Thomas Lundh

Tubular and glomerular kidney effects in Swedish women with low environmental cadmium exposure

Cadmium is a well-known nephrotoxic agent in food and tobacco, but the exposure level that is critical for kidney effects in the general population is not defined. Within a population-based women’s health survey in southern Sweden (Women’s Health in the Lund Area, WHILA), we investigated cadmium exposure in relation to tubular and glomerular function, from 1999 through early 2000 in 820 women (71% participation rate) 53–64 years of age. Multiple linear regression showed cadmium in blood (median, 0.38 μg/L) and urine (0.52 μg/L; density adjusted = 0.67 μg/g creatinine) to be significantly associated with effects on renal tubules (as indicated by increased levels of human complex-forming protein and N-acetyl-β-d-glucosaminidase in urine), after adjusting for age, body mass index, blood lead, diabetes, hypertension, and regular use of nephrotoxic drugs. The associations remained significant even at the low exposure in women who had never smoked. We also found associations with markers of glomerular effects: glomerular filtration rate and creatinine clearance. Significant effects were seen already at a mean urinary cadmium level of 0.6 μg/L (0.8 μg/g creatinine). Cadmium potentiated diabetes-induced effects on kidney. In conclusion, tubular renal effects occurred at lower cadmium levels than previously demonstrated, and more important, glomerular effects were also observed. Although the effects were small, they may represent early signs of adverse effects, affecting large segments of the population. Subjects with diabetes seem to be at increased risk.

Cadmium-induced effects on bone in a population-based study of women

High cadmium exposure is known to cause bone damage, but the association between low-level cadmium exposure and osteoporosis remains to be clarified. Using a population-based women’s health survey in southern Sweden [Women’s Health in the Lund Area (WHILA)] with no known historical cadmium contamination, we investigated cadmium-related effects on bone in 820 women (53–64 years of age). We measured cadmium in blood and urine and lead in blood, an array of markers of bone metabolism, and forearm bone mineral density (BMD). Associations were evaluated in multiple linear regression analysis including information on the possible confounders or effect modifiers: weight, menopausal status, use of hormone replacement therapy, age at menarche, alcohol consumption, smoking history, and physical activity. Median urinary cadmium was 0.52 μg/L adjusted to density (0.67 μg/g creatinine). After multivariate adjustment, BMD, parathyroid hormone, and urinary deoxypyridinoline (U-DPD) were adversely associated with concentrations of urinary cadmium (p < 0.05) in all subjects. These associations persisted in the group of never-smokers, which had the lowest cadmium exposure (mainly dietary). For U-DPD, there was a significant interaction between cadmium and menopause (p = 0.022). Our results suggest negative effects of low-level cadmium exposure on bone, possibly exerted via increased bone resorption, which seemed to be intensified after menopause. Based on the prevalence of osteoporosis and the low level of exposure, the observed effects, although slight, should be considered as early signals of potentially more adverse health effects.

Metal Concentrations in Plasma and Cerebrospinal Fluid in Patients with Alzheimer’s Disease

Background/Aims: The homeostasis of essential metals such as copper, iron, selenium and zinc may be altered in the brain of subjects with Alzheimer’s disease (AD). Methods: Concentrations of metals (magnesium, calcium, vanadium, manganese, iron, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, tin, antimony, cesium, mercury and lead) were determined in plasma and cerebrospinal fluid (CSF) by inductively coupled plasma mass spectrometry in 173 patients with AD and in 87 patients with the combination of AD and minor vascular components (AD + vasc). Comparison was made with 54 healthy controls. Results: The plasma concentrations of manganese and total mercury were significantly higher in subjects with AD (p < 0.001) and AD + vasc (p ≤ 0.013) than in controls. In CSF, however, the concentrations of vanadium, manganese, rubidium, antimony, cesium and lead were significantly lower among subjects with AD (p ≤ 0.010) and AD + vasc (p ≤ 0.047) than in controls. Strong positive correlations were noted between plasma Cs versus CSF Cs in subjects with AD (rs = 0.50; p < 0.001), and AD + vasc (rs = 0.68; p < 0.001). Conclusion: Besides the raised plasma mercury concentrations, no consistent metal pattern in plasma or CSF was observed in patients with AD.

