Bettina Julin

Long-term Dietary Cadmium Intake and Postmenopausal Endometrial Cancer Incidence: A Population-Based Prospective Cohort Study

Environmental pollutants mimicking the effects of estrogen are suggested to contribute to the high incidence of hormone-related cancers, but supporting data are sparse. A potent estrogen-like activity of the pollutant cadmium, mediated via the estrogen receptor-alpha, has been shown in vivo. We prospectively examined the association between cadmium exposure and incidence of postmenopausal endometrial cancer. The Swedish Mammography Cohort is a population-based prospective cohort of 30,210 postmenopausal women free of cancer diagnose at baseline (1987) and who completed a food frequency questionnaire at baseline and in 1997. We estimated the dietary cadmium intake based on the questionnaire data and the cadmium content in all foods. During 16.0 years (484,274 person-years) of follow-up between the baseline and mid-2006, we ascertained 378 incident cases of endometrioid adenocarcinoma. The average estimated dietary cadmium intake was 15 mug/day (80% from cereals and vegetables). Cadmium intake was statistically significantly associated with increased risk of endometrial cancer in all women; the multivariate relative risk (RR) was 1.39 [95% confidence interval (CI), 1.04-1.86; P(trend) = 0.019], comparing highest tertile versus lowest. Among never-smoking women with body mass index (BMI) of <27 kg/m(2), the RR was 1.86 (95% CI, 1.13-3.08; P(trend) = 0.009). We observed a 2.9-fold increased risk (95% CI, 1.05-7.79) associated with long-term cadmium intake consistently above the median at both baseline 1987 and in 1997 in never-smoking women with low bioavailable estrogen (BMI of <27 kg/m(2) and nonusers of postmenopausal hormones). Our results support the hypothesis that cadmium may exert estrogenic effects and thereby increase the risk of hormone-related cancers.

Population Toxicokinetic Modeling of Cadmium for Health Risk Assessment

Background Cadmium is a widespread environmental pollutant that has been shown to exert toxic effects on kidney and bones in humans after long-term exposure. Urinary cadmium concentration is considered a good biomarker of accumulated cadmium in kidney, and diet is the main source of cadmium among nonsmokers. Objective Modeling the link between urinary cadmium and dietary cadmium intake is a key step in the risk assessment of long-term cadmium exposure. There is, however, little knowledge on how this link may vary, especially for susceptible population strata. Methods We used a large population-based study (the Swedish Mammography Cohort), with repeated dietary intake data covering a period of 20 years, to compare estimated dietary cadmium intake with urinary cadmium concentrations on an individual basis. A modified version of the Nordberg-Kjellström model and a one-compartment model were evaluated in terms of their predictions of urinary cadmium. We integrated the models and quantified the between-person variability of cadmium half-life in the population. Finally, sensitivity analyses and Monte Carlo simulations were performed to illustrate how the latter model could serve as a robust tool supporting the risk assessment of cadmium in humans. Results The one-compartment population model appeared to be an adequate modeling option to link cadmium intake to urinary cadmium and to describe the population variability. We estimated the cadmium half-life to be about 11.6 years, with about 25% population variability. Conclusions Population toxicokinetic models can be robust and useful tools for risk assessment of chemicals, because they allow quantification and integration of population variability in toxicokinetics.

Dietary Cadmium Exposure and Risk of Postmenopausal Breast Cancer: A Population-Based Prospective Cohort Study

