Lead in Tissues of Deseased Lead Smelter Workers

J. Trace Elements Med. BioI. Vol. 9, pp. 136-143 (1995)

Lead in Tissues of Deseased Lead Smelter Workers L. GERHARDSSON*·l , V. ENGLYST** , N.-G. LUNDSTROM, G. NORDBERG, S. SANDBERG AND F. STEINVALL Department of Environmental Medicine, University of Umea, S-901 87 Umea, Sweden *Department of Occupational and Environmental Medicine, University Hospital, S-221 85 Lund, Sweden **The Company Health Service Center, Boliden Meditek, S-932 81 Skelleftehamn, Sweden (Received November 94/May 95)

Summary

Smelter workers are exposed to a number of metals and other substances in dust, fumes and gases. The concentrations of lead in liver, lung, kidney, brain, hair and nails were determined in 32 deceased, long-term exposed male lead smelter workers, and compared with those of 10 male controls. The lead levels in liver, lung, kidney and brain were analyzed by atomic absorption spectrophotometry. X-ray fluorescence was used for the determinations in hair and nails. Lead in blood had been determined repeatedly in the lead workers since 1950, which made it possible to calculate a time-integrated blood lead index for each worker. The highest lead levels in soft tissues were found in liver, followed in order of concentration by kidney, lung and brain, among both exposed workers and controls. These organ lead concentrations were all significantly higher among the workers as compared with the control group (p::; 0.02). The largest difference between workers and controls was found in brain tissue (ratio between median values = 5.6). The lead levels in hair and nails were of the same magnitude in the two groups. The workers- showed positive correlations between lead concentrations in liver and kidney (Spearman's rho = r,=0.59; p < 0.001), liver and hair (r,=0.51; p = 0.003), liver and nails (r =0.52; p = 0.002) and hair and nails (r,=0.52; p=0.002). Lead concentrations in kidney correlated well with lead levels in hair (r,=0.57; p = 0.001) and nails (r5=0.51; p = 0.003), respectively. The positive correlation between the lead concentrations in liver and kidney indicates that these organs belong to the same soft tissue lead pool in the body. In retired lead workers, positive correlations were observed between the lead concentrations in liver and the cumulative blood lead index (CBU) (r,=0.50; p = 0.016), as well as between lead levels in kidney and CBU (r,=0.51; p = 0.014). 5

Keywords: Smelter workers, lead, soft tissues, hair, nails, biological monitoring. Introduction

The smelter The production at the Ronnskar copper and lead smelter started in 1930. The plant now integrates smelter and refining processes for ores and other raw materials, such as concentrates. and scrap. Copper and lead are the main products. Other metals, such as silver, gold, platiReprint requests to: Dr. Lars Gerhardsson, Department of Occupational and Environmental Medicine, University Hospital, S221 85 Lund, Sweden. © 1995 by Gustav Fischer Verlag Stuttgart· Jena . New York

num, and palladium are extracted as by-products, as well as selenium and nickel. Other important by-products are arsenic, zinc and sulphuric acid. The processes have previously been described in detail (l,2). About 70 % of the airborne particles in the lead refinery was respirable. The proportion of respirable dust was higher for workers dealing directly with smeltingmaterials, and lower for workers handling crushed raw materials. The working force has varied between 2000 and 3000 workers for many years, but is now down to about 1000 workers. The turnover has been low, and an employment time of 30 - 40 years is not uncommon.

Lead in tissues of deseased lead smelter workers

Metabolism

At occupational exposure, the main intake of lead is through inhalation. At a particle size of 0.05 !lm and a respiratory rate of 15 inhalations/min, about 40 % of the inhaled lead is deposited in the airways. At a particle size of 0.5 !lm, the deposition is lower, amounting to about 20 % (3).