The relationship between cadmium in kidney and cadmium in urine and blood in an environmentally exposed population

INTRODUCTION Cadmium (Cd) is toxic to the kidney and a major part of the body burden occurs here. Cd in urine (U-Cd) and blood (B-Cd) are widely-used biomarkers for assessing Cd exposure or body burden. However, empirical general population data on the relationship between Cd in kidney (K-Cd), urine, and blood are scarce. Our objectives were to determine the relationship between cadmium in kidney, urine, and blood, and calculate the elimination half-time of Cd from the kidney. METHODS Kidney cortex biopsies, urine, and blood samples were collected from 109 living kidney donors. Cd concentrations were determined and the relationships between K-Cd, U-Cd, and B-Cd were investigated in regression models. The half-time of K-Cd was estimated from the elimination constant. RESULTS There was a strong association between K-Cd and U-Cd adjusted for creatinine (rp=0.70, p<0.001), while the association with B-Cd was weaker (rp=0.44, p<0.001). The relationship between K-Cd and U-Cd was nonlinear, with slower elimination of Cd at high K-Cd. Estimates of the K-Cd half-time varied between 18 and 44years. A K-Cd of 25μg/g corresponds to U-Cd of 0.42μg/g creatinine in overnight urine (U-Cd/K-Cd ratio: about 1:60). Multivariate models showed Cd in blood and urinary albumin as determinants for U-Cd excretion. DISCUSSION In healthy individuals with low-level Cd exposure, there was a strong correlation between Cd in kidney and urine, especially after adjustment for creatinine. Urinary Cd was also affected by Cd in blood and urinary albumin. Previous estimates of the U-Cd/K-Cd ratio may underestimate K-Cd at low U-Cd.

Associations between proteins and heavy metals in urine at low environmental exposures: Evidence of reverse causality

Heavy metals can cause renal effects on vulnerable populations but it is uncertain whether these metals still pose health risks at the low exposure levels now prevailing in most industrialized countries. In a cross-sectional study performed on 736 adolescents, we assessed the associations between the concentrations of cadmium and lead in blood and urine and the urinary concentrations of albumin and of low-molecular-weight (LMW) proteins, retinol-binding protein (RBP) and β(2)-microglobulin. Multiple regression analyses were tested using urinary markers normalized to urinary creatinine or specific gravity. Median metal concentrations were in blood (μg/L): lead, 15.1, cadmium, 0.18 and in urine (μg/g creatinine): cadmium, 0.09 and lead, 0.82. Multivariate analyses revealed significant associations in urine between RBP and cadmium as well as between β(2)-microglobulin and lead whereas no associations were seen with metals in blood. These associations were completely abolished in subjects with increased urinary albumin, which may be explained by the competitive inhibition of LMW protein reabsorption by albumin. Given the evidence that cadmium and lead circulate mainly bound to LMW proteins, these associations observed at low exposure might simply reflect the interindividual variations in the renal uptake of proteins sharing the same affinity for tubular binding sites.

Genetic variation in glutathione-related genes and body burden of methylmercury.

Background Exposure to toxic methylmercury (MeHg) through fish consumption is a large problem worldwide, and it has led to governmental recommendations of reduced fish consumption and blacklisting of mercury-contaminated fish. The elimination kinetics of MeHg varies greatly among individuals. Knowledge about the reasons for such variation is of importance for improving the risk assessment for MeHg. One possible explanation is hereditary differences in MeHg metabolism. MeHg is eliminated from the body as a glutathione (GSH) conjugate. Objectives We conducted this study to assess the influence of polymorphisms in GSH-synthesizing [glutamyl-cysteine ligase modifier subunit (GCLM-588) and glutamyl-cysteine ligase catalytic subunit (GCLC-129)] or GSH-conjugating [glutathione S-transferase pi 1 (GSTP1–105 and GSTP1–114)] genes on MeHg retention. Methods Based on information obtained from questionnaires, 292 subjects from northern Sweden had a high consumption of fish (lean/fat fish two to three times per week or more). We measured total Hg in erythrocytes (Ery-Hg) and long-chain n-3 polyunsaturated fatty acids in plasma (P-PUFA; an exposure marker for fish intake). Results The GSTP1 genotype modified Ery-Hg; effects were seen for GSTP1–105 and −114 separately, and combining them resulted in stronger effects. We found evidence of effect modification: individuals with zero or one variant allele demonstrated a steeper regression slope for Ery-Hg (p = 0.038) compared with individuals with two or more variant alleles. The GCLM-588 genotype also influenced Ery-Hg (p = 0.035): Individuals with the GCLM-588 TT genotype demonstrated the highest Ery-Hg, but we saw no evidence of effect modification with increasing P-PUFA. Conclusions These results suggest a role of GSH-related polymorphisms in MeHg metabolism.

