Low-level exposure to lead and atherosclerosis in the carotid arteries: Results from the Swedish population-based cohort SCAPIS.

BACKGROUND: Lead exposure is associated with cardiovascular disease. Atherosclerosis has been hypothesized to be one of the underlying mechanisms behind this association. AIM: To investigate whether lead exposure is associated with an increased risk of atherosclerosis in the carotid arteries in a large Swedish population-based cohort. METHODS: We performed a cross-sectional study using data from the population-based Swedish CardioPulmonary bioImage Study (SCAPIS), including 5622 middle-aged men and women, enrolled 2013-2018. Blood lead (B-Pb), measured by inductively coupled plasma mass spectrometry, was used as exposure biomarker. The presence of atherosclerotic plaque in the carotid arteries (yes/no), total plaque area (mm2) and the presence of large plaques (>25 mm2) were determined by ultrasonography. Associations between B-Pb and the different outcomes were analysed using Poisson and linear regression models, adjusted for potential confounders. RESULTS: Atherosclerotic plaque was present in 57% of the individuals, for whom the median total plaque area was 16 mm2 (range: 0.2-222). The median B-Pb concentration was 14 µg/L (range: 0.75-203). After adjusting for potential confounders, individuals in the fourth quartile of B-Pb (Q4) had a prevalence ratio (PR) for plaque of 1.08 (95% CI: 1.01, 1.16) when compared with the first quartile (Q1). A 10 µg/L increase in B-Pb concentrations was associated with an increase of 0.92 mm2 (95% CI: 0.14, 1.71) in total plaque area. The PR for large plaque was 1.09 (95% CI: 0.84, 1.42 for Q4 vs Q1). CONCLUSIONS: This study shows an association between B-Pb and atherosclerosis in the carotid arteries providing some support for the hypothesis that atherosclerosis is one of the mechanisms underlying the association between lead exposure and cardiovascular disease.

Exploring a new method for the assessment of metal exposure by analysis of exhaled breath of welders.

PURPOSE: Air monitoring has been the accepted exposure assessment of toxic metals from, e.g., welding, but a method characterizing the actual dose delivered to the lungs would be preferable. Sampling of particles in exhaled breath can be used for the biomonitoring of both endogenous biomarkers and markers of exposure. We have explored a new method for the sampling of metals in exhaled breath from the small airways in a study on welders. METHODS: Our method for particle sampling, Particles in Exhaled Air (PExA®), is based on particle counting and inertial impaction. We applied it on 19 stainless steel welders before and after a workday. In parallel, air monitoring of chromium, manganese and nickel was performed as well as blood sampling after work. RESULTS: Despite substantial exposure to welding fumes, we were unable to show any significant change in the metal content of exhaled particles after, compared with before, exposure. However, the significance might be obscured by a substantial analytical background noise, due to metal background in the sampling media and possible contamination during sampling, as an increase in the median metal contents were indicated. CONCLUSIONS: If efforts to reduce background and contamination are successful, the PExA® method could be an important tool in the investigations of metals in exhaled breath, as the method collects particles from the small airways in contrast to other methods. In this paper, we discuss the discrepancy between our findings and results from studies, using the exhaled breath condensate (EBC) methodology.

Cerebrospinal fluid metallomics in cerebral amyloid angiopathy: an exploratory analysis.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is associated with symptomatic intracerebral haemorrhage. Biomarkers of clinically silent bleeding events, such as cerebrospinal fluid (CSF) ferritin and iron, might provide novel measures of disease presence and severity. METHODS: We performed an exploratory study comparing CSF iron, ferritin, and other metal levels in patients with CAA, control subjects (CS) and patients with Alzheimer's disease (AD). Ferritin was measured using a latex fixation test; metal analyses were performed using inductively coupled plasma mass spectrometry. RESULTS: CAA patients (n = 10) had higher levels of CSF iron than the AD (n = 20) and CS (n = 10) groups (medians 23.42, 15.48 and 17.71 µg/L, respectively, p = 0.0015); the difference between CAA and AD groups was significant in unadjusted and age-adjusted analyses. We observed a difference in CSF ferritin (medians 10.10, 7.77 and 8.01 ng/ml, for CAA, AD and CS groups, respectively, p = 0.01); the difference between the CAA and AD groups was significant in unadjusted, but not age-adjusted, analyses. We also observed differences between the CAA and AD groups in CSF nickel and cobalt (unadjusted analyses). CONCLUSIONS: In this exploratory study, we provide preliminary evidence for a distinct CSF metallomic profile in patients with CAA. Replication and validation of these results in larger cohorts is needed.

