Niklas Forsgard

Cadmium exposure and atherosclerotic carotid plaques -Results from the Malmö diet and Cancer study.

BACKGROUND Epidemiological studies indicate that cadmium exposure through diet and smoking is associated with increased risk of cardiovascular disease. There are few data on the relationship between cadmium and plaques, the hallmark of underlying atherosclerotic disease. OBJECTIVES To examine the association between exposure to cadmium and the prevalence and size of atherosclerotic plaques in the carotid artery. METHODS A population sample of 4639 Swedish middle-aged women and men was examined in 1991-1994. Carotid plaque was determined by B-mode ultrasound. Cadmium in blood was analyzed by inductively coupled plasma mass spectrometry. RESULTS Comparing quartile 4 with quartile 1 of blood cadmium, the odds ratio (OR) for prevalence of any plaque was 1.9 (95% confidence interval 1.6-2.2) after adjustment for sex and, age; 1.4 (1.1-1.8) after additional adjustment for smoking status; 1.4 (1.1-1.7) after the addition of education level and life style factors; 1.3 (1.03-1.8) after additional adjustment for risk factors and predictors of cardiovascular disease. No effect modification by sex was found in the cadmium-related prevalence of plaques. Similarly, ORs for the prevalence of small and large plaques were after full adjustment 1.4 (1.0-2.1) and 1.4 (0.9-2.0), respectively. The subgroup of never smokers showed no association between cadmium and atherosclerotic plaques. CONCLUSIONS These results extend previous studies on cadmium exposure and clinical cardiovascular events by adding data on the association between cadmium and underlying atherosclerosis in humans. The role of smoking remains unclear. It may both cause residual confounding and be a source of pro-atherogenic cadmium exposure.

Clearance of cardiac troponin T with and without kidney function

OBJECTIVE The extent of kidney-dependent clearance of the cardiac damage biomarker cardiac troponin T (cTnT) is not known. METHODS AND RESULTS We examined clearance of cTnT after injection of heart extracts in rats with or without clamped kidney vessels. The extent of degradation of cTnT to fragments able to pass the glomerular membrane and the kidney extraction index of cTnT was examined in human subjects. After a bolus injection of rat cardiac extract, simulating a large myocardial infarction, there was no significant difference in clearance of cTnT with or without kidney function. However, a slower clearance was observed late in the clearance process, when cTnT levels were low. When low levels of rat cardiac extract were infused at a constant rate to steady state, clamping of the renal vessels resulted in significant 2-fold reduction in clearance of cTnT. Over 60% of the measured cTnT in human subjects had a molecular weight below 17kDa, expected to have a relatively free passage over the glomerular membrane. The extraction index of cTnT in three heart failure patients undergoing renal vein catheterization was 8-19%. Kidney function adjusted cTnT levels increased the area under the ROC curve for diagnosis of myocardial infarction of the cTnT analysis in an emergency room cohort. CONCLUSIONS At high concentrations, often found after a large myocardial infarction, extrarenal clearance of cTnT dominates. At low levels of cTnT, often found in patients with stable cTnT elevations, renal clearance also contribute to the clearance of cTnT. This potentially explains why stable cTnT levels tend to be higher in patients with low kidney function.

Cadmium exposure and incidence of diabetes mellitus - results from the malmö diet and cancer study.

Background Cadmium is a pollutant with multiple adverse health effects: renal dysfunction, osteoporosis and fractures, cancer, and probably cardiovascular disease. Some studies have reported associations between cadmium and impaired fasting glucose and diabetes. However, this relationship is controversial and there is a lack of longitudinal studies. Objectives To examine prospectively whether cadmium in blood is associated with incidence of diabetes mellitus. Methods The study population consists of 4585 subjects without history of diabetes (aged 46 to 67 years, 60% women), who participated in the Malmö Diet and Cancer study during 1991–1994. Blood cadmium levels were estimated from hematocrit and cadmium concentrations in erythrocytes. Incident cases of diabetes were identified from national and local diabetes registers. Results Cadmium concentrations in blood were not associated with blood glucose and insulin levels at the baseline examination. However, cadmium was positively associated with HbA1c in former smokers and current smokers. During a mean follow-up of 15.2±4.2 years, 622 (299 men and 323 women) were diagnosed with new-onset of diabetes. The incidence of diabetes was not significantly associated with blood cadmium level at baseline, neither in men or women. The hazard ratio (4th vs 1st quartile) was 1.11 (95% confidence interval 0.82–1.49), when adjusted for potential confounders. Conclusions Elevated blood cadmium levels are not associated with increased incidence of diabetes. The positive association between HbA1c and blood cadmium levels has a likely explanation in mechanisms related to erythrocyte turnover and smoking.

Low-level exposure to lead, blood pressure, and hypertension in a population-based cohort.

BACKGROUND Environmental lead exposure is a possible causative factor for increased blood pressure and hypertension, but large studies at low-level exposure are scarce, and results inconsistent. OBJECTIVE We aimed to examine the effects of environmental exposure to lead in a large population-based sample. METHODS We assessed associations between blood lead and systolic/diastolic blood pressure and hypertension in 4452 individuals (46-67 years) living in Malmö, Sweden, in 1991-1994. Blood pressure was measured using a mercury sphygmomanometer after 10min supine rest. Hypertension was defined as high systolic (≥140mmHg) or diastolic (≥90mmHg) blood pressure and/or current use of antihypertensive medication. Blood lead was calculated from lead in erythrocytes and haematocrit. Multivariable associations between blood lead and blood pressure or hypertension were assessed by linear and logistic regression. Two-thirds of the cohort was re-examined 16 years later. RESULTS At baseline, mean blood pressure was 141/87mmHg, 16% used antihypertensive medication, 63% had hypertension, and mean blood lead was 28µg/L. Blood lead in the fourth quartile was associated with significantly higher systolic and diastolic blood pressure (point estimates: 1-2mmHg) and increased prevalence of hypertension (odds ratio: 1.3, 95% confidence interval: 1.1-1.5) versus the other quartiles after adjustment for sex, age, smoking, alcohol, waist circumference, and education. Associations were also significant with blood lead as a continuous variable. Blood lead at baseline, having a half-life of about one month, was not associated with antihypertensive treatment at the 16-year follow-up. CONCLUSIONS Low-level lead exposure increases blood pressure and may increase the risk of hypertension.

