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Background: Cadmium (Cd) is a toxic metal, which the non-smoking population is mainly exposed to through diet. Current health-based guidance values are based on renal toxicity; however, emerging evidence suggests that bone and the cardiovascular system might be more sensitive to Cd exposure., Objective: To assess the association of urinary Cd (U-Cd) with incidence of fractures, myocardial infarction, heart failure, ischemic stroke and mortality in postmenopausal women., Methods: We used data from 4024 women, aged 56-85 in the population-based prospective Swedish Mammography Cohort-Clinical. U-Cd was measured by ICP-MS at baseline (2004-2009) and categorized into tertiles. Incident cases of the outcomes were ascertained via register linkage through 2019. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression., Results: The median U-Cd at baseline was 0.33 µg/g creatinine (cr) (5-95 percentiles 0.15-0.77). We ascertained the following incident cases: 903 first fracture of any type, 149 myocardial infarction, 174 heart failure, 162 ischemic stroke and 545 total deaths during the approximately 11 years of follow-up. U-Cd was dose-dependently associated with risk of any fracture (HR: 1.20, 95% CI: 1.01 to 1.43, p trend : 0.04) and all-cause mortality (HR: 1.38, 95% CI: 1.10 to 1.74, p trend : <0.01) when comparing the highest tertile of U-Cd (median 0.54 µg/g cr) with the lowest (median 0.20 µg/g cr). No clear associations were observed for myocardial infarction, heart failure or stroke., Discussion: Long-term Cd exposure might be associated with risk of fractures and all-cause mortality at lower levels than previously suggested., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cadmium in tobacco smoke may contribute to the development of pulmonary emphysema. However, there is poor understanding of the mechanisms behind the pathogenic role of cadmium in this and other smoking-related lung diseases. The traditional focus on the total body burden of cadmium, estimated through analysis of urine, may not fully reflect the local burden of cadmium, since it is inhaled by smokers. Thus, assessing the local accumulation of cadmium in the lungs appears more relevant, given that there is tissue-specific retention of cadmium.In this review, we outline the principal sources of cadmium exposure and the clinical effects of occupational exposure. In addition, we review evidence on local cadmium and its association with alterations in innate immunity in tobacco smokers. Moreover, we scrutinise the data on cadmium as a cause of lung disease in translational models.We conclude that cadmium may contribute to smoking-related lung diseases, possibly via an altered redox balance and by making macrophages dysfunctional. However, there is a need for new studies on local cadmium levels and their relation to pathology in long-term tobacco smokers, as well as for more in-depth studies on cellular and molecular mechanisms, to elucidate the importance of cadmium in smoking-related lung diseases., Competing Interests: Conflict of interest: G. Ganguly reports grants from VINNOVA during the conduct of the study., (Copyright ©ERS 2018.)