The ubiquitous food contaminant cadmium has features of an estrogen mimetic that may promote the development of estrogen-dependent malignancies, such as breast cancer. However, no prospective studies of cadmium exposure and breast cancer risk have been reported. We examined the association between dietary cadmium exposure (at baseline, 1987) and the risk of overall and estrogen receptor (ER)-defined (ER(+) or ER(-)) breast cancer within a population-based prospective cohort of 55,987 postmenopausal women. During an average of 12.2 years of follow-up, 2,112 incident cases of invasive breast cancer were ascertained (1,626 ER(+) and 290 ER(-)). After adjusting for confounders, including consumption of whole grains and vegetables (which account for 40% of the dietary exposure, but also contain putative anticarcinogenic phytochemicals), dietary cadmium intake was positively associated with overall breast cancer tumors, comparing the highest tertile with the lowest [rate ratio (RR), 1.21; 95% confidence interval (CI), 1.07-1.36; P(trend) = 0.02]. Among lean and normal weight women, statistically significant associations were observed for all tumors (RR, 1.27; 95% CI, 1.07-1.50) and for ER(+) tumors (RR, 1.25; 95% CI, 1.03-1.52) and similar, but not statistically significant associations were found for ER(-) tumors (RR, 1.22; 95% CI, 0.76-1.93). The risk of breast cancer increased with increasing cadmium exposure similarly within each tertile of whole grain/vegetable consumption and decreased with increasing consumption of whole grain/vegetables within each tertile of cadmium exposure (P(interaction) = 0.73). Overall, these results suggest a role for dietary cadmium in postmenopausal breast cancer development.

Associations between dietary cadmium exposure and bone mineral density and risk of osteoporosis and fractures among women

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.

Dietary cadmium exposure and prostate cancer incidence: a population-based prospective cohort study.

Background:Experimental data convincingly propose the toxic metal cadmium as a prostate carcinogen. Cadmium is widely dispersed into the environment and, consequently, food is contaminated.Methods:A population-based cohort of 41 089 Swedish men aged 45–79 years was followed prospectively from 1998 through 2009 to assess the association between food frequency questionnaire-based estimates of dietary cadmium exposure (at baseline, 1998) and incidence of prostate cancer (3085 cases, of which 894 were localised and 794 advanced) and through 2008 for prostate cancer mortality (326 fatal cases).Results:Mean dietary cadmium exposure was 19 μg per day±s.d. 3.7. Multivariable-adjusted dietary cadmium exposure was positively associated with overall prostate cancer, comparing extreme tertiles; rate ratio (RR) 1.13 (95% confidence interval (CI): 1.03–1.24). For subtypes of prostate cancer, the RR was 1.29 (95% CI: 1.08–1.53) for localised, 1.05 (95% CI: 0.87–1.25) for advanced, and 1.14 (95% CI: 0.86–1.51) for fatal cases. No statistically significant difference was observed in the multivariable-adjusted risk estimates between tumour subtypes (Pheterogeneity=0.27). For localised prostate cancer, RR was 1.55 (1.16–2.08) among men with a small waist circumference and RR 1.45 (1.15, 1.83) among ever smokers.Conclusion:Our findings provide support that dietary cadmium exposure may have a role in prostate cancer development.

Dietary Cadmium Exposure and Fracture Incidence Among Men : A Population-Based Prospective Cohort Study

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.

Relation between dietary cadmium intake and biomarkers of cadmium exposure in premenopausal women accounting for body iron stores

BackgroundCadmium 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.MethodsIn a sample of 57 non-smoking Swedish women aged 20-50 years, we assessed Pearsons 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.ResultsThe 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 womens iron status.ConclusionsOur 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.

Exposure to traffic noise and markers of obesity

Objectives Limited evidence suggests adverse effects of traffic noise exposure on the metabolic system. This study investigates the association between road traffic noise and obesity markers as well as the role of combined exposure to multiple sources of traffic noise. Methods In a cross-sectional study performed in 2002–2006, we assessed exposure to noise from road traffic, railways and aircraft at the residences of 5075 Swedish men and women, primarily from suburban and semirural areas of Stockholm County. A detailed questionnaire and medical examination provided information on markers of obesity and potential confounders. Multiple linear and logistic regression models were used to assess associations between traffic noise and body mass index (BMI), waist circumference and waist–hip ratio using WHO definitions of obesity. Results Road traffic noise was significantly related to waist circumference with a 0.21 cm (95% CI 0.01 to 0.41) increase per 5 dB(A