Caterina Vacchi-Suzzi

Dietary Intake Estimates and Urinary Cadmium Levels in Danish Postmenopausal Women

Background Cadmium is a known carcinogen that can disrupt endocrine signalling. Cigarette smoking and food are the most common routes of non-occupational exposure to cadmium. Cadmium accumulates in the kidney and can be measured in urine, making urine cadmium (U-Cd) a biomarker of long-term exposure. However dietary-cadmium (D-Cd) intake estimates are often used as surrogate indicator of cadmium exposure in non-smoking subjects. It is therefore important to investigate the concordance between D-Cd estimates obtained with Food Frequency Questionnaires and U-Cd. Methods U-Cd levels were compared with estimated dietary-cadmium (D-Cd) intake in 1764 post-menopausal women from the Danish Diet, Cancer and Health cohort. For each participant, a food frequency questionnaire, and measures of cadmium content in standard recipes were used to judge the daily intake of cadmium, normalized by daily caloric intake. Cadmium was measured by ICP-MS in spot urine sampled at baseline and normalized by urinary creatinine. Information on diet, socio-demographics and smoking were self-reported at baseline. Results Linear regressions between U-Cd and D-Cd alone revealed minimal but significant positive correlation in never smokers (R2 = 0.0076, β = 1.5% increase per 1 ng Cd kcal-1, p = 0.0085, n = 782), and negative correlation in current smokers (R2 = 0.0184, β = 7.1% decrease per 1 ng Cd kcal-1 change, p = 0.0006, n = 584). In the full study population, most of the variability in U-Cd was explained by smoking status (R2 = 0.2450, n = 1764). A forward selection model revealed that the strongest predictors of U-Cd were age in never smokers (Δ R2 = 0.04), smoking duration in former smokers (Δ R2 = 0.06) and pack-years in current smokers (Δ R2 = 0.07). Food items that contributed to U-Cd were leafy vegetables and soy-based products, but explained very little of the variance in U-Cd. Conclusions Dietary-Cd intake estimated from food frequency questionnaires correlates only minimally with U-Cd biomarker, and its use as a Cd exposure indicator may be of limited utility in epidemiologic studies.

Is Urinary Cadmium a Biomarker of Long-term Exposure in Humans? A Review

Cadmium is a naturally-occurring element, and humans are exposed from cigarettes, food, and industrial sources. Following exposure, cadmium accumulates in the kidney and is slowly released into the urine, usually proportionally to the levels found in the kidneys. Cadmium levels in a single spot urine sample have been considered indicative of long-term exposure to cadmium; however, such a potentially exceptional biomarker requires careful scrutiny. In this review, we report good to excellent temporal stability of urinary cadmium (intraclass correlation coefficient 0.66–0.81) regardless of spot urine or first morning void sampling. Factors such as changes in smoking habits and diseases characterized by increased excretion of proteins may produce short-term changes in urinary cadmium levels. We recommend that epidemiologists use this powerful biomarker in prospective studies stratified by smoking status, along with thoughtful consideration of additional factors that can influence renal physiology and cadmium excretion.

Mercury exposure and a shift toward oxidative stress in avid seafood consumers.

Mechanisms of mercury (Hg) toxicity at low doses from seafood consumption, the most common exposure route, are not well understood. We tested the hypothesis that seafood Hg exposure is related to a shift in redox status, indicated by a decrease in the ratio of reduced to oxidized glutathione (GSH:GSSG) in blood, or increase in redox potential (Eh). We also examined whether key seafood nutrients (selenium (Se), omega-3 fatty acids) confound or modify this shift. We measured blood concentrations of total Hg, Se, GSH, GSSG, and the Omega-3 Index (% omega-3s of total fatty acids in red blood cell membranes) in seafood consumers in Long Island, NY. We examined relationships between Hg, GSH:GSSG ratio and Eh. Elevated blood Hg (>5.8µgL(-1)) was associated with lower GSH:GSSG (β=-116.73, p=0.01), with no evidence of confounding by Se or Omega-3 Index. However, in models stratified by Omega-3 Index levels, Hg-GSH:GSSG associations were weakened among those with high Omega-3 Index levels (>6% of fatty acids, β=-63.46, p=0.28), and heightened among those with low Omega-3 Index (β=-182.53, p<0.01). We observed comparable patterns for Eh in relation to Hg. These results support the hypothesis that Hg exposure from seafood is linked to a shift in redox status toward oxidative stress, modified by omega-3 fatty acids in this population. Further work should examine the role of different seafood nutrients and Hg-induced shifts in redox status in the diverse health effects associated with elevated Hg exposure.

Temporal variability of urinary cadmium in spot urine samples and first morning voids

Cadmium is a carcinogenic heavy metal. Urinary levels of cadmium are considered to be an indicator of long-term body burden, as cadmium accumulates in the kidneys and has a half-life of at least 10 years. However, the temporal stability of the biomarker in urine samples from a non-occupationally exposed population has not been rigorously established. We used repeated measurements of urinary cadmium (U-Cd) in spot urine samples and first morning voids from two separate cohorts, to assess the temporal stability of the samples. Urine samples from two cohorts including individuals of both sexes were measured for cadmium and creatinine. The first cohort (Home Observation of Perinatal Exposure (HOPE)) consisted of 21 never-smokers, who provided four first morning urine samples 2–5 days apart, and one additional sample roughly 1 month later. The second cohort (World Trade Center-Health Program (WTC-HP)) consisted of 78 individuals, including 52 never-smokers, 22 former smokers and 4 current smokers, who provided 2 spot urine samples 6 months apart, on average. Intra-class correlation was computed for groups of replicates from each individual to assess temporal variability. The median creatinine-adjusted U-Cd level (0.19 and 0.21 μg/g in the HOPE and WTC-HP, respectively) was similar to levels recorded in the United States by the National Health and Nutrition Examination Survey. The intra-class correlation (ICC) was high (0.76 and 0.78 for HOPE and WTC-HP, respectively) and similar between cohorts, irrespective of whether samples were collected days or months apart. Both single spot or first morning urine cadmium samples show good to excellent reproducibility in low-exposure populations.