About 10 % of ingested lead is absorbed in the gastrointestinal tract. This fraction may be higher in infants and children, during fasting and in certain nutritional deficiencies (4). Absorbed lead is mainly accumulated in the skeleton, which contains more than 90 % of the lead body burden (5). The biological half-time is long, in cortical (compact) bone about 10 years, compared to a couple of years in trabecular bone (6, 7). The biological halftime in blood and in the soft tissue compartments of man is approximately 3-4 weeks (8). Absorbed lead is excreted from the body mainly through the urine and the feces. The excretion into urine is mainly through glomerular filtration, as indicated by experimental animal studies (9). Small amounts are excreted in sweat, hair and nails (3). Health effects

The exposure at the smelter may have both acute and long-term adverse health effects. Inorganic lead may e.g. affect the hematopoietic system, the nervous system, the kidneys, the gastrointestinal tract, the reproductive system and the cardiovascular system (3). The delayed effects are usually studied up to retirement. Too little is known about adverse effects that may develop or aggravate after retirement (l). In this study, lead concentrations in soft tissues, hair and nails of 10ng-telID exposed lead smelter workers have been compared with those of non-occupationally exposed referents. The tissue lead concentrations have been related to different exposure parameters, e.g. employment time and time integrated blood lead, and also to levels in hair and nails, as these organs are readily available for biological monitoring.

Materials and Methods

Tissue sampling

Tissue samples of liver, lung, kidney, brain, hair and nails were collected from 32 deceased male lead smelter workers (9 active, 23 retired) and 10 deceased male reference individuals. The referents were from a rural area some 50 km from the smelter (Burtdisk and 10m) and

137

from the city of Skelleftea, about 17 km from the smelter. The material was collected, irrespective of diagnoses, from 1976 to 1987 by one and the same technician at the county hospital of Skelleftea. Since 1950, blood lead determinations have been performed repeatedly in lead workers, which made it possible to calculate a time-integrated blood lead index for each worker. In connection with routine autopsies, samples of about 50 - 100 g wet weight were taken from soft tissues with ordinary autopsy instruments, as well as small specimens of hair and nails. Liver samples were taken about 1 cm below the diaphragmatic surface of the right liver lobe. Lung specimens were taken from the lower part of the right upper lung lobe, and kidney samples from the cortex of the upper part of the right kidney. Brain samples were collected from the right occipital brain lobe, hair from the back of the head and nail specimens from the left hallux (distal half). All samples were stored in acid-washed polyethene vessels at -20°C at the department of Environmental Medicine in Umea. Job classification and smoking habits

Extensive employment information was provided by the company. Data about smoking habits were obtained by questionnaires answered by relatives of the deceased subjects, supplemented by telephone interviews.

Analytical methods

Atomic absorption spectrophotometry: the concentrations of lead in liver, lung, kidney and brain were determined by atomic absorption spectrophotometry with graphite furnace (AAS-GFA; Varian AA 875 with graphite furnace GTA 95) at the department of Environmental Medicine, University of Umea. Samples of about 1-2 g wet weight from liver, kidney, lung and brain were taken with quartz instruments, transferred to a quartz vessel and dried over-night at a temperature of 110°C. During an ashing step, the temperature was gradually increased up to 450°C during 8 hours, where it remained stable for another 10 hours. Thereafter, 5 ml 1M HN03 was added, and the samples were left to solubilize overnight at room temperature. The solution was manually rotated with an acid-washed glass rod. All instruments and vessels used were acid-washed. The final solution was transferred to acid washed tubes before the analysis. Samples with high lead concentrations were further diluted by addition of 0.5 M HN03 • Sample solutions were analyzed in duplicate using stand-