Is Cadmium a Risk Factor for Breast Cancer - Results from a Nested Case-Control Study Using Data from the Malmö Diet and Cancer Study.

BACKGROUND: Some studies have shown that cadmium (Cd) is associated with breast cancer risk. One hypothesis is that Cd has estrogen-like properties. This case-control study investigated the association between breast cancer risk and blood Cd (BCd) levels. METHODS: All breast cancers in the Malmö Diet and Cancer cohort were identified through linkage to the Swedish Cancer Registry, baseline (1991-1996) through 2014. Two controls per case were selected from the same cohort. BCd was analyzed at baseline. Associations were analyzed using logistic regression. RESULTS: Mean BCd was 0.51 µg/L among 1,274 cases and 0.46 among 2,572 controls. There was an overall increased risk of breast cancer [OR, 1.18; 95% confidence interval (CI), 1.05-1.36] per µg/L of BCd. An increased risk was, however, only found at high BCd [OR, 1.34 (95% CI, 1.05-1.73)] for BCd more than 1.20 µg/L. The group with the highest BCd was mainly smokers. A spline indicated that at BCd less than 1.0 µg/L, the OR was not increased. The association with BCd was stronger in current smokers and at body mass index (BMI) above 25, while no modification due to receptor status was found. CONCLUSIONS: The results indicated increased risk of breast cancer only for high Cd exposure, which occurred mainly among smokers. This made it difficult to disentangle the effects of smoking and Cd, despite inclusion of smoking habits in the models. IMPACT: This study provides support for reducing Cd exposure through smoking cessation and dietary choice. On the population level, preventive measures against Cd pollution are warranted.

Cadmium Exposure and Coronary Artery Atherosclerosis: A Cross-Sectional Population-Based Study of Swedish Middle-Aged Adults.

BACKGROUND: The general population is ubiquitously exposed to the toxic metal cadmium through the diet and smoking. Cadmium exposure is associated with increased morbidity and mortality in myocardial infarction and stroke. Atherosclerosis is the main underlying mechanism of myocardial infarction. However, associations between cadmium and coronary artery atherosclerosis have not been examined. OBJECTIVES: Our study sought to examine the hypothesis that blood cadmium (B-Cd) is positively associated with coronary artery calcification, as a measure of coronary artery atherosclerosis in the population-based Swedish SCAPIS study. METHODS: Our analysis included 5,627 individuals (51% women), age 50-64 y, enrolled from 2013 to 2018. The coronary artery calcium score (CACS) was obtained from computed tomography. Blood cadmium was determined by inductively coupled plasma mass spectrometry (ICP-MS). Associations between B-Cd and coronary artery calcium score (CACS Agatston score) were evaluated using prevalence ratios (PRs) in models adjusted for sex, age, smoking, hypertension, diabetes, low-density cholesterol/high-density cholesterol ratio, and family history. RESULTS: The median B-Cd concentration was 0.24µg/L. The prevalence of positive coronary artery calcium (CACS>0) was 41% and the prevalence of CACS≥100 was 13%. Relative to the lowest quartile (Q) of B-Cd (<0.16µg/L), the highest quartile (median 0.63µg/L) was associated with a small but significant increase in CACS>0 (PR 1.1; 95% CI: 1.0, 1.3), and a greater relative increase in CACS≥100 (PR 1.6; 95% CI: 1.3, 2.0). When restricted to 2,446 never-smokers, corresponding PRs were 1.1 (95% CI 0.9, 1.3) for CACS>0 (63 cases in Q4) and 1.7 (95% CI 1.1, 2.7) for CACS≥100 (17 cases in Q4). DISCUSSION: Blood cadmium in the highest quartile was associated with CACS in a general population sample with low to moderate cadmium exposure. This supports the hypothesis that atherosclerosis is an important mechanism underlying the associations between cadmium and incident cardiovascular disease. The findings suggest that public health measures to reduce cadmium exposure are warranted. https://doi.org/10.1289/EHP8523.

Exposures to lead during urban combat training.

