Andrejs Schütz

Low level exposure to cadmium and early kidney damage: the OSCAR study

OBJECTIVES To study the dose-response relation between cadmium dose and renal tubular damage in a population of workers and people environmentally or occupationally exposed to low concentrations of cadmium. METHODS Early kidney damage in 1021 people, occupationally or environmentally exposed to cadmium, was assessed from cadmium in urine to estimate dose, and protein HC (α1-microglobulin) in urine to assess tubular proteinuria. RESULTS There was an age and sex adjusted correlation between cadmium in urine and urinary protein HC. The prevalence of tubular proteinuria ranged from 5% among unexposed people to 50% in the most exposed group. The corresponding prevalence odds ratio was 6.0 (95% confidence interval (95% CI) 1.6 to 22) for the highest exposure group, adjusted for age and sex. Multiple logistic regression analysis showed an increasing prevalence of tubular proteinuria with urinary cadmium as well as with age. After adjustment to the mean age of the study population (53 years), the results show an increased prevalence of 10% tubular proteinuria (taking into account a background prevalence of 5%) at a urinary cadmium concentration of 1.0 nmol/mmol creatinine. CONCLUSION Renal tubular damage due to exposure to cadmium develops at lower levels of cadmium body burden than previously anticipated.

Toxic and essential elements in placentas of Swedish women.

OBJECTIVES To evaluate interactions between toxic and essential elements in the mother-fetus relationship and possible predictors of trace element concentrations in placenta and cord blood. DESIGN AND METHODS A group of 106 Swedish women was investigated for concentrations of cadmium, lead, and several essential elements in placenta as well as cadmium, lead, zinc, and selenium in venous blood collected at gestational week (gw) 36 and umbilical cord blood. Relations between these elements and maternal and childs characteristics were examined. RESULTS The concentrations of cadmium in placenta ranged from 10 to 170 nmol/kg, with the median value (Md) being 46 nmol/kg. Cord blood cadmium (Md of 0.19 nmol/L) was only about 10% of that in maternal blood. Smokers had significantly higher cadmium concentrations in blood (p < 0.001) and placenta (p = 0.001) than non-smokers. The median placental concentration of lead was 26 nmol/kg (range 0-630 nmol/kg). The lead levels in cord blood (Md of 54 nmol/L) were almost the same as in maternal blood. Statistically significant negative associations were found between cord blood lead, on one hand, and childs weight, length, and head circumference, on the other. The placental levels (medians and ranges) of the essential elements (micromol/kg) were 160 (120-280) for zinc, 2.4 (2.0-3.3) for selenium, 15 (10-20) for copper, 0.084 (0.02-0.32) for cobalt, 0.055 (0.03-0.12) for molybdenum, and 1.2 (0. 65-5.1) for manganese, respectively. Several of the essential elements in placenta correlated significantly with each other. Multiparous mothers had significantly lower concentrations of zinc (p = 0.002) and selenium (p = 0.049) in serum as well as zinc (p = 0. 001) and calcium (p = 0.004) in placenta than nulliparous ones. Also, cord blood zinc decreased with parity. CONCLUSIONS The results showed that lead, but not cadmium crossed easily the placental barrier. There were no negative effects of cadmium on the zinc status. Cord blood lead, on the other hand, was a negative predictor of childs birth weight, length and head circumference, indicating that lead might have negative influence on growth in children even at very low exposure levels. There was a depletion of maternal stores of essential elements with increasing parity.

