzymatic activity of N-acetyl-ß-D-glucosaminidase (NAG).
Results: The mean exposure time in miners was 15 years. The total number of cycles of exposure ranged from 13 to 119. The mean annual time-weighted exposure was 0.29 mg m–3 and the mean integrated exposure intensity (IEI) was 1413 mg m–3-h. Throughout the period of exposure the average urine mercury concentration in miners was 68.24 µg l–1 and the average sum of peak urine mercury concentrations was 3901 µg l–1. Albumin, IgG and 1-microglobulin in urine were significantly elevated in the exposed miners compared with the unexposed controls (t = 2.17, P = 0.03; t = 2.81, P < 0.01; and t = 2.07, P = 0.04). No significant differences were found in the urine NAG activity when the exposed miners and the unexposed workers were compared. Among the indicators of renal function only 1-microglobulin in the urine correlated significantly with the IEI (r = 0.73; P 
0.01) and with the sum of peak mercury urine concentrations (r = 0.67; P 0.01) in the group of miners who still worked, while no significant correlations were found between these parameters in the group of the retired miners.
Conclusion: The results of the differences in albumin, IgG and 1-microglobulin concentrations in urine between the exposed miners and unexposed controls suggest that a long-term occupational exposure to Hg0 could cause renal dysfunction. A high correlation between 1-microglobulin in urine and the IEI as well as between 1-microglobulin in urine and the sum of peak urine mercury concentrations in the group of active but no longer exposed miners indicates that a long-term occupational exposure to Hg0 may cause a non-permanent tubular dysfunction.
Keywords: elemental mercury • kidney function • occupational exposure
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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In its 500-year history (1490–1994), the Idrija Mercury Mine has produced a total of 147 000 tons of commercial mercury (Hg), which represented over 13% of the entire world production to date. In 1994, the final shutdown of the mine began. From the very beginning of the extraction and processing of ore in the mine, miners and smelters were exposed to the harmful effects of Hg during their work. To reduce the personal exposure, a health and safety programme was implemented in the mine after 1965. It included technical measures, the regular use of the personal protection equipment, periodic rotation of workers and limitation of time of exposure. Regular monitoring of Hg concentration in the air, and biological monitoring were performed after 1965 (Kobal and Dizdarevic, 1997
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The kidneys are one of the main target organs for elemental Hg (Hg0), which accumulates in the kidneys especially in the area of the proximal tubuli (Passow et al., 1961; Berlin, 1986).
Experimental studies carried out on animals have shown immunologically mediated glomerulonephritis after the exposure to Hg (Berlin, 1986; Pelletier et al., 1987; Bagenstose et al., 1999). Glomerulonephritis and nephrotic syndrome have been reported in subjects exposed to Hg0 (Becker et al., 1962; Kazantzis et al., 1962; Strunge, 1970; Tubbs et al., 1982; Bernard and Lauwerys, 1989). According to some authors, the increased excretion of high- and low-molecular-weight proteins and the increased activity of some tubular lysosomal enzymes in the urine [as N-acetyl-ß-D-glucosaminidase (NAG)] are often the first indicators of renal dysfunction after the occupational exposure to Hg0 (Buchet et al., 1980; Stonard et al., 1983; Roels et al., 1985; Barregard et al., 1988; Kobal et al., 2000).
The results of the studies in this field do not agree entirely with the dose and duration of exposure to Hg0 that could cause renal dysfunction. Some authors connect proteinuria with a present increased absorption of Hg, which is manifested mostly as the increased excretion of Hg in urine (Kazantzis et al., 1962; Roels et al., 1985; Ellingsen et al., 1993). However, Buchet et al. (1980) and Stonard et al. (1983) suggest that proteinuria may also be connected with a long-term exposure to Hg0. Some authors believe that a slight subclinical glomerular dysfunction may be present in some exposed workers (Buchet et al., 1980; Ellingsen et al., 1993), while the others detect only slight renal tubular effects (Stonard et al., 1983; Roels et al., 1985; Himeno et al., 1986; Barregard et al., 1988; Langworth et al., 1992). Another group of researchers points out that occupational exposure to Hg0 might be connected with glomerular and tubular dysfunction (Kobal et al., 2000).