138

L. Gerhardsson, V. Englyst, N.-G . Lundstrom, G. Nordberg, S. Sandberg and F. Steinvall

ard addition technique. Based on ten readings for both a blank solution and 10 llg/L of lead standard, the detection limit was 0.6 llg!L of Pb in the solution. For tissues, this figure corresponds to a detection limit lower than 2 llg!kg tissue (wet weight). Accuracy of tissue determinations: reference samples (NIST SRM 1577a Bovine liver; National Institute of Standards and Technology, Gaithersburg, MD) were run in parallel with the tissue determinations of lead in lung, liver, kidney and brain. The results consistently showed good agreement with the expected concentrations (all analyses::; + 15 %; 50 % of quality control runs::; + 10 %). X-ray fluorescence: lead concentrations in hair and nails were determined by energy-dispersive X-ray fluorescence (EDXRF) at Scandlab, Stockholm, using a Kevex Ultra Trace 0600 System (10). The system includes a Si(Li)-detector and a silver X-ray tube. For these analysis a high voltage of 35 kV was applied. The anode current was adjusted to 30-40 mA, giving a dead time of 5 %. The counting time was set to 1500 seconds, and all measurements were performed in a vacuum. Hair as well as nails were carefully washed in acetone-ultra pure water (1 :5) before the analysis. Then five to six hair strands were placed between two Formvar films connected to two slide frames, which were placed together, stabilizing the hair strands between the frames. From the nail samples, thin, long-stretched specimens were cut with a sharp quartz knife and placed between two Formvar films in a similar way. Approximately 1 cm of the hair strands and the nail specimens were irradiated during the analysis. In order to get a calibration matrix, premeasured hair and nail specimens were carefully weighted and digested in ultra-pure nitric acid (Merck). The acid solution was spiked with standard concentrations of lead followed by a drying step on a hot plate. The residue was solubilized in ammonia water (4 %) and put drop-wise onto Formvar and evaporated. The count rate for each standard element was related to the Compton scatter in the energy region of 18 - 20 ke V. This ratio was plotted versus standard concentrations which were related to the dry weight of the specimens. The calibration matrix obtained was stored in a computer system and used for the calculation of metal concentrations. The precision of the measurements was about 3.5 % and the minimum detection limit approximately 0.5 llg/g of Pb dry weight. Accuracy of hair analyses: the accuracy of the determinations of lead in hair by X-ray fluorescence was validated by AAS at the company's Research laboratory. The difference between the methods was less than 34 % (60

% of measurements ::;15 % difference; 100 % < 34 % difference) for measurements at different lead levels, covering a range from the detection limit up to about 80 mg!kg of Pb dry weight. This test-interval includes about 95 % of the studied workers. Although mainly the surface layer of hair strands is analyzed by EDXRF, the results obtained by this technique agreed reasonably well with those obtained by AAS.

Blood lead analysis: the lead register at the company is based on data from the biological and environmental monitoring programs. The lead workers at the smelter have been regularly monitored by blood lead measurements since 1950. During the period January 1950 to December 1987, 81081 blood lead determinations were made in samples from 7714 workers. Some of the workers have left nearly 300 blood lead samples during their employment in the lead department. These unique blood lead records have been used to calculate a time-integrated blood lead index for each lead smelter worker from 1950 onwards. This cumulative blood lead dose was expressed as a summation of the annual mean blood lead values for each worker. The cumulative blood lead index (CBLI; llmol!L) gives a more realistic estimation of the previous lead exposure than the exposure-time (employmenttime) (11). Emission spectrometry was used for the blood lead analyses during the period 1950 - 1969. This method was replaced by AAS in 1967 (12). The two methods were used in parallel during 1967 - 1969. The analyses performed by AAS showed a narrower standard deviation and somewhat lower blood lead values as compared with emission spectrometry (difference between methods < 10 %) (1). Quality control of blood lead: the quality control program during the 1950's and 1960's included an exchange of blood lead samples with laboratories in West Germany and the United Kingdom (13, 14). Since the 1970's, the company's Researchlaboratory has participated in a national quality control programme originating from the National Board of Occupational Health and Safety, Stockholm (15, 16). The results of the quality control programme have consistently been in good agreement with expected concentrations, as previously reported (1).

Statistics Earlier studies have shown that levels of trace elements in tissues do not usually follow a normal distribution (positive skewness; 1). Accordingly, non-parametric statistical processing was applied, e.g. Kruskal-Wallis one-way analysis of variance, Mann-Whitney's U-test,

Lead in tissues of deseased lead smelter workers

and Spearman rank-order correlation coefficients. A difference between the studied groups (Kruskal-Wallis p < 0.05) was evaluated further with Mann-Whitney's U-test (pairwise comparisons). p-values less than 0.05 (twotailed tests) were considered statistically significant. Student's t-test was used for the comparison of age, exposure-time and length of retirement. All analyses were performed with SPSS/pC+ software (Statistical Package for the Social Sciences), version 4.0.

