Lars Gerhardsson

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.

Delta-aminolevulinic acid dehydratase polymorphism: influence on lead levels and kidney function in humans.

Delta-aminolevulinic acid dehydratase (ALAD) polymorphism has been reported to modify lead pharmacokinetics (i.e., individuals who express the ALAD2 allele [ALAD2 subjects] have higher blood lead levels than homozygotes for the ALAD1 allele [ALAD1 subjects]). In our study of 89 lead-exposed workers (7 ALAD2 homozygotes or heterozygotes) and 34 unexposed workers (10 ALAD2 heterozygotes), concentrations of urinary calcium and creatinine were lower in ALAD2 subjects than in ALAD1 subjects (respective medians: calcium--78 mg/l versus 185 mg/l, p = .003; creatinine--11.2 mmol/l versus 14.9 mmol/l, p = .008). No association was found between ALAD genotype and blood lead levels or bone lead levels. However, expression of the ALAD2 allele occurred less frequently among lead-exposed workers than in unexposed controls. The results indicated the presence of ALAD allele-specific differences in kidney function, as well as a possible genetic healthy-worker selection.

Effects of Lead on the Endocrine System in Lead Smelter Workers

Abstract In this study of the effects of lead on the endocrine system, 77 secondary lead-smelter workers (i.e., 62 active and 15 retired) were compared with 26 referents. Lead concentrations were determined in plasma with inductively coupled plasma mass spectrometry (i.e., index of recent exposure), in blood with atomic absorption spectrophotometry and in fingerbone with K x-ray fluorescence technique (i.e., index of long-term exposure). In addition, pituitary hormones were determined in serum by fluoroimmunoassay and thyroid hormones and testosterone in serum were determined with radioimmunoassay. Nine lead workers and 11 referents were challenged with gonadotrophin-releasing hormone and thyrotrophin-releasing hormone, followed by measurements of stimulated pituitary hormone levels in serum. Median levels of lead in plasma were 0.14 μg/dl (range = 0.04–3.7 μg/dl) in active lead workers, 0.08 μg/dl (range = 0.05–0.4 μg/dl) in retired lead workers and 0.03 μg/dl (range = 0.02–0.04 μg/dl) in referents (1 μg/dl = 48.3 nmol/l). Corresponding blood lead concentrations were 33.2 μg/dl (range = 8.3–93.2 μg/dl), 18.6 μg/dl (range = 10.4–49.7 μg/dl) and 4.1 μg/dl (range 0.8–6.2 μg/dl), respectively. Respective bone lead levels were 21 μg/gm (range = -13 to 99 μg/gm), 55 μg/gm (range = 3–88 μg/gm) and 2 μg/gm (range = -21 to 14 μg/gm). Concentrations of basal serum hormone (i.e., free thyroid hormones, thyrotrophin, sex hormone binding globulin and testosterone) were similar in the 3 groups. There were no significant associations between the hormones mentioned herein and blood plasma, blood lead and bone lead levels. In the challenge test, stimulated follicle-stimulating hormone levels were significantly lower in lead workers (p = .014) than in referents, indicating an effect of lead at the pituitary level. Also, there was a tendency toward lower basal stimulated follicle-stimulating hormone concentrations in lead workers (p = .08). This effect, however, was not associated with blood plasma level, blood lead level, or bone lead level. In conclusion, a moderate exposure to lead was associated with only minor changes in the male endocrine function, particularly affecting the hypothalamic-pituitary axis. Given that sperm parameters were not studied, the authors could not draw conclusions about fertility consequences.