In the studies conducted to evaluate the impact of occupational exposure to Hg0 on renal function, glomerular function is most commonly determined by the analysis of high-molecular-weight proteins in urine (such as albumin, transferin and IgG), whereas tubular function is determined by the analysis of low-molecular-weight proteins in urine (such as 1-microglobulin, ß2-microglobulin and retinol-binding protein) and the activity of some tubular enzymes. Buchet et al. (1980) found increased urinary concentrations of the enzyme ß-galactosidase, albumin, transferin and IgG in chloralkali workers when compared with the unexposed control group mainly when the urinary Hg concentrations exceeded 50 µg g–1 creatinine, while Stonard et al. (1983) established a small increase in the prevalence of higher activities of the urinary enzyme NAG and gamma glutamyl transferase when the urinary Hg concentration exceeded 100 µg g–1 creatinine. Roels et al. (1985) discovered an increased urinary ß-galactosidase activity and an increased urinary excretion of the retinol-binding protein among subjects exposed to Hg vapour mainly when urinary Hg concentrations exceeded 50 µg g–1 creatinine, while no differences were found in the urinary excretion of amino acids, total proteins, albumin and ß2-microglobulin between the exposed subjects and controls. Himeno et al. (1986) measured increased urinary NAG activities in workers exposed to Hg0 in a thermometer factory and Barregard et al. (1988) established a slightly elevated urinary NAG activity among chloralkali workers when urinary Hg concentrations exceeded 35 µg g–1 creatinine, while Ellingsen et al. (1993) found no differences in NAG activity and isoenzymes NAG A and NAG B activity between the exposed workers and the controls.
In the previous studies high Hg retention and accumulation were found post mortem in the kidneys of some ex-miners from the Idrija Mercury Mine even several years after exposure (Kosta et al., 1974; Falnoga et al., 2000).
As the results in the previous studies were contradictory the basic aim of this research was to study the effects of a long-term exposure to Hg0 vapours on renal function in miners in the post-exposure period.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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The study took place in the period of the final shutdown of the Idrija Mercury Mine (from 1999 to 2000) when the miners were no longer exposed to Hg0. The population studied comprised 53 Hg miners, all men, who were employed in the mine from 1959 to 2000 and were still alive in the observed period (1999–2000) and 53 population-based male controls. The study group of miners included 33 active miners who were exposed to Hg0 in the past but not at the time of the study and 20 retired miners who were exposed to Hg0 during their working life period.
All the observed miners were intermittently exposed to Hg0 vapours in the period when the mine was actively operated. For the study, they were selected according to the following criteria: at least 1 year exposure to Hg0; no history of occupational exposure to lead, cadmium or other nephrotoxic substances; no history of renal disease, diabetes mellitus or multisystemic diseases; no evidence of haematuria, pyuria, glycosuria, urinary tract infections or neoplasia in the first 2 years of exposure to Hg0 and no consumption of analgetics or antibiotics 2 weeks prior to the examination. The controls had no history of occupational exposure to Hg, lead or cadmium and came from the places that lie at least 40 km from the Idrija Mercury Mine. There were no known sources of Hg pollution in their environment. Hg0 in the air was also monitored at these places in 2000: there were five available data for air concentrations of Hg0 and the values were negligible (2.1–2.3 ng m–3).
All the subjects were clinically examined to exclude the previously-mentioned diseases. Data on occupational history, current and previous diagnoses, the use of medicaments, smoking and alcohol intake were registered by a questionnaire and controlled at the interview.
Environmental and biological data on the group of miners observed were collected from 1959 to 2000 from workload records, daily reports on Hg0 air measurements, medical records and personal records of biological monitoring.
From 1965 onwards the concentrations of Hg0 in the air were measured daily by UV photometry using two portable instruments—Beckmann Mercury Vapour Meter—K23 before 1989, and later using Mercury Vapour Indicator—MVI Shawcity. The K23 was calibrated in mg m–3 in the range of 0.005–0.100 mg m–3 and 0.003–3.000 mg m–3. Reproducibility was ± 10%. The MVI was calibrated in µg m–3 in the range of 0–2000 µg m–3, reproducibility was ± 5%. From 1975 stationary sampling of pit air was also carried out monthly by the aspiration of air through a KMnO4 solution using battery-operated pumps at the flow rate of 1–2 l min–1. The samples of air were analysed by means of the dithizone method until 1970, and later by means of the Cold Vapour Atomic Absorption Spectrophotometry (CVAAS) (Hatch and Ott, 1968; Horvat, 1989; Liang and Boolm, 1993). The detection limit of Hg was 0.50 pg and the coefficient of variation (CV) amounted to 3% at values >20 pg.