Low-level cadmium exposure and osteoporosis

Osteoporosis is a major cause of morbidity worldwide. A number of risk factors, such as age and gender, are well established. High cadmium exposure causes renal damage and in severe cases also causes osteoporosis and osteomalacia. We have examined whether long‐term low‐level cadmium exposure increases the risk of osteoporosis. Bone mineral density (BMD) in the forearm was measured in 520 men and 544 women, aged 16–81 years, environmentally or occupationally exposed to cadmium, using dual‐energy X‐ray absorptiometry (DXA) technique. Cadmium in urine was used as the dose estimate and protein HC was used as a marker of renal tubular damage. There was a clear dose‐response relation between cadmium dose and the prevalence of tubular proteinuria. Inverse relations were found between cadmium dose, tubular proteinuria, and BMD, particularly apparent in persons over 60 years of age. There was a dose‐response relation between cadmium dose and osteoporosis. The odds ratios (ORs) for men were 2.2 (95% CI, 1.0‐4.8) in the dose group 0.5‐3 nmol Cd/mmol creatinine and 5.3 (2.0‐14) in the highest dose category (≥3 nmol/mmol creatinine) compared with the lowest dose group (<0.5 nmol Cd/mmol creatinine). For women, the OR was 1.8 (0.65‐5.3) in the dose group 0.5‐3 nmol Cd/mmol creatinine. We conclude that exposure to low levels of cadmium is associated with an increased risk of osteoporosis.

Cadmium Exposure in Pregnancy and Lactation in Relation to Iron Status

OBJECTIVES The purpose of this study was to determine the impact of iron status on cadmium dose among pregnant women. METHODS Iron status and cadmium concentration in blood, urine, and placenta were determined among women followed for 2 years from early pregnancy. RESULTS Blood cadmium and urinary cadmium were correlated with iron status throughout the study period. Urinary cadmium increased longitudinally among women with exhausted iron stores during their pregnancy. The increase in urinary cadmium with age was more pronounced in multiparous than in nulliparous women. CONCLUSIONS Iron deficiency during pregnancy leads to increased cadmium absorption and body burden. Multiparous women exhibit additional increases with increasing age.

Total and Inorganic Mercury in Breast Milk and Blood in Relation to Fish Consumption and Amalgam Fillings in Lactating Women

Total mercury concentrations (mean +/- standard deviation) in breast milk, blood, and hair samples collected 6 wk after delivery from 30 women who lived in the north of Sweden were 0.6 +/- 0.4 ng/g (3.0 +/- 2.0 nmol/kg), 2.3 +/- 1.0 ng/g (11.5 +/- 5.0 nmol/kg), and 0.28 +/- 0.16 microg/g (1.40 +/- 0.80 micromol/kg), respectively. In milk, an average of 51% of total mercury was in the form of inorganic mercury, whereas in blood an average of only 26% was present in the inorganic form. Total and inorganic mercury levels in blood (r = .55, p = .003; and r = .46, p = .01 6; respectively) and milk (r = .47, p = .01; and r = .45, p = .018; respectively) were correlated with the number of amalgam fillings. The concentrations of total mercury and organic mercury (calculated by subtraction of inorganic mercury from total mercury) in blood (r = .59, p = .0006, and r = .56, p = .001; respectively) and total mercury in hair (r = .52, p = .006) were correlated with the estimated recent exposure to methylmercury via intake of fish. There was no significant between the milk levels of mercury in any chemical form and the estimated methylmercury intake. A significant correlation was found between levels of total mercury in blood and in milk (r = .66, p = .0001), with milk levels being an average of 27% of the blood levels. There was an association between inorganic mercury in blood and milk (r = .96, p < .0001); the average level of inorganic mercury in milk was 55% of the level of inorganic mercury in blood. No significant correlations were found between the levels of any form of mercury in milk and the levels of organic mercury in blood. The results indicated that there was an efficient transfer of inorganic mercury from blood to milk and that, in this population, mercury from amalgam fillings was the main source of mercury in milk. Exposure of the infant to mercury from breast milk was calculated to range up to 0.3 microg/kg x d, of which approximately one-half was inorganic mercury. This exposure, however, corresponds to approximately one-half the tolerable daily intake for adults recommended by the World Health Organization. We concluded that efforts should be made to decrease mercury burden in fertile women.