Lung cancer risks among lead smelter workers also exposed to arsenic

Recent publications indicate an increased incidence of lung cancer in non-ferrous smelter workers exposed to lead. The present study provides further data on selected subgroups in one such cohort. The cohort was based on 3979 smelter workers employed for at least 1 year between 1928 and 1979, and also exposed to lead and included in the Blood Lead Register that was started at the smelter in 1950. Two subcohorts were formed from the original cohort. One consists of 710 workers employed at the lead departments (Lead subcohort 1), and the other of 383 workers employed at the lead departments (Lead subcohort 2), but never at other works where an excess lung cancer risk was previously identified. Standardized Cancer Incidence Rates (SIR) 1958-1987 were calculated relative to county rates. In the subcohorts, arsenic exposure in lung cancer cases was assessed in detail based on occupational hygiene information from the company. Lung cancer incidence was raised in both subcohorts (Lead subcohort 1: SIR 2.4; 95% CI 1.2-4.5; Lead subcohort 2: SIR 3.6; 95% CI 1.2-8.3). Total cancer incidence in the cohorts was not increased. A detailed study of arsenic exposure in the 10 lung cancer cases in these two subcohorts revealed that all but one of these cases had a significant exposure also to arsenic. An elevated incidence of lung cancer was observed in smelter workers exposed to lead. However, considerable arsenic exposure also occurred in a majority of the lung cancer cases in the investigated subcohorts. In this multifactorial exposure situation it has not been possible to separate the carcinogenic effects of lead and arsenic, but a possible interaction between these metals may be involved in explaining the carcinogenic risks.

Lead—biological monitoring of exposure and effects

The dominant exposure sources of lead, an ubiquitously present metal, include, in many geographical regions, leaded gasoline, water, paint, and industrial emissions. These sources may cause exposure via inhalation and ingestion. At inhalation, 10–60% of the particles with a of size 0.01–5 μm will be deposited in the alveolar region. Gastrointestinal absorption in adults is ∼10–20%. Lead accumulates in bone and teeth. The skeleton contains >90% of the total body burden in adults, less in children. Turnover in bone is slow, the half-time in trabecular bone being ∼1 year compared to decades in cortical bone. Other compartments in blood and soft tissues have a half-time of ∼1 month. Excretion is mainly through urine and feces. Lead toxicity may affect several organ systems, e.g., the hematopoietic system, the peripheral and central nervous system, the kidneys, the gastrointestinal tract, the cardiovascular system, and the reproducytive system. Lead is an animal carcinogen, but conclusive evidence for carcinogenesis in humans is lacking. Lead determinations in blood (B-Pb) is presently the prevailing indicator of lead exposure and risk. However, serum/plasma levels of lead may be more suitable as such an index, mainly because of the nonlinearity of B-Pb in relation to both exposure and effects. Other, less frequently used indices include lead concentrations in urine, mobilization tests, and disturbances of heme metabolism. During the last two decades in vivo determination of lead in bone, e.g., tibia, calcaneus, and finger bone, by X-ray fluorescence has been used for biological monitoring of long-term exposure. Recent data indicate that there is an accumulation of lead in finger bone, which is related to both time of exposure and B-Pb. In a three-dimensional model, lead in finger bone and the exposure time may be used for retrospective estimation of previous B-Pb, reflecting the historic lead exposure. Such estimates will be of particular value in cross-sectional studies of long-term health effects in lead-exposed populations. J. Trace Elem. Exp. Med. 11:289–301, 1998.

Exposure and toxic effects of elemental mercury in gold-mining activities in Ecuador

Traditional gold mining, using metallic mercury (Hg(0)) to form gold amalgam, followed by burning to remove the Hg(0), is widely used in South America, Africa and Asia. The gold is sold to merchants who burn it again to eliminate remaining Hg(0). In Ecuador, 200 gold miners, 37 gold merchants and 72 referents were studied. The median Hg concentrations in urine (U-Hg) were 3.3 (range 0.23-170), 37 (3.2-420), and 1.6 (0.2-13)μg/g creatinine, respectively, and in whole blood (B-Hg) were 5.2, 30, and 5.0 μg/L, respectively. Biomarker concentrations among merchants were statistically significantly higher than among miners and referents; also the miners differed from the referents. Burning of gold amalgam among miners was intermittent; U-Hg decreased in the burning-free period. In computerized neuromotor examinations, B-Hg and U-Hg concentrations were associated with increases in the centre frequency of the tremor, as well as in reaction time and postural stability.Retention of Hg (B-Hg), and the elimination rate (U-Hg) appears to be modified by polymorphism in a gene of an enzyme in the glutathione synthesis (GCLM), but there were no significant genetic modifications for the associations between exposure and neurotoxicity.Thus, the gold merchants have a much higher exposure and risk than the miners, in whom the exposure varies over time. The metabolism of Hg is modified by genetic traits. The present exposure to Hg had limited neurotoxic effects.

Mortality and cancer incidence among secondary lead smelter workers.