Lead exposure is still a major concern for occupations that regularly train or work with firearms, such as law enforcement and military personnel. Due to the increasing number of women of fertile age in such professions, there is a strong incentive to monitor lead exposures during firearms training. Personal air sampling was performed during two sessions of a nine-day urban combat training (UCT) course for cadets in the Swedish Armed Forces, one session employing leaded ammunition (leaded scenario) and one session employing unleaded ammunition (unleaded scenario). Blood lead levels (BLLs) were measured before and after the course for 42 cadets and five instructors. During the leaded scenario, the instructors' airborne exposure (geometric mean, GM, 72.0 µg/m3) was higher than that of cadets (GM 42.9 µg/m3). During the unleaded scenario, airborne concentrations were similar for instructors and cadets and considerably lower than during the leaded scenario (GM 2.9 µg/m3). Despite comparably low external lead exposures during the course, we saw a statistically significant increase in systemic exposure for cadets (BLL GM increased from 1.09 to 1.71 µg/dL, p < 0.001). For the five instructors, notable differences were seen depending on task. The largest increase was seen for the two instructors performing close supervision during the leaded scenario (BLL GM increased from 2.41 µg/dL to 4.83 µg/dL). For the remaining three instructors the BLLs were unchanged (BLL GMs were 1.25 µg/dL before the course and 1.26 µg/dL after). None of the participants exceeded the applicable biological exposure limits, but extrapolating our findings shows that instructors in the leaded scenario may reach levels around 10 µg/dL after a year of repeated exposures. We conclude that comparably low airborne concentrations can contribute to the body burden of lead and that additional measures to reduce exposure are warranted, particularly for instructors.

Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease.

BACKGROUND: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. OBJECTIVE: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. METHODS: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-ß (Aß) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. RESULTS: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aß42, T-tau, P-tau, and CSF/serum albumin ratios (p < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOEɛ4 carriers. CONCLUSION: CSF iron levels are elevated with cerebral microbleeds in APOEɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.

A Possible Mechanism behind Faster Clearance and Higher Peak Concentrations of Cardiac Troponin I Compared with Troponin T in Acute Myocardial Infarction.

BACKGROUND: Although cardiac troponin I (cTnI) and troponin T (cTnT) form a complex in the human myocardium and bind to thin filaments in the sarcomere, cTnI often reaches higher concentrations and returns to normal concentrations faster than cTnT in patients with acute myocardial infarction (MI). METHODS: We compared the overall clearance of cTnT and cTnI in rats and in patients with heart failure and examined the release of cTnT and cTnI from damaged human cardiac tissue in vitro. RESULTS: Ground rat heart tissue was injected into the quadriceps muscle in rats to simulate myocardial damage with a defined onset. cTnT and cTnI peaked at the same time after injection. cTnI returned to baseline concentrations after 54 h, compared with 168 h for cTnT. There was no difference in the rate of clearance of solubilized cTnT or cTnI after intravenous or intramuscular injection. Renal clearance of cTnT and cTnI was similar in 7 heart failure patients. cTnI was degraded and released faster and reached higher concentrations than cTnT when human cardiac tissue was incubated in 37°C plasma. CONCLUSION: Once cTnI and cTnT are released to the circulation, there seems to be no difference in clearance. However, cTnI is degraded and released faster than cTnT from necrotic cardiac tissue. Faster degradation and release may be the main reason why cTnI reaches higher peak concentrations and returns to normal concentrations faster in patients with MI.

Blood Lead Levels and Risk of Atherosclerosis in the Carotid Artery: Results from a Swedish Cohort.

BACKGROUND: Lead exposure has been associated with increased incidence of adverse clinical cardiovascular outcomes. Atherosclerosis has been suggested as one of the underlying mechanisms, and findings from experimental studies support this, but human data are scarce. OBJECTIVES: Our objective was to determine the association between environmental lead exposure based on blood lead (B-Pb) concentrations and the prevalence of atherosclerotic plaque in the carotid artery. METHODS: We used cross-sectional data from the Malmö Diet and Cancer Study cardiovascular cohort (MDCS-CC; recruitment in 1991-1994) covering 4,172 middle-aged men and women. B-Pb at baseline, measured by inductively coupled plasma mass spectrometry, was used as the exposure biomarker. The presence of atherosclerotic plaque in the carotid artery was determined by B-mode ultrasonography. We used logistic regression to estimate odds ratios (ORs) for prevalence of plaque in the carotid artery according to B-Pb quartiles. RESULTS: The median B-Pb was 25µg/L (range: 1.5-258), and 36% of the cohort had any atherosclerotic plaque. After controlling for confounders and known cardiovascular risk factors, the OR for prevalence of plaque in the highest quartile (Q4) of B-Pb compared with the lowest quartile (Q1) was 1.35 (95% CI: 1.09, 1.66) in the total group, 1.58 (95% CI: 1.20, 2.08) among women, and 1.18 (95% CI: 0.83, 1.69) among men. Among women, associations were limited to those who were postmenopausal [OR for Q4 vs. Q1=1.72 (95% CI: 1.26, 2.34) vs. OR=0.96 (95% CI: 0.49, 1.89 in premenopausal women)]. Associations were weak and nonsignificant in never-smokers [OR for Q4 vs. Q1=1.14 (95% CI: 0.81, 1.61)]. DISCUSSION: Our study shows an association between B-Pb concentrations and occurrence of atherosclerotic plaque in the carotid artery, adding evidence for an underlying pro-atherogenic role of lead in cardiovascular disease. Associations appeared to be limited to postmenopausal (vs. premenopausal) women. https://doi.org/10.1289/EHP5057.