Before 1970, the urine Hg concentrations were analysed with the help of the dithizone method, and later with the help of the CVAAS (Gray, 1952; Hatch and Ott, 1968; Magos and Clarkson, 1972; Horvat, 1989; Liang and Boolm, 1993). Eight hour urine (night–morning) was collected in metal-free polypropylene tubes during the night. The detection limit of Hg was 0.10 µg l–1 and the CV ranged from 5 to 10%, depending on the concentration (Horvat, 1989; Miklavcic, 1999). The Hg concentrations determined in the post-exposure period were corrected for the urinary creatinine concentration.
On the basis of mine exposure records and exposure data, the following environmental indicators of the past exposure to Hg0 were calculated for each miner: the duration of exposure expressed as years of exposure and the number of days of actual Hg exposure, the number of cycles of exposure, the annual time-weighted exposure (ATWE) and the integrated exposure intensity (IEI).
Years of exposure were defined as years when the miners were intermittently exposed to Hg0 and the number of days of Hg exposure was defined as the sum of the days of actual exposure to Hg0. The cycles of exposure were defined as exposure to Hg0 that lasted from 3 to 34 days.
ATWE was calculated yearly for each miner using the following equation:
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t is the entire time of exposure to Hg0 in the respective year expressed in hours.
The IEI was determined for each miner for the whole period of exposure:
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Besides the aforementioned air monitoring during the ore excavation, the air monitoring of Hg0 was conducted regularly (every week) in the mine also at the time of the study.
Biological monitoring of Hg was regularly carried out in all the miners before, during and after each cycle of exposure in the exposure period. The results of biological monitoring from the period of exposure were used to calculate the following cumulative biological indicators of past exposure to Hg0 for each miner: the average urine Hg concentration of the entire period of exposure calculated as the average of mean yearly urine Hg concentrations in the whole period of exposure and the sum of the peak urine Hg in all exposure cycles.
In the post-exposure period biological monitoring was carried out once during the medical check-up of each miner and control.
Quantitative analyses of proteins in urine were performed using a Behring BN II nephelometer (Schotters et al., 1988; Hofmann and Guder, 1989). Precision of nephelometric procedures was as follows: albumin in urine (CV 5.10%), sensitivity limit 8.70 mg l–1; IgG in urine (CV 2.50%), sensitivity limit 3.84 mg l–1; 1-microglobulin in urine (CV 9.40%), sensitivity limit 5.50 mg l–1 (Kobal et al., 2000). The enzymatic activity of NAG in urine was determined by a colorimetric method (Noto et al., 1983; Yakata et al., 1983; Klein and Geibel, 1990). The CV for the method ranged from 2.87 to 5.92% depending on the concentration; the sensitivity limit was 0.01 µcat/l–1.
Creatinine in urine was measured on a Roche/Hitachi 917 automated biochemical analyser.
Renal function was assessed by determining the high-molecular-weight proteins in urine as indicators of glomerular function and low-molecular-weight proteins in urine as indicators of tubular function. Glomerular renal function was determined by a quantitative analysis of albumin (66 460 Da) and IgG (150 000 Da) in urine, while tubular renal function was assessed by the quantitative analysis of 1-microglobulin (from 30 000 to 33 000 Da) in urine and by the determination of the enzymatic activity of NAG and its isoenzymes NAG A and NAG B in urine. The protein concentrations in urine were expressed per gram of creatinine.
The regular statistical methods were used to analyse the exposure data. The correlations between individual variables were calculated using Pearson's correlation coefficient. The differences in the means of different variables between the exposed and non-exposed groups were analysed by the t-test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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The subjects in this study were all males. The average age of the miners was 47 years and that of the controls 45 years. No significant differences in cigarette smoking and alcohol consumption were found between the exposed miners and the unexposed controls.