Fish intake, mercury, long-chain n-3 polyunsaturated fatty acids and risk of stroke in northern Sweden

Results of previous studies on fish intake and stroke risk have been inconclusive. Different stroke types have often not been separated. Our aim was to elucidate whether intake of fish, Hg or the sum of proportions of fatty acids EPA (20 : 5n-3) and DHA (22 : 6n-3) influence the risk of haemorrhagic or ischaemic stroke. Within a population-based cohort from a community intervention programme, 369 stroke cases and 738 matched controls were identified and included in the present nested case-control study. Information on fish intake had been recorded at recruitment, i.e. before diagnosis. Hg levels were determined in erythrocyte membranes, also collected at recruitment, and the relative content of fatty acids was measured in erythrocyte membranes or plasma phospholipids. The results showed that in women there was a non-significant decrease in stroke risk with increasing fish intake (OR 0.90 (95 % CI 0.73, 1.11) per meal per week). The risk in women differed significantly (P = 0.03) from that in men, in whom the OR for stroke rose with increasing fish intake (OR 1.24 (95 % CI 1.01, 1.51) per meal per week). The corresponding risk in men for Hg was 0.99 (95 % CI 0.93, 1.06), and for the sum of proportions of EPA and DHA 1.08 (95 % CI 0.92, 1.28). We conclude that the relationship between stroke risk and fish intake seems to be different in men and women. Increased levels of EPA and DHA do not decrease the risk for stroke and there is no association between stroke risk and Hg at these low levels.

Relationships between trace element concentrations in human blood and serum

Trace element interactions can affect the absorption, metabolism, or effects of elements. Also, different elements may derive from the same source. Associations in biological media between element concentrations may indicate such phenomena. A large number of correlations were found between 13 trace elements (Co, Cu, Zn, Se, Rb, Rh, Pd, Cd, W, Pt, Hg, Tl, and Pb) in human blood and/or serum, as investigated in 372 Swedish adolescents. Notably, serum Se correlated with blood Pb and blood Hg and Cu and Zn were correlated to each other in both blood and serum. The elements Pt, Pd and Rh, spread in the environment through use of catalytic converters in cars, were closely correlated in both blood and serum. Apart from the correlations with a probable biological or exposure-related explanation, several other correlations, of yet unknown importance and origin, were found.

Yearly measurements of blood lead in Swedish children since 1978: an update focusing on the petrol lead free period 1995-2001.

Background and Aims: To assess blood lead concentrations (B-Pb) in children not exposed to petrol lead. In a previous paper we reported the results for the period 1978–94 (2441 children measured). A substantial decrease of B-Pb was found, which reflected a beneficial effect of gradual banning of petrol lead. Since 1994, petrol sold in Sweden has not contained lead. Methods: In the south of Sweden, each year from 1995 to 2001, B-Pb was measured in 329 boys and 345 girls, aged 7–11 years. Results: The geometric mean (GM) of B-Pb was 21 (range 6–80) μg/l. There was no consistent change of B-Pb from 1995 to 2001. Children living near a lead smelter had raised B-Pb (GM 24 μg/l, range 11–80). Passive smoking, but not age and sex, influenced B-Pb significantly. Conclusions: B-Pb in Swedish children, no longer exposed to petrol lead, seems to have stabilised at an average level close to 20 μg/l (provided there is no nearby industrial lead emission).

Lead, mercury, and cadmium in blood and their relation to diet among Swedish adults

The aim of the present study was to examine the body burden of lead (Pb), mercury (Hg), and cadmium (Cd) in blood among Swedish adults and the association between blood levels, diet and other lifestyle factors. The study was based on a subgroup (n=273) of the national survey Riksmaten 2010-2011 (4-day food records and questionnaire). Lead, Hg, and Cd were measured in whole blood, and Cd additionally in urine, by mass or fluorescence spectrometry methods. The median values (5-95th percentiles) of the metals in blood were as follows; Pb: 13.4 (5.8-28.6) μg/L, Hg: 1.13 (0.31-3.45) μg/L, and Cd: 0.19 (0.09-1.08) μg/L. All three metals increased with increasing age. Lead levels in blood were positively associated with intakes of game and alcohol, Hg was related to fish intake, and blood Cd related to smoking and low iron stores and to a low meat intake. Body burdens of the studied metals were generally below health based reference values, but several individuals had blood Pb levels above the reference point for possible nephrotoxic and developmental neurotoxic effects. As health effects cannot be excluded, individuals with high Pb exposure should aim at decreasing their body burden, both from food and from other exposure routes.