Blood cadmium and depressive symptoms: Confounded by cigarette smoking

Our aim was to explore the association between blood cadmium (BCd) and depressive symptoms, adjusting for pack years and blood cotinine, and also stratifying by smoking status. Using data from the US National Health and Nutrition Examination Survey (NHANES) 2005-2012, we categorized depressive symptoms using the PHQ-9 (Patient Health Questionnaire-9) survey and modeled depressive symptoms in relation to BCd adjusted for blood cotinine, pack years of smoking, and other covariates. We also stratified by self-reported smoking status (current, former, never). There were 11,209 subjects from 2005 to 2012, age ≥ 18 with PHQ-9, smoking, and blood cadmium data available. 876 (7.8%) met criteria for depressive symptoms. Depressive symptoms were associated with BCd levels in a crude model and with adjustment for pack years and cotinine. The association disappeared when analyzed among current, former, or never smokers. Consistent with the literature, we found an association between BCd and depressive symptoms; however, that association disappears in analyses stratified by smoking status. This suggests residual confounding may be present. It is important to stratify by smoking status when investigating health outcomes associated with BCd.

Expression of Genes Involved in Stress, Toxicity, Inflammation, and Autoimmunity in Relation to Cadmium, Mercury, and Lead in Human Blood: A Pilot Study

There is growing evidence of immunotoxicity related to exposure to toxic trace metals, and an examination of gene expression patterns in peripheral blood samples may provide insights into the potential development of these outcomes. This pilot study aimed to correlate the blood levels of three heavy metals (mercury, cadmium, and lead) with differences in gene expression in 24 participants from the Long Island Study of Seafood Consumption. We measured the peripheral blood mRNA expression of 98 genes that are implicated in stress, toxicity, inflammation, and autoimmunity. We fit multiple linear regression models with multiple testing correction to correlate exposure biomarkers with mRNA abundance. The mean blood Hg in this cohort was 16.1 µg/L, which was nearly three times the Environmental Protection Agency (EPA) reference dose (5.8 µg/L). The levels of the other metals were consistent with those in the general population: the mean Pb was 26.8 µg/L, and the mean Cd was 0.43 µg/L. The expression of three genes was associated with mercury, four were associated with cadmium, and five were associated with lead, although none were significant after multiple testing correction. Little evidence was found to associate metal exposure with mRNA abundance for the tested genes that were associated with stress, toxicity, inflammation, or autoimmunity. Future work should provide a more complete picture of physiological reactions to heavy metal exposure.

Low levels of lead and glutathione markers of redox status in human blood

Exposure to lead (Pb) is implicated in a plethora of health threats in both adults and children. Increased exposure levels are associated with oxidative stress in the blood of workers exposed at occupational levels. However, it is not known whether lower Pb exposure levels are related to a shift toward a more oxidized state. To assess the association between blood lead level (BLL) and glutathione (GSH) redox biomarkers in a population of healthy adults, BLL and four GSH markers (GSH, GSSG, GSH/GSSG ratio and redox potential Eh) were measured in the blood of a cross-sectional cohort of 282 avid seafood-eating healthy adults living on Long Island (NY). Additionally, blood levels of two other metals known to affect GSH redox status, selenium (Se) and mercury (Hg), and omega-3 index were tested for effect modification. Regression models were further adjusted for demographic and smoking status. Increasing exposure to Pb, measured in blood, was not associated with GSSG, but was associated with lower levels of GSH/GSSG ratio and more positive GSH redox potential Eh, driven by its association with GSH. No effect modification was observed in analyses stratified by Hg, Se, omega-3 index, sex, age, or smoking. Blood Pb is associated with lower levels of GSH and the GSH/GSSG ratio in this cross-sectional study of healthy adults.

Erratum to: Is Urinary Cadmium a Biomarker of Long-term Exposure in Humans? A Review

Cadmium is a naturally-occurring element, and humans are exposed from cigarettes, food, and industrial sources. Following exposure, cadmium accumulates in the kidney and is slowly released into the urine, usually proportionally to the levels found in the kidneys. Cadmium levels in a single spot urine sample have been considered indicative of long-term exposure to cadmium; however, such a potentially exceptional biomarker requires careful scrutiny. In this review, we report good to excellent temporal stability of urinary cadmium (intraclass correlation coefficient 0.66–0.81) regardless of spot urine or first morning void sampling. Factors such as changes in smoking habits and diseases characterized by increased excretion of proteins may produce short-term changes in urinary cadmium levels. We recommend that epidemiologists use this powerful biomarker in prospective studies stratified by smoking status, along with thoughtful consideration of additional factors that can influence renal physiology and cadmium excretion.