At the time of the observation, the period since the last exposure, of the 33 active miners was between 0.69 and 28.46 years (average 2.84 years), and that of the retired miners between 2.77 and 28.46 years (average 11.57 years). Their durations of exposure were between 7 and 31 years, and during those periods the exposures were intermittent, with cycles of exposure. The average total duration of exposure to Hg0 was 863 days and the total number of cycles of exposure ranged from 13 to 119. The average ATWE in miners was 0.29 mg m–3 and the mean IEI was 1413 mg m–3-h (Table 1).
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At the time of observation, the concentration of Hg0 in the mine was 0.008 to 45 µg m–3, but none of the miners studied had been exposed to this since they had ceased to work in the mine.
The mean urine Hg concentration for the entire period of exposure in the miners was 68.24 µg l–1 and the average sum of the peak urine Hg concentrations was 3901 µg l–1 (Table 2).
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The average urine Hg concentration at the time of examination was relatively low in both miners and controls and it was 2.12 µg g–1 creatinine in miners and 1.36 µg g–1 creatinine in controls (Table 2). However, a statistically significant difference was found in this parameter in all miners and the controls (t = 3.12, P < 0.01).
High correlations were calculated between some environmental and biological indicators of the past exposure. The sum of the peak urine Hg concentrations correlated significantly with the number of years of exposure (r = 0.80, P 0.01), the number of days of actual Hg exposure (r = 0.70, P 0.01), the number of cycles of exposure (r = 0.88; P 0.01) and IEI (r = 0.67, P 0.01).
The indicators of renal function, albumin, IgG and 1-microglobulin in urine were significantly elevated at the level of P 0.05 in exposed miners compared with the control group (t = 2.17, P = 0.03; t = 2.81, P < 0.01 and t = 2.07, P = 0.04), whereas there were no statistically significant differences in the excretion of NAG (t = 0.97, P = 0.34) and its isoenzyme B (t = 0.58, P = 0.56) in urine. The mean values for indicators of renal function in miners and controls are presented in Table 3.
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Significant correlations were found neither between the indicators of renal function and the environmental indicators of exposure nor between the indicators of renal function and biological indicators of exposure. But when the miners were divided into two groups, i.e. those who still worked but were no longer exposed (n = 33) and those who were already retired (n =20) at the time of observation, a significant correlation was calculated between
1-microglobulin in the urine and the IEI (r = 0.73; P 0.01) as well as between 1-microglobulin in the urine and the sum of peak urine Hg concentrations (r = 0.67; P 0.01) in the group of miners who still worked in the mine. |
DISCUSSION AND CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Besides the central nervous system, the kidneys are one of the main target organs for Hg0, which accumulates in the kidneys especially in the area of the proximal tubuli. The long-term effects of Hg toxicity on the kidneys are not well studied. Most of the studies in this field investigated those subjects who were still exposed to Hg0 at the time of the research (in the period of ongoing exposure to Hg0) (Buchet et al., 1980
; Stonard et al., 1983; Roels et al., 1985; Himeno et al., 1986; Langworth et al., 1992) and only a few studied subjects in the post-exposure period (Barregard et al., 1988; Ellingsen et al., 1993). Some studies demonstrated mainly glomerular dysfunction in some exposed workers (Buchet et al., 1980; Ellingsen et al., 1993), while the others presented mainly slight tubular effects (Stonard et al., 1983; Roels et al., 1985; Himeno et al., 1986; Barregard et al., 1988; Langworth et al., 1992). On the other hand Kobal et al. (2000) suggested glomerular and tubular dysfunction in miners who were exposed to Hg0. The basic aim of the current research was to study the effects of a long-term exposure to Hg0 vapours on renal function in miners in the post-exposure period.
The miners were examined in the period of the final shutdown of the Idrija Mercury Mine when they were no longer exposed to Hg0. On an average, the exposure ceased 6.05 years before the observation.
During their work, the miners of the Idrija Mercury Mine were exposed to relatively high levels of Hg0 in their working environment, which was reflected in the higher Hg concentrations in urine. The average urine Hg concentration of the entire period of exposure in miners exceeded the current biological limit value in Slovenia, i.e. 50 µg l–1 (Regulations governing the safety of workers exposed to chemical substances at work, 2001). On the other hand, the mean urine Hg concentration measured in miners at the time of the study was relatively low and much below the current biological limit value.