Recent epidemiological as well as in vivo and in vitro studies collectively suggest that the metalloestrogen cadmium (Cd) could be a potential risk factor for hormone-related cancers in particularly breast cancer. Assessment of the association between Cd exposure and levels of endogenous sex hormones is of pivotal importance, as increased levels of such have been associated with a higher risk of breast cancer in postmenopausal women. The present study investigated the perceived relationship (multivariable-adjusted linear regression analyses) between Cd exposure [blood Cd (B-Cd) and urinary Cd (U-Cd)], and serum levels of androstenedione, testosterone, estradiol, and sex-hormone binding globulin (SHBG), in 438 postmenopausal Swedish women without hormone replacement therapy (HRT). A significant positive association between B-Cd (median 3.4 nmol/L) and serum testosterone levels, as well as a significant inverse association between B-Cd and serum estradiol levels and with the estradiol/testosterone ratio were encountered. However, U-Cd (median 0.69 nmol/mmol creatinine) was inversely associated with serum estradiol levels only. Our data may suggest that Cd interferes with the levels of testosterone and estradiol in postmenopausal women, which might have implications for breast cancer risk., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The kidney is widely regarded as the critical organ for cadmium toxicity, however, considerable uncertainty remains regarding the clinical significance of the renal effects of cadmium at low levels of exposure. Food is the primary source of cadmium exposure in the general population with tobacco representing an important additional source. We aimed to assess the association between dietary cadmium exposure and chronic kidney disease (CKD) incidence in two large population-based, prospective cohorts of men (Cohort of Swedish Men (COSM)) and women (The Swedish Mammography Cohort (SMC)) with no history of kidney disease. At baseline 1997, men (45-79 years) and women (48-83 years), completed a self-administered questionnaire on diet and lifestyle. Dietary cadmium exposure for each individual was estimated using dietary data and concentrations of cadmium in food. During 13 years of follow-up, we ascertained 599 incident cases of CKD among men (in 481,591 person-years) and 253 cases among women (in 415,432 person-years) through linkage of the cohorts to national inpatient and outpatient registers. Hazard ratios (HR) were calculated using the Cox proportional-hazard regression model. Estimated dietary cadmium exposure was not associated with increased CKD incidence among men HR 0.97 (95% confidence interval (CI): 0.77-1.21) or women HR 0.74 (95% CI: 0.53-1.04), comparing highest tertile with lowest. Our results do not support a strong association between dietary cadmium exposure and CKD at the exposure levels seen in the general population., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Background: Exposure to cadmium (Cd) has long been recognized as a health hazard, both in industry and in general populations with high exposure. Under the currently prevailing health risk assessment, the relationship between urinary Cd (U-Cd) concentrations and tubular proteinuria is used. However, doubts have recently been raised regarding the justification of basing the risk assessment on this relationship at very low exposure., Objectives: Our objective was to review available information on health effects of Cd exposure with respect to human health risk assessment., Discussion: The associations between U-Cd and urinary proteins at very low exposure may not be due to Cd toxicity, and the clinical significance of slight proteinuria may also be limited. More importantly, other effects have been reported at very low Cd exposure. There is reason to challenge the basis of the existing health risk assessment for Cd. Our review of the literature found that exposure to low concentrations of Cd is associated with effects on bone, including increased risk of osteoporosis and fractures, and that this observation has implications for the health risk assessment of Cd. Other effects associated with Cd should also be considered, in particular cancer, although the information is still too limited for appropriate use in quantitative risk assessment., Conclusion: Non-renal effects should be considered critical effects in the health risk assessment of Cd.

Background: The toxic metal cadmium is suggested to increase the risk of cardiovascular disease, but only one incidence study has explored this association. We evaluated the association between quartiles of food frequency questionnaire-based estimates of cadmium exposure from food (the predominant source of exposure to the metal) and incident cardiovascular disease and its subtypes., Methods: From the population-based Swedish Mammography cohort, 33,333 women were followed prospectively from baseline (1997) through 2010. We estimated relative risks (RRs) with 95% confidence intervals (CIs) using Cox proportional hazard models., Results: During 12 years of follow-up, we identified 3155 incident cases of total cardiovascular disease (1322 cases of myocardial infarction and 1833 cases of total stroke [1485 ischemic and 208 hemorrhagic stroke]). Dietary cadmium exposure was not associated with risk of total cardiovascular disease, myocardial infarction, or total stroke or its subtypes. For total cardiovascular disease, the multivariable-adjusted RR comparing the highest quartile of cadmium exposure with the lowest was 0.96 (95% CI = 0.85-1.09). The corresponding RRs were 1.07 (0.88-1.29) for myocardial infarction, 0.90 (0.76-1.05) for total stroke, 0.89 (0.74-1.06) for ischemic stroke, and 1.11 (0.68-1.80) for hemorrhagic stroke., Conclusions: Our study lends no support to an overall association between low-level exposure to cadmium via food and incident cardiovascular disease.