OBJECTIVES--To examine the mortality pattern and the cancer incidence in a cohort of long term smelter workers exposed to lead. METHODS--The cohort consists of 664 male lead battery workers, employed for at least three months in 1942-87. From 1969 the values of all blood lead samples repeatedly obtained from these workers every two to three months, have been collected in a database. The expected mortality and morbidity 1969-89 was estimated from the county rates, specified for cause, sex, five-year age groups, and calendar year. Individual exposure matrices have been calculated and used for dose-response analyses. RESULTS--The total cohort showed an increased overall mortality (standardised mortality ratio (SMR) 1.44; 95% confidence interval (95% CI) 1.16-1.79), an increased mortality from ischaemic heart diseases (SMR 1.72; 95% CI 1.20-2.42) and all malignant neoplasms (SMR 1.65; 95% CI 1.09-2.44). These risk estimates were unaffected or slightly decreased when applying a latency period of 15 years, and no dose-response pattern was shown. The non-significantly raised cancer incidence in the gastrointestinal tract (11 malignancies) in the total cohort, increased to a barely significant level in the quartile with the highest cumulative lead exposure (standardised incidence ratio (SIR) 2.34, 95% CI 1.07-4.45). No clear dose response pattern was evident when further subdividing the data into those first employed up to 1969 v those first employed after 1969 when the blood lead monitoring programme started. The risk estimate for malignancies in the gastrointestinal tract was not related to latency time. The cancer incidence was not increased at other sites. CONCLUSIONS--A slightly increased incidence of gastrointestinal cancers was found in workers exposed to lead and employed before 1970. The lead cohort also showed an increased mortality from ischaemic heart diseases. These risk estimates did not show a dose-response pattern and were not associated with latency time. The results must also be interpreted with caution because of limited numbers, and lack of dietary and smoking data.

CSF Mg and Ca as diagnostic markers for dementia with Lewy bodies.

Accumulating evidence implicates a role for altered metal homeostasis in the pathogenesis of neurodegenerative disorders such as Alzheimers disease (AD). However, few investigations have addressed this issue in dementia with Lewy bodies (DLB). The aim of the present study was to investigate metal concentrations in cerebrospinal fluid (CSF) and plasma from patients with DLB and other neurodegenerative disorders. To that end, CSF and plasma samples were collected from 29 patients with DLB, 174 patients with AD, 90 patients with AD with minor vascular components, and 51 healthy volunteers. Total concentrations of Mg, Ca, Mn, Fe, Cu, Zn, Rb, Sr, and Cs were determined using mass spectrometry. Patients with DLB had elevated Ca and Mg levels in CSF and Mg levels in plasma as compared to all other groups (p<0.001). Furthermore, a combination of CSF-Mg and CSF-Ca could distinguish DLB from AD with a sensitivity of 93% and a specificity of 85%. Cu levels in both CSF and plasma tended to be higher in DLB compared to the other groups, but these trends failed to reach significance after correction for multiple comparisons. Mn, Fe, Zn, Rb, and Sr concentration in CSF or plasma were similar in all groups. The observed elevations of CSF-Mg, CSF-Ca and CSF-Cu may contribute to or be associated with the neurodegenerative process in DLB. Furthermore, determination of CSF-Mg and CSF-Ca concentration may be a valuable tool in distinguishing DLB from AD.

Lung cancer development in primary smelter workers : a nested case-referent study.

Objective: The objective of this study was to study the impact of work-related exposure to mainly arsenic and lead versus smoking in primary smelter workers developing lung cancer. Methods: In a cohort of 3979 primary smelter workers, 46 subjects had contracted respiratory malignancies. They were compared with 141 age-matched male referents by conditional logistic regression analysis. Results: Cases showed a significantly higher smoking rate as compared with referents: odds ratio (OR) = 4.0; 95% confidence interval (CI) = 1.6–10.1; P = 0.003. When restricted to smokers (33 cases, 63 referents), the cumulative air arsenic exposure index, but not the lead exposure indices, was significantly higher among the cases: OR = 1.07; 95% CI = 1.02–1.11; P = 0.005. Conclusions: Cumulative arsenic exposure and smoking were identified as risk factors for the development of lung cancer; lead exposure, however, was not.

Interactions in Metal Toxicology

Human exposures to metals and metalloids such as arsenic frequently occur as mixtures, and hence it is important to consider interactions among these elements in terms of both mechanisms of action ...