Although the active miners worked in a non-exposed environment at the time of the study, the air in their previous job environment was still monitored. The obtained values ranged from 0.008 to 45 µg m–3.
The highest correlation between the environmental and biological indicators of the past exposure was found between the sum of the peak urine Hg concentrations and the number of cycles of exposure. Since a high correlation was also calculated between the sum of the peak urine Hg concentrations and the IEI, we would recommend that if no biological monitoring data exist, the IEI should be used for the assessment of biological exposure as it includes the time of exposure and exposure intensity. There is no other available literature discussing the correlation between cumulative environmental and biological indicators of exposure such as the IEI and peak urine Hg concentration. However, an important correlation between the air and urine Hg concentrations was found in several studies (Mattiussi et al., 1982; Richter et al., 1982; Yoshida, 1985; Nordhagen et al., 1994; Cianciola et al., 1997; Tsuji et al., 2003).
The increased excretion of albumin, IgG and 1-microglobulin in the urine in miners indicates the possibility of moderate glomerular and tubular renal dysfunction in miners no longer exposed to Hg0 if compared with the control group. The results of our study are similar to the results obtained by Buchet et al. (1980) who reported renal dysfunction as evidenced by elevated prevalence of higher concentrations of albumin, transferrin, IgG and ß-galactosidase in the urine of the chloralkali workers, observed at the time of exposure to Hg0. Contrary to the current study, Ellingsen et al. (1993) found no differences in urinary albumin concentrations between the chloralkali workers whose exposure ceased on average 12.3 years before the study and unexposed referents. No differences in the urinary excretion of albumin, ß2-microglobulin or 1-microglobulin in workers still exposed to Hg0 were determined by Roels et al. (1985), Himeno et al. (1986), as well as Langworth et al. (1992).
No significant differences were found in urine NAG and its isoenzyme NAG B activity when comparing the exposed miners and the unexposed workers. The results of our study are in agreement with the results obtained by Ellingsen et al. (1993), who found no differences in urinary concentrations of NAG and isoenzymes NAG A and NAG B among the chloralkali workers previously exposed to Hg vapour and the referents, as well as with the results of Stonard et al. (1983), who observed the workers at the time of exposure to Hg0. On the contrary, Himeno et al. (1986) reported significantly increased urinary NAG activities in exposed workers compared with those of the controls. Based on the results of the current study and the results of the study carried out by Ellingsen et al. (1993), we may indicate that NAG and its isoenzymes could probably not be considered as indicators of renal function in the post-exposure period.
In the group of miners who still worked at the time of observation but were no longer exposed to Hg0, a high correlation was found between 1-microglobulin in urine and the IEI as well as between 1-microglobulin in urine and the sum of peak urine Hg concentrations. This may indicate that a long-term occupational exposure to Hg0 can temporarily cause tubular dysfunction that can also be observed for a certain period after the cessation of exposure. The hypothesis that renal dysfunction might be temporary was also based on the results of the correlations between 1-microglobulin in the urine and the IEI and between 1-microglobulin in the urine and the sum of peak urine Hg concentrations, which were not significant in retired miners. The time since the last exposure to Hg0 was on average significantly longer in the retired miners than in miners who were still active.
In order to prove this hypothesis, the study should be expanded so that the miner's renal function could be observed in different periods after exposure. In this way it would be possible to find out the time needed for the regeneration of kidney function.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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The research was carried out within the framework of the project ‘The Effects of Mercury on Idrija Inhabitants’, which was approved by the Commission for Medical Ethics of the Republic of Slovenia on 30 May 1997. It was headed by Prof Dr Josko Osredkar, Institute of Clinical Chemistry and Biochemistry, University Medical Centre, Ljubljana and coordinated by Dr Alfred B. Kobal, Department of Occupational Medicine, Idrija Health Centre. The laboratory analyses were carried out in the laboratory of the Institute of Clinical Chemistry and Biochemistry, University Medical Centre, Ljubljana, the Idrija Mercury Mine and the Department of Environmental Sciences, Jozef Stefan Institute in Ljubljana.
Received November 23, 2004; in final form March 25, 2005
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