Results

Age, time of exposure and length of retirement Mean values for the age of smelter workers and referents, and mean values for time of exposure and duration of retirement of the workers are presented in Table I. As shown in the table, the age was of the same magnitude for exposed workers and controls.

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Table I. Mean values (± SD) for age, exposure time and length of retirement among smelter workers and controls. N = number of individuals. N

Mean age (a)

Groups All workers All controls

32 10

67.4 ± 9.5 70.6 ± 8.7

Exposure time (a)

Period of retirement (a)

31.4 ± 8.7

6.4 ± 5.4

trois. The largest difference between workers and referents was thus found in brain tissue. The lead levels in hair and nails did not differ significantly between workers and referents. Lead levels in the studied organs were of the same magnitude (Kruskal Wallis one-way analysis of variance) when the workers were subdivided into smokers, exsmokers and non-smokers. The extremely high lead value in hair in one of the workers, who died at the plant (2925 mg/kg) is probably due to a direct lead contamination at his work-site.

Causes of death CorrelatiolZ coefficients . The main cause of death among the smelter workers was cardiovascular diseases (53 %), followed by malignancies (34 %). Of the controls about 70 % died from cardiovascular diseases. Tissue concentrations Median values and ranges of lead cOllcentrations in liver, lung, kidney, brain, hair and nails in smelter workers and controls are presented in Table 2. The lead concentrations in brain (median value 5.6 times higher than in the control group; p < 0.001, Mann-Whitney), liver (ratio 3.7; p < 0.001), lung (ratio 2.5, p < 0.001) and kidney (ratio 2.2; p = 0.02) were all significantly higher among the exposed workers (N=32) as compared with the con-

Among all smelter workers (N=32), strong positive correlations were found between lead concentrations in liver and kidney (Spealman's rho = rs=0.59; p < 0.001, Figure 1), liver and hair (rs=0.51; p = 0.003), liver and nails (rs=0.52; p = 0.002) and hair and nails (rs =0.52; p = 0.002). Lead concentrations in kidney correlated well with both lead levels in hair (rs=0.57; p = 0.001) and nails (rs=0.51; p = 0.003). In retired lead workers (N=23), positive correlations were observed between lead concentrations in liver and cumulative blood lead index (CBLI) (rs=0.50; p = 0.016; Figure 2), as well as between lead levels in kidney and CBLI (rs=0.51; p = 0.014). Positive correlations were also observed between lead levels in liver and kidney (r,=0.54; p=0.008), and brain and liver

Table 2. Median values and ranges (within brackets) of lead concentrations in liver. lung, kidney. brain, hair, nails and CBU in smelter workers and controls. Concentrations of CBU in /-lmol/L. Concentrations in hair and nails in /-lg/kg dry weight. All other values in /-lg/kg wet weight. N = number of subjects. Group

N

Liver

Lung

Kidney

Brain

Hair

Nails

CBU

All workers

32

520 (40-2580)

150 (60-1930)

275 (60-1040)

50 (10-990)

3100 (600-2925000)

1200 (200-59600)

66.3 (19.3-105.0)

Active workers

9

770 (350-2580)

290 (120-830)

390 (240-1040)

70 (20-280)

8000 (1500-2925000)

11900 (1400-59600)

61.1 (19.3-75.5)

Retired workers

23

490 (40-2010)

130 (60-1930)

210 (60-590)

50 (10-990)

2600 (600-9300)

600 (200-3400)

80.5 (26.8-105.0)

Referents

10

140 (90-610)

60 (20-110)

125 (30-410)

8.5 (3-60)

2050 (300-96000)

1050 (300-5000)