Inductively Coupled Plasma Mass Spectrometry for Direct Multi-element Analysis of Diluted Human Blood and Serum

A method for the inductively coupled plasma mass spectrometry (ICP-MS) multi-element analysis of diluted human blood and serum was used for the following elements: Co, Ni, Cu, Zn, Ga, Se, Rb, Mo, Rh, Pd, Cd, Sn, Sb, W, Pt, Hg, Tl and Pb. Sample pretreatment was a simple dilution (ten times for blood and five times for serum) with a solution containing 5 g l -1 of 25% ammonia, 0.5 g l -1 Triton X-100, and 0.5 g l -1 EDTA in Millipore water. In and Sc were used as internal standards. For sample introduction a flow-injection-type technique (based on time instead of volume) was used. The determinations were carried out first in a peak-jumping mode for selected masses, and then in a scanning mode. Each determination of a preparation took 75 s. The results for reference samples agreed with recommended or certified values for Co, Cu, Zn, Rb, Cd, Tl and Pb in blood, and for Rb, Mo and Cd in serum. For Ni and Hg in blood, and Cu and Zn in serum, the results agreed with one of two reference samples. The detection limits for all these elements (except for Tl) were sufficient for analysis of samples from the general population. On the other hand, the results for Se in blood, and for Co, Ni, Se, Sn and Hg in serum did not agree with recommended or certified values. No reference samples are available for Ga, Mo, Rh, Pd, Sn, Sb, W, or Pt in blood, or for Ga, Rh, Pd, W, Pt, or Pb in serum. Generally, the limits of detection for the elements in the latter group (below 0.15 µg l -1 ) are close to or above the levels present in the general population.

Fish as a source of exposure to mercury and selenium

In a total of 395 subjects with varying fish consumption habits, mercury levels in whole blood (B-Hg), and selenium levels in plasma (P-Se) were studied. Also, in subcohorts, mercury levels in blood cells (Ery-Hg; n = 79), plasma (P-Hg; n = 158) and urine (U-Hg; n = 125) were analysed. There were statistically significant associations between fish intake on the one hand, and B-Hg, Ery-Hg and P-Hg, on the other, but not so with U-Hg. In subjects who never had fish, the average B-Hg was 1.8 ng/g, in subjects who had at least two fish meals each week, 6.7 ng/g. Ery-Hg, and to a less extent P-Hg, were associated with levels of marine n-3 polyunsaturated fatty acids (PUFA) in serum phosphatidylcholine. P-Hg and U-Hg were associated with numbers of teeth with amalgam fillings. P-Se also correlated with fish intake. In subjects who never had fish, P-Se averaged 80 micrograms/l, in subjects who had at least two fish meals per week, 91 micrograms/l. There was an association between PUFA and P-Se. Further, there were statistically significant associations between P-Se on the one hand, and B-Hg, Ery-Hg and P-Hg on the other. The data clearly demonstrate the importance of fish for the exposure to methylmercury and selenium in the Swedish diet, and the impact of amalgam as a source of exposure to inorganic mercury.

Measurement by ICP-MS of lead in plasma and whole blood of lead workers and controls.