Cadmium exposure is associated with soluble urokinase plasminogen activator receptor, a circulating marker of inflammation and future cardiovascular disease

Background Diet and smoking are the main sources of cadmium exposure in the general population. Cadmium increases the risk of cardiovascular diseases, and experimental studies show that it induces inflammation. Blood cadmium levels are associated with macrophages in human atherosclerotic plaques. Soluble urokinase‐type plasminogen activator receptor (suPAR) is an emerging biomarker for cardiovascular events related to inflammation and atherosclerotic plaques. The aim was to examine whether blood cadmium levels are associated with circulating suPAR and other markers of inflammation. Methods A population sample of 4648 Swedish middle‐aged women and men was examined cross‐sectionally in 1991–1994. Plasma suPAR was assessed by ELISA, leukocytes were measured by standard methods, and blood cadmium was analysed by inductively coupled plasma mass spectrometry. Prevalent cardiovascular disease, ultrasound‐assessed carotid plaque occurrence, and several possible confounding factors were recorded. Results After full adjustment for risk factors and confounding variables, a 3‐fold increase in blood cadmium was associated with an 10.9% increase in suPAR concentration (p<0.001). In never‐smokers, a 3‐fold increase in blood cadmium was associated with a 3.7% increase in suPAR concentration (p<0.01) after full adjustment. Blood cadmium was not associated with C‐reactive protein, white blood cell count and Lp‐PLA2 but with neutrophil/lymphocyte ratio in one of two statistical models. Conclusions Exposure to cadmium was associated with increased plasma suPAR in the general population, independently of smoking and cardiovascular disease. These results imply that cadmium is a possible cause for raised levels of this inflammatory marker. HighlightsCadmium is a toxic proinflammatory, proatherosclerotic metal.Soluble urokinase‐type plasminogen activator receptor (suPAR) in plasma is a promising proinflammatory marker of atherosclerosis.Blood cadmium and plasma suPAR were measured in a cohort of 4648 Swedish men and women.Blood cadmium was positively associated with plasma suPAR, also in never smokers.

Analysis of manganese and iron in exhaled endogenous particles

Background: many full-time welders experience some sort of respiratory disorder e.g., asthma, bronchitis and metal fume fever. Thus, welding aerosols are thought to cause airway inflammation. There is a need for markers of welding aerosols in exposure assessments, and as most welding aerosols contain manganese and iron, these metals may possibly be used as an indicator. We have previously developed a novel non-invasive technique to collect endogenous particles in exhaled air (PEx). This study is designed to (i) develop a method for analysis of manganese and iron in PEx and (ii) investigate whether the manganese and/or iron content of PEx changes after exposure to welding aerosols. Methods: nine individuals were experimentally exposed to welding fumes. PEx was collected at three time points for each individual; before, after and 24 hours after exposure. Analyses of PEx samples were performed using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Results: four out of nine individuals showed an increase in manganese and iron levels after exposure to welding aerosols. The mean manganese and iron concentration increased from, <LOD to 82–84 pg L−1 (range from 0 to LOD for values <LOD) and 20–86 to 2600 pg L−1 of exhaled air respectively. Conclusions: an ICP-MS method for analysis of manganese and iron in PEx has been developed. The method could easily be expanded to include other trace metals of interest, such as cadmium, nickel or chromium. This first attempt to evaluate PEx as a tool for exposure assessments of airborne metals indicates that the method has potential.

Lipid composition of particles in exhaled air (PEx) from workers exposed to welding fumes

More than two million workers are exposed to pneumotoxic welding aerosols and there is a need for biomarkers of effects on the respiratory system. The lipid composition of the respiratory tract lining fluid (RTLF) is such a potential marker. The most abundant pulmonary surfactant phospholipid is dipalmitoylphosphocholine (DPPC). It is specific for the airways, while palmitoyloleoylphosphatidylcholine (POPC) is a common lipid in tissues and body fluids. We hypothesize that the amounts of or ratio between DPPC and DOPC are changed due to short term and/or long term exposure to welding fumes. We have developed a method for the collection of PEx, based on counting of the exhaled particles and subsequent collection by impaction on a teflon membrane. We have also developed a method for analysis of lipids in PEx based on LC/MS. We measured the exposure to iron, manganese, chromium and nickel of 18 stainless steel welders and also analyzed DPPC and DOPC in PEx samples taken at the end of the exposure measurement day. The welders working history was also recoded and summarized as welding years. Spirometry and nitrogen multiple breath wash out were also measured but the results are not yet evaluated. There were no significant correlations between the short term exposure to either iron, manganese, chromium or nickel and the fraction of DPPC in PEx or the ratio DPPC/DOPC. However, there was a tendency of correlation (Spearman correlation coefficient= 0.407 with p-value 0.09) between welding years and the DPPC/DOPC ratio. In this pilot study we could not establish short term effects of welding exposure on the RTFL lipid composition but a tendency of change due the long time exposure.