L. Gerhardsson, V. EngJyst, N.-G. Lundstrom, G. Nordberg, S. Sandberg and F. Steinvall

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Discussion

Reference values Multiple and lin ear regression analysis Published reports on reference values of lead in soft No significant associations of clinical interest were tissues, hair and nails vary. The observed lead concentrafound between the variables lead conq:ntrations in liver, tions in hair and nail s in the control group are of the same lung, kidney, brain, hair and nails on the one hand, and the variables cumulative blood lead index, age, period of retirement and exposure time on the other, when a mu ltiple regression analysis was performed among all lead workers. The corresponding organ concentrations showed no 'b 0 significant relations to the variable age in the control :t group. ?L A linear regression analysis was also undertaken in ..... smelter workers who died in service (period in retirement :J>, = 0 years; N=9). No significant associations were ob- -:l .:Lserved between organ concentrations of lead in liver, 0 .lung, kidney, brain, hair and nails on the one hand, and previous lead exposure expressed as cumulative blood lead index on the other. However, after logarithmic trans- Z; formation to get a better model fit, lead concentrations in kidney and CBLl were strongly related in retired workers (N=23; Figure 3) wi!h the following regression equation: Kidney Pb =0.01 x CBLl + 4.6 (multiple r =0.43; P =0.04) 120 100 Variable 95% CI of B { .,atile blood lead inde\ (/lmol L) 4.9 X 10.4 - 0.02 CBLl Figure 3. Relationship between lead concentrations in kidney (Iog3.8 - 5.3 Constant transformed) and cumulative blood lead index for 23 retired lead

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smelter workers.

Lead in tissues of deseased lead smelter workers

magnitude as reported levels from different reference populations (17, 18, 19, 20, 21). The lead levels in liver, lung, kidney and brain among the referents are in agreement with, or somewhat lower than, reported values in occupationally unexposed subjects (17,18, 22). Lead distribution After absorption in the lungs and the gastrointestinal tract, lead is transported by plasma and erythrocytes, and distributed to different organs. Among the soft tissues, the highest accumulation has been observed in liver and kidney (23, 24), which is in agreement with our present and previous (22) studies of deceased smelter workers. Lead can, to some extent, pass the blood brain barrier (5, 24). Results from animal experiments indicate that there is no constant relationship between lead concentrations in blood and soft tissues. The levels in liver and kidney seem to be higher than in blood, while they are lower in the central nervous system (brain) (3). These findings are in agreement with the data presented for both workers and controls in this study. As shown in Table 2, the highest lead accumulation among all workers and controls was noted in liver, followed in order by kidney, lung and brain. However, the lead uptake in brain is not insignificant. The ratio between the median lead concentrations of all workers vs controls was the highest in brain (5.6), which could be compared with a quotient of 3.7 in liver and 2.5 in lung. Reports from animal experiments indicate that the lead uptake into the nervous system is probably higher in children than in adults (3). Biological monitoring In humans, the excretion of lead is mainly through the urine and feces. At low exposures, excretion in feces is about half that in urine, and at higher levels probably relatively smaller. A non-linear relationship between the urinary excretion and the blood lead levels has been reported (3, 8). Lead is also to a limited extent excreted in sweat, hair and nails (3). The latter observation is in agreement with the results in our study, showing lead concentrations in hair and nails of the same magnitude, when comparing workers and controls. No significant association was found between the lead levels in these organs and the previous lead exposure at the plant expressed as cumulative blood lead index. The results indicate that hair and nails a)"e less suitable as exposure indicators for biological monitoring of lead-exposed individuals. However, several studies have shown an association between lead levels in blood and hair (25,26). Longitudinal analysis of hair strands have been used to calculate a