Cardiac arrest in Wilson's disease after curative liver transplantation: a life-threatening complication of myocardial copper excess?

We report the case of a 38-year-old man who presented with cardiac arrest 1 year after curative liver transplantation for Wilson's disease. Clinical work-up proofed myocardial copper and iron accumulation using mass spectrometry, which led most likely to myocardial fibrosis as visualized by cardiovascular magnetic resonance (unprecedented delayed enhancement pattern) and endomyocardial biopsy. Consequently, cardiac arrest due to ventricular fibrillation and subsequent episodes of sustained ventricular tachycardia were considered as primary cardiac manifestation of Wilson's disease. This can, as illustrated by our case, occur even late after curative liver transplantation, which is an important fact that treating physicians should be aware of during clinical follow-up of these patients.

Blood Lead Levels and Decreased Kidney Function in a Population-Based Cohort.

BACKGROUND: Environmental lead exposure has been associated with decreased kidney function, but evidence from large prospective cohort studies examining low exposure levels is scarce. We assessed the association of low levels of lead exposure with kidney function and kidney disease. STUDY DESIGN: Prospective population-based cohort. SETTING & PARTICIPANTS: 4,341 individuals aged 46 to 67 years enrolled into the Malmö Diet and Cancer Study-Cardiovascular Cohort (1991-1994) and 2,567 individuals subsequently followed up (2007-2012). PREDICTOR: Blood lead concentrations in quartiles (Q1-Q4) at baseline. OUTCOMES: Change in estimated glomerular filtration rate (eGFR) between the baseline and follow-up visit based on serum creatinine level alone or in combination with cystatin C level. Chronic kidney disease (CKD) incidence (185 cases) through 2013 detected using a national registry. MEASUREMENTS: Multivariable-adjusted linear regression models to assess associations between lead levels and eGFRs at baseline and follow-up and change in eGFRs over time. Cox regression was used to examine associations between lead levels and CKD incidence. Validation of 100 randomly selected CKD cases showed very good agreement between registry data and medical records and laboratory data. RESULTS: At baseline, 60% of study participants were women, mean age was 57 years, and median lead level was 25 (range, 1.5-258) µg/L. After a mean of 16 years of follow-up, eGFR decreased on average by 6mL/min/1.73m2 (based on creatinine) and 24mL/min/1.73m2 (based on a combined creatinine and cystatin C equation). eGFR change was higher in Q3 and Q4 of blood lead levels compared with Q1 (P for trend = 0.001). The HR for incident CKD in Q4 was 1.49 (95% CI, 1.07-2.08) compared with Q1 to Q3 combined. LIMITATIONS: Lead level measured only at baseline, moderate number of CKD cases, potential unmeasured confounding. CONCLUSIONS: Low-level lead exposure was associated with decreased kidney function and incident CKD. Our findings suggest lead nephrotoxicity even at low levels of exposure.

Circulating cadmium concentration and risk of aortic aneurysms: A nested case-control study within the Malmö Diet and Cancer cohort.