Osteoporosis and its main health outcome, fragility fractures, are large and escalating public health problems. Cadmium, a widespread food contaminant, is a proposed risk factor; still the association between estimated dietary cadmium exposure and bone mineral density (BMD) has never been assessed. Within a sub-cohort of the Swedish Mammography Cohort, we assessed dietary cadmium exposure based on a food frequency questionnaire (1997) and urinary cadmium (2004-2008) in relation to total-body BMD and risk of osteoporosis and fractures (1997-2009) among 2676 women (aged 56-69 years). In multivariable-adjusted linear regression, dietary cadmium was inversely associated with BMD at the total body and lumbar spine. After further adjustment for dietary factors important for bone health and cadmium bioavailability--calcium, magnesium, iron and fiber, the associations became more pronounced. A 32% increased risk of osteoporosis (95% CI: 2-71%) and 31% increased risk for any first incident fracture (95% CI: 2-69%) were observed comparing high dietary cadmium exposure (≥13 μg/day, median) with lower exposures (<13 μg/day). By combining high dietary with high urinary cadmium (≥0.50 μg/g creatinine), odds ratios among never-smokers were 2.65 (95% CI: 1.43-4.91) for osteoporosis and 3.05 (95% CI: 1.66-5.59) for fractures. In conclusion, even low-level cadmium exposure from food is associated with low BMD and an increased risk of osteoporosis and fractures. The partial masking of the associations by essential nutrients indicates important interplay between dietary factors and contaminants present in food. In separate analyses, dietary and urinary cadmium underestimated the association with bone effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Cadmium is a widespread environmental pollutant with adverse effects on kidneys and bone, but with insufficiently elucidated public health consequences such as risk of end-stage renal diseases, fractures and cancer. Urinary cadmium is considered a valid biomarker of lifetime kidney accumulation from overall cadmium exposure and thus used in the assessment of cadmium-induced health effects. We aimed to assess the relationship between dietary cadmium intake assessed by analyses of duplicate food portions and cadmium concentrations in urine and blood, taking the toxicokinetics of cadmium into consideration., Methods: In a sample of 57 non-smoking Swedish women aged 20-50 years, we assessed Pearson's correlation coefficients between: 1) Dietary intake of cadmium assessed by analyses of cadmium in duplicate food portions collected during four consecutive days and cadmium concentrations in urine, 2) Partial correlations between the duplicate food portions and urinary and blood cadmium concentrations, respectively, and 3) Model-predicted urinary cadmium concentration predicted from the dietary intake using a one-compartment toxicokinetic model (with individual data on age, weight and gastrointestinal cadmium absorption) and urinary cadmium concentration., Results: The mean concentration of cadmium in urine was 0.18 (+/- s.d.0.12) μg/g creatinine and the model-predicted urinary cadmium concentration was 0.19 (+/- s.d.0.15) μg/g creatinine. The partial Pearson correlations between analyzed dietary cadmium intake and urinary cadmium or blood concentrations were r = 0.43 and 0.42, respectively. The correlation between diet and urinary cadmium increased to r = 0.54 when using a one-compartment model with individual gastrointestinal cadmium absorption coefficients based on the women's iron status., Conclusions: Our results indicate that measured dietary cadmium intake can reasonably well predict biomarkers of both long-term kidney accumulation (urine) and short-term exposure (blood). The predictions are improved when taking data on the iron status into account.

Cadmium is an osteotoxic metal present in food. It causes multiple fractures in those highly exposed and is associated with reduced bone mineral density at considerably lower exposures. Little is known about fracture rates following low-level cadmium exposure. We assessed the associations between dietary cadmium exposure and fracture incidence. Within a population-based prospective cohort of 22,173 Swedish men, we estimated individual dietary cadmium exposure using food frequency questionnaire data and levels of cadmium in food. The average intake was 19 µg/day. Hazard ratios (HRs) for any fracture and hip fracture were estimated using Cox's regression. During 10 years of follow-up, we ascertained 2183 cases of any fracture and 374 hip fractures by computerized linkage of the cohort to registry data. Multivariable-adjusted dietary cadmium intake was associated with a statistically significant 19% [HR = 1.19, 95% confidence interval (CI) 1.06-1.34] higher rate of any fracture comparing highest tertile with lowest (p ≤ .01 for trend). Moreover, men in the highest tertile of dietary cadmium and lowest tertile of fruit and vegetable consumption had a 41% higher rate of any fracture compared with contrasting tertiles. Hip fracture rates also were higher in the highest tertile of cadmium intake but only statistically significant among never smokers (HR = 1.70, 95% CI 1.04-2.77). Our results indicate that dietary cadmium exposure at general population levels is associated with an increased rate of fractures among men. This association was independent of smoking and was most pronounced among men with low fruit and vegetable consumption., (Copyright © 2011 American Society for Bone and Mineral Research.)