141

time-integrated exposure index, as hair grows at an average rate of approximately 1 cm per month. Thus, scalp hair has been used for biological monitoring, as it reflects lead concentrations in the blood at the time of hair fornlation (3, 26). The interpretation of such data is complicated, as there are both interindividual and intraindividual differences in hair lead levels, related partly to gender and hair colour (27). There can even be differences in hair lead concentrations of an individual, between hairs obtained from the same region of the scalp (3) . Furthermore, there is always a risk of external contamination (26). This is exemplified by the extremely high lead concentration in hair (2925 mg/kg) in one of the workers in our study, who died while working at the plant. One way to overcome the problem of external contamination is to wash the hair prior to analysis. However, washing of hair of exposed subjects before sampling and analysis may cause loss of endogenous lead (28). The risk is higher in the case of subjects with long hair that has been washed many times. Thus, frequent hair washing may lead to a spuriously low index of the body burden at the time of hair formation (3). Due to these difficulties, biological monitoring of lead in hair has only been minimally used. Metabolic model From a theoretical point of view it may be assumed that the metabolism of lead involves a large number of different compartments with varying levels of lead and different kinetics (3). Assuming a five-compartment model, the small lead-pool in plasma is in contact with at least four other lead pools, namely red blood cells, soft tissues (e.g. liver and kidney), trabecular (spongy) bone and cortical (compact) bone (29). If this model is accepted, it is easier to understand the strong positive cOlTelation that was observed between lead levels in liver and kidney among smelter workers and controls in our investigation. Similar results have been reported by Oldereid et al (30) in a study of 41 men who had died suddenly. Previous lead exposure A commonly used exposure estimate is the employment. time. However, this estimate has several drawbacks. The intensity of the exposure could have changed considerably during the follow-up period. Furthermore, the individual lead uptake varies between different individuals with the same airborne lead exposure, due to individual-dependent factors, such as different absorption and elimination patterns (31). Also, hygienic factors, such as snuff-taking, smoking habits, and routines for

142

L. Gerhardsson, V. Englyst, N,-G, Lundstrom, G. Nordberg, S. Sandberg and F. Steinvall

washing of the hands, as well as the nature of work (heavy or light) will influence the individual lead uptake. As previously reported (6, 11,31), the CBLI is a more accurate way of descIibing the earlier individual lead exposure among exposed workers than the time of employment. Lead in blood is known to be a good indicator of the internal lead dose. It reflects the total recent intake, and shows a good correlation with biological effects in cIitical organs such as bone marrow, nervous system and kidneys (4). Consequently, long-term monitoring of lead in blood forms a good basis for dose-response evaluation, and is also better than compaIisons with environmental air lead concentrations based on time and place. A third way of estimating the previous lead exposure is the determination in vivo of the lead concentration in bone, e.g. in mainly cortical bone, such as finger-bone and tibia (7, 11). Regression and correlation analysis Multiple and linear regression analysis showed no significant associations of clinical interest between the studied lead organ concentrations in all lead workers on the one hand, and the variables CBLI, age, exposure time, and length of retirement, on the other. In retired lead workers, however, there was a positive correlation between lead concentrations in kidney and CBLI. No variables contributed significantly in the model when the regression of lead in liver and CBLI was evaluated. The correlations between lead levels in liver and kidney on the one hand, and employment time on the other, were not significant (p == 0.08 and p == 0.1 I, respectively) in this group. As shown in Table 2, the lead concentrations in hair and nails were of the same magnitude when comparing lead workers and controls. The biological half-time of lead in blood, and in soft tissues such as liver and kidney, is about one month (8). Previous studies have shown a weak correlation between blood lead concentrations and employment time in active lead workers (8). Weak correlations have also been observed between blood and bone lead levels among active lead workers. On the other hand, the correlation between blood and bone lead concentrations was strong among retired lead workers (6, 8, 11,32). This was explained by the fact that in active lead workers, the ongoing absorption via the lungs and the gastrointestinal tract has a dominant impact on lead in blood. In retired lead workers,.however, the endogenous exposure from the skeletal pool wiIl have the strongest impact on the blood lead concentration. Our findings are, thus, in agreement with these earlier reported data. Because the bone lead concentration shows a strong correlation to CBLI (6,11), it is possible to use the bone lead level as a

cumulative dose estimate. Accordingly, lead concentrations in the soft tissue pool, e.g. in liver and kidney, may show a positive correlation to CBLI, as was found in the retired lead workers in this study. However, the statistical analyses are hampered by the limited population size (32 smelter workers) and the difficulties in further subdividing the material into subgroups.

Acknowledgements

Financial support was given by the Swedish Work Environment Fund, Project No. 88-0399. Valuable comments have been given by statistician Roland Perfekt. Valuable help with the figures has been given by Mr Mikael Adamsson.

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