BACKGROUND AND AIMS: Diet and smoking expose the general population to cadmium (Cd), which is a toxic metal that accumulates in the arterial wall. In experimental studies, Cd causes reductions in proliferation of smooth muscle cells and cellular synthesis of procollagen. The aim of this study was to examine whether blood Cd levels, a valid measure of Cd exposure, are associated with increased risk of abdominal aortic aneurysm (AAA). METHODS: All middle-aged men and women enrolled in the Malmö Diet and Cancer study (n = 30 447) were followed from the baseline examination in 1991-1996 through 2009. A total of 297 cases with AAA and two randomly selected control subjects for each case, matched for age and sex, were included. Blood Cd was analysed by inductively coupled plasma mass spectrometry. Diagnoses of AAA, thoracic aortic aneurysm and aortic dissection were obtained from registers. RESULTS: Increased blood Cd was associated with increased risk of incident AAA after adjustment for smoking and other established risk factors for AAA. The highest tertile of blood Cd concentrations had a rate ratio of 2.5 (95% confidence interval 1.3, 5.0) for incident AAA. Concentration of blood Cd (log transformed) was not associated with AAA in never-smokers (n = 24). CONCLUSIONS: Blood Cd levels corresponding to the upper tertile of the distribution in the age- and sex-matched control group were associated with a 2.5-fold increase in rate ratio for incident AAA. This relationship was not found in the small group of never-smokers.

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 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.

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 as measured in blood in relation to macrophage density in symptomatic atherosclerotic plaques from human carotid artery.

BACKGROUND AND AIMS: The general population is exposed to cadmium through diet and smoking. Cadmium is pro-atherogenic and pro-inflammatory in experimental and observational studies. Cadmium levels in blood and carotid plaque endarterectomies correlate. Cadmium concentrations are much higher in plaque-areas that most frequently rupture. Here we investigated if blood cadmium concentrations are associated with macrophage density and the accumulation of CD14 as indicator of macrophage activation by lipopolysaccharide (LPS) in endarterectomies from patients with symptomatic carotid plaques. METHODS: Endarterectomies from ninety nine patients were fixed in formalin, embedded in paraffin, serially sectioned and stained for assessment of morphology. As predefined, the two section levels with most prevalent plaque rupture were used for further analyses. Macrophages were assessed as area of staining for CD68 (%). Blood cadmium was measured with ICP-MS. RESULTS: The CD68 median [25,75 percentiles] from the average of both sections were higher in cadmium tertile 3 than in tertile 1 (9.8 [4.9,16.1] % and 3.8 (0.6,12.4) %, p = 0.017). This difference remained in a multiple linear regression analysis with (10)log meanCD68 as dependent variable and adjustment for sex, age, smoking, statin treatment, index event, time between event and surgery (beta coefficient 0.44 [95% CI 0.05-0.87]. CD14 was not associated with blood cadmium. CONCLUSIONS: The results showed that blood cadmium was associated with proinflammatory macrophage density in the sections of carotid plaques with most frequent rupture, previously shown to contain most cadmium. No association between cadmium and LPS-mediated macrophage-activation was found. Cadmium exposure may promote plaque inflammation.

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.

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.

Morphine brain pharmacokinetics at very low concentrations studied with accelerator mass spectrometry and liquid chromatography-tandem mass spectrometry.

Morphine has been predicted to show nonlinear blood-brain barrier transport at lower concentrations. In this study, we investigated the possibility of separating active influx of morphine from its efflux by using very low morphine concentrations and compared accelerator mass spectrometry (AMS) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a method for analyzing microdialysis samples. A 10-min bolus infusion of morphine, followed by a constant-rate infusion, was given to male rats (n = 6) to achieve high (250 ng/ml), medium (50 ng/ml), and low (10 ng/ml) steady-state plasma concentrations. An additional rat received infusions to achieve low (10 ng/ml), very low (2 ng/ml), and ultralow (0.4 ng/ml) concentrations. Unbound morphine concentrations from brain extracellular fluid and blood were sampled by microdialysis and analyzed by LC-MS/MS and AMS. The average partition coefficient for unbound drug (K(p,uu)) values for the low and medium steady-state levels were 0.22 ± 0.08 and 0.21 ± 0.05, respectively, when measured by AMS [not significant (NS); p = 0.5]. For the medium and high steady-state levels, K(p,uu) values were 0.24 ± 0.05 and 0.26 ± 0.05, respectively, when measured by LC-MS/MS (NS; p = 0.2). For the low, very low, and ultralow steady-state levels, K(p,uu) values were 0.16 ± 0.01, 0.16 ± 0.02, and 0.18 ± 0.03, respectively, when measured by AMS. The medium-concentration K(p,uu) values were, on average, 16% lower when measured by AMS than by LC-MS/MS. There were no significant changes in K(p,uu) over a 625-fold concentration range (0.4-250 ng/ml). It was not possible to separate active uptake transport from active efflux using these low concentrations. The two analytical methods provided indistinguishable results for plasma concentrations but differed by up to 38% for microdialysis samples; however, this difference did not affect our conclusions.