Human biomonitoring (HBM) data in Europe are often fragmented and collected in different EU countries and sampling periods. Exposure levels for children and adult women in Europe were evaluated over time. For the period 2000–2010, literature and aggregated data were collected in a harmonized way across studies. Between 2011–2012, biobanked samples from the DEMOCOPHES project were used. For 2014–2021, HBM data were generated within the HBM4EU Aligned Studies. Time patterns on internal exposure were evaluated visually and statistically using the 50th and 90th percentiles (P50/P90) for phthalates/DINCH and organophosphorus flame retardants (OPFRs) in children (5–12 years), and cadmium, bisphenols and polycyclic aromatic hydrocarbons (PAHs) in women (24–52 years). Restricted phthalate metabolites show decreasing patterns for children. Phthalate substitute, DINCH, shows a non-significant increasing pattern. For OPFRs, no trends were statistically significant. For women, BPA shows a clear decreasing pattern, while substitutes BPF and BPS show an increasing pattern coinciding with the BPA restrictions introduced. No clear patterns are observed for PAHs or cadmium. Although the causal relations were not studied as such, exposure levels to chemicals restricted at EU level visually decreased, while the levels for some of their substitutes increased. The results support policy efficacy monitoring and the policy-supportive role played by HBM. [ABSTRACT FROM AUTHOR]

Estrogen-like effects of cadmium (Cd) have been reported in several animal studies, and recent epidemiological findings suggest increased risk of hormone-dependent cancers after Cd exposure. The mechanisms underlying these effects are still under investigation. Our aim was to study the effects of Cd on cellular signaling pathways in vivo with special focus on estrogen signaling and to perform benchmark dose analysis on the effects. Transgenic adult ERE-luciferase male mice were exposed subcutaneously to 0.5–500 μg CdCl2 per kg body weight (bw) or 17α-ethinylestradiol (EE2) for 3 days. These doses had no effects on organ and bw or testicular histology, indicating subtoxic exposure levels. The transgene luciferase, reporting genomic estrogen response, was significantly increased by EE2 but not by Cd. However, Cd significantly affected kinase phosphorylation and endogenous gene expression. Interestingly, gene expression changes displayed a traditional dose-response relationship, with benchmark dose levels for the expression of Mt1, Mt2, p53, c-fos, and Mdm2 being 92.9, 19.9, 7.6, 259, and 25.9 μg/kg bw, respectively, but changes in kinase phosphorylation were only detected at low exposure levels. Phosphorylation of Erk1/2 was significantly increased even in the lowest dose group, 0.5 μg/kg bw, rendering pErk1/2 a more sensitive sensor of exposure than changes in gene expression. Collectively, our data suggest that the effects triggered by Cd in vivo are markedly concentration dependent. Furthermore, we conclude that the estrogen-like effects of Cd are likely to result from a mechanism different from steroidal estrogens. [ABSTRACT FROM PUBLISHER]