OBJECTIVES: To test a simple procedure for preparing samples for measurement of lead in blood plasma (P-Pb) and whole blood (B-Pb) by inductively coupled plasma mass spectrometry (ICP-MS), to measure P-Pb and B-Pb in lead workers and controls, and to evaluate any differences in the relation between B-Pb and P-Pb between people. METHODS: P-Pb and B-Pb were measured by ICP-MS in 43 male lead smelter workers and seven controls without occupational exposure to lead. For analysis, plasma and whole blood were diluted 1 in 4 and 1 in 9, respectively, with a diluted ammonia solution containing Triton-X 100 and EDTA. The samples were handled under routine laboratory conditions, without clean room facilities. RESULTS: P-Pb was measured with good precision (CV = 5%) even at concentrations present in the controls. Freeze storage of the samples had no effect on the results. The detection limit was 0.015 microgram/l. The P-Pb was 0.15 (range 0.1-0.3) microgram/l in controls and 1.2 (0.3-3.6) micrograms/l in lead workers, although the corresponding B-Pbs were 40 (24-59) micrograms/l and 281 (60-530) micrograms/l (1 microgram Pb/I = 4.8 nmol/l). B-Pb was closely associated with P-Pb (r = 0.90). The association was evidently non-linear; the ratio B-Pb/P-Pb decreased with increasing P-Pb. CONCLUSIONS: By means of ICP-MS and a simple dilution procedure, P-Pb may be measured accurately and with good precision down to concentrations present in controls. Contamination of blood at sampling and analysis is no major problem. With increasing P-Pb, the percentage of lead in plasma increases. In studies of lead toxicity, P-Pb should be considered as a complement to current indicators of lead exposure and risk.

Parameters of immunological competence in subjects with high consumption of fish contaminated with persistent organochlorine compounds

SummaryConsumption of fatty fish species, like salmon and herring, from the Baltic Sea is an important source of human exposure to persistent organochlorine compounds, e.g. polychlorinated dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs). Many of these compounds show immunotoxic and hepatotoxic effects in animals. We have now studied immunological competence, including lymphocyte subsets, in 23 males with a high consumption of fish from the Baltic Sea and in a control group of 20 males with virtually no fish consumption. The high consumers had lower proportions and numbers of natural killer (NK) cells, identified by the CD 56 marker, in peripheral blood than the non-consumers. Weekly intake of fatty fish correlated negatively with proportions of NK cells (rs = −0.32, P = 0.04). There were also, in a sub-sample of 11 subjects, significant negative correlations between numbers of NK cells and blood levels of a toxic non-ortho-PCB congener (IUPAC 126; rs = −0.68, P = 0.02) and a mono-ortho congener (IUPAC 118; rs = −.76, P = 0.01). A similar correlation, in 12 subjects, was seen for p,p′-DDT (rs = −0.76, P = 0.01). The corresponding negative correlation, in 13 subjects, with blood levels of PCDD/Fs was not significant (rs = −0.57, P = 0.07). No significant association was seen between organic mercury in erythrocytes and NK cells. Fish consumption was not associated with levels of any other lymphocyte subset. Neither were there any correlations with plasma immunoglobulins or liver enzyme activities. Our study indicates that accumulation of persistent organochlorine compounds in high consumers of fatty fish may adversely affect NK cell levels.

Long-term Use of Nicotine Chewing Gum and Mercury Exposure from Dental Amalgam Fillings

In experimental studies, chewing gum has been shown to increase the release rate of mercury vapor from dental amalgam fillings. The aim of the present study was to investigate the influence of long-term frequent chewing on mercury levels in plasma and urine. Mercury levels in plasma (P-Hg) and urine (U-Hg), and urinary cotinine were examined in 18 subjects who regularly used nicotine chewing gum, and in 19 referents. Age and number of amalgam surfaces were similar in the two groups. Total mercury concentrations in plasma and urine were determined by means of cold vapor atomic absorption spectrometry. Urinary cotinine was determined by gas chromatography-mass spectrometry. The chewers had been using 10 (median) pieces of gum per day for the past 27 (median) months. P-Hg and U-Hg levels were significantly higher in the chewers (27 nmol/L and 6.5 nmol/mmol creatinine) than in the referents (4.9 nmol/L and 1.2 nmol/mmol creatinine). In both groups, significant correlations were found between P-Hg or U-Hg on the one hand and the number of amalgam surfaces on the other. In the chewers, no correlations were found between P-Hg or U-Hg and chewing time per day or cotinine in urine. Cotinine in urine increased with the number of pieces of chewing gum used. The impact of excessive chewing on mercury levels was considerable.