All people are exposed to cadmium (Cd) via food; smokers are additionally exposed. High Cd exposure is associated with severe bone damage, but the public health impact in relation to osteoporosis and fractures at low environmental exposure remains to be clarified. Within the population-based Swedish Mammography Cohort, we assessed urinary Cd [U-Cd, µg/g of creatinine (cr)] as a marker of lifetime exposure and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) among 2688 women. Register-based information on fractures was retrieved from 1997 to 2009. Associations were evaluated by multivariable regression analyses. In linear regression, U-Cd was inversely associated with BMD at the total body ( p < .001), femoral neck ( p = .025), total hip ( p = .004), lumbar spine ( p = .088), and volumetric femoral neck ( p = .013). In comparison with women with U-Cd < 0.50 µg/g of cr, those with U-Cd ≥ 0.75 µg/g of cr had odds ratios (ORs) of 2.45 [95% confidence interval (CI) 1.51-3.97] and 1.97 (95% CI 1.24-3.14) for osteoporosis at the femoral neck and lumbar spine, respectively. Among never-smokers, the corresponding ORs were 3.47 (95% CI 1.46-8.23) and 3.26 (95% CI 1.44-7.38). For any first fracture ( n = 395), the OR was 1.16 (95% CI 0.89-1.50) comparing U-Cd ≥ 0.50 µg/g of cr with lower levels. Among never-smokers, the ORs (95% CIs) were 2.03 (1.33-3.09) for any first fracture, 2.06 (1.28-3.32) for first osteoporotic fracture, 2.18 (1.20-3.94) for first distal forearm fracture, and 1.89 (1.25-2.85) for multiple incident fractures. U-Cd at low environmental exposure from food in a general population of women showed modest but significant association with both BMD and fractures, especially in never-smokers, indicating a larger concern than previously known. © 2011 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Toxicity of chemicals and environmental pollutants may be expressed differently in women than in men. Until recently, most research involved men. With the initiation of studies on the effects of environmental pollutants in women, there is increasing evidence of effects at specific periods in a woman's life; however, accrual of data is slow. This review focuses on the kinetics and effects of the toxic metals lead and cadmium related to menopause. Data on other metals are extremely limited. One of the few well described examples of menopausal-related effects of metals is the very painful disease called Itai-itai, which is a combination of osteoporosis, osteomalacia and renal damage caused by consumption of cadmium-polluted rice. Recent data demonstrate mild effects of cadmium on both kidney and bone with present environmental exposure levels. Women may be at greater risk than men, because of increased gastrointestinal uptake of cadmium at low iron stores, which is common in women of childbearing age. Thus, improvement of iron status, which often occurs at menopause, has a positive effect on cadmium exposure in the sense that its absorption decreases. Cadmium accumulates in the kidney with a half-life of 10-30 years. The health effects appear around menopause, concurrent with the peak in renal cadmium concentrations. About 90% of body lead is localised to bone. There is a significant release of bone lead after the menopause, in association with the acceleration of bone resorption. Thus, postmenopausal women may be at increased risk of adverse effects of lead. [ABSTRACT FROM AUTHOR]

Objectives. The purpose of this study was to determine the impact of iron status on cadmium dose among pregnant women. Methods. Iron status and cadmium concentration in blood, urine, and placenta were determined among women followed for 2 years from early pregnancy. Results. Blood cadmium and urinary cadmium were correlated with iron status throughout the study period. Urinary cadmium increased longitudinally among women with exhausted iron stores during their pregnancy. The increase in urinary cadmium with age was more pronounced in multiparous than in nulliparous women. Conclusions. Iron deficiency during pregnancy leads to increased cadmium absorption and body burden. Multiparous women exhibit additional increases with increasing age. (Am J Public Health. 2002;92:284-287) [ABSTRACT FROM AUTHOR]

Abstract: Cadmium exposure is associated with increased urinary calcium excretion. Hypercalciuria is recognised as a major risk factor for kidney stone formation. Increased prevalence of kidney stones among those occupationally exposed to cadmium has previously been suggested. Food is the main source of cadmium exposure in the general population with tobacco representing an important additional source among smokers. We aimed to assess the association between dietary cadmium exposure and kidney stone incidence in two large population-based, prospective cohorts of men (Cohort of Swedish Men; COSM) and women (The Swedish Mammography Cohort; SMC). Those with a history of kidney stones were excluded. At baseline 1997, men (45–79yrs) and women (48 to 83yrs), completed a self-administered questionnaire on diet and lifestyle. During 12years of follow-up, we ascertained 707 cases of kidney stones in men and 290 in women through linkage of the cohorts to the national inpatient and outpatient registers. Individual dietary cadmium exposure was estimated using dietary data and concentrations of cadmium in food. Hazard ratios (HR) were calculated using the Cox proportional hazards regression models with adjustment for other risk factors. Estimated dietary cadmium exposure was not associated with increased kidney stone incidence among men HR 0.97 (95% confidence interval (CI): 0.77–1.23) or women HR 0.99 (95% CI: 0.89–1.43), comparing the highest tertile with the lowest. In conclusion, our results do not support a strong association between dietary cadmium and kidney stone risk at the exposure levels seen in the general population. [Copyright &y& Elsevier]

Abstract: The main focus of this study was to evaluate the long-term effects of Cd on forearm bone mineral density after the cessation of the ingestion of Cd-polluted rice. A total of 458 persons (294 women, 164 men) from three Cd exposure areas (low, moderately, and heavy) participated in this study. Those living in the moderate and heavy exposure areas ceased ingesting Cd-polluted rice (0.51 and 3.7mg/kg, respectively) in 1996 (10 years prior to present analysis). The participants completed a questionnaire and bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) at the proximal radius and ulna. The changes and change percentage in forearm bone density and the prevalence of osteoporosis between 1998 and 2006 were used as markers of bone recovery. The Cd concentrations in urine (UCd) and blood (BCd) in 1998 were used as Cd exposure markers. The values of the BMD change and change percentage of groups in which UCd was above 5μg/g creatinine (μg/g crea) and BCd was above 10μg/L were significantly higher than those of the low-exposure groups (in women, p<0.001; in men, p>0.05). The BMD change and change percentage correlated positively with the UCd and BCd (in women, p<0.01; in men, p>0.05). Analysis of the Z-score revealed that the prevalence of osteoporosis in 2006 was higher than that in 1998 and increased along with the level of UCd and BCd in both women and men, especially for those subjects with the higher BCd [BCd>5μg/L, OR=3.45 (0.95–13.6); BCd>10μg/L, OR=4.51(1.57–13.54)] and UCd [UCd>10μg/g crea, OR=4.74 (1.82–12.81)] in women. It is concluded that decreasing dietary cadmium exposure at the population level is not associated with bone recovery at the individual level, and the adverse bone effects of Cd exposure persisted after the main source of Cd exposure had been blocked, especially in women. [Copyright &y& Elsevier]

Cadmium is a widespread environmental pollutant, which is associated with increased risk of osteoporosis. It has been proposed that cadmium's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. To test this, we assessed the association of cadmium-induced bone and kidney effects with serum 1,25-dihydroxyvitamin D (1,25(OH)2D); measured by enzyme immunoassay. For the assessment, we selected 85 postmenopausal women, based on low (0.14–0.39μg/L) or high (0.66–2.1μg/L) urinary cadmium, within a cross-sectional population-based women's health survey in Southern Sweden. We also measured 25-hydroxy vitamin D, cadmium in blood, bone mineral density and several markers of bone remodeling and kidney effects. Although there were clear differences in both kidney and bone effect markers between women with low and high cadmium exposure, the 1,25(OH)2D concentrations were not significantly different (median, 111pmol/L (5–95th percentile, 67–170pmol/L) in low- and 125pmol/L (66–200pmol/L) in high-cadmium groups; p=0.08). Also, there was no association between 1,25(OH)2D and markers of bone or kidney effects. It is concluded that the low levels of cadmium exposure present in the studied women, although high enough to be associated with lower bone mineral density and increased bone resorption, were not associated with lower serum concentrations of 1,25(OH)2D. Hence, decreased circulating levels of 1,25(OH)2D are unlikely to be the proposed link between cadmium-induced effects on kidney and bone. [Copyright &y& Elsevier]

Abstract: Cadmium is a widespread environmental contaminant present in food. The absorption in the intestine increases in individuals with low iron stores, but the effect of zinc deficiency is not clear. The aim of the present study was to assess the influence of iron and zinc status on cadmium accumulation in pregnant Bangladeshi women. We measured cadmium in urine from 890 women using inductively coupled plasma mass spectrometry (ICPMS). Further, we also measured ferritin and zinc in plasma. The median cadmium concentration in urine was 0.59 μg/L (adjusted to mean specific gravity of 1.012 g/mL). Analysis of covariance (ANCOVA) showed that urinary cadmium was associated with plasma ferritin and plasma zinc via a significant interaction between dichotomized plasma ferritin and plasma zinc. The analysis was adjusted for age and socioeconomic status. Women with low iron stores and adequate zinc status had significantly higher urinary cadmium compared to women with both adequate iron stores and zinc status. There was no difference in urinary cadmium between women with both low iron stores and zinc status compared to those with both adequate iron stores and zinc status. In conclusion, low iron stores were associated with increased cadmium accumulation, but only at adequate zinc status. [Copyright &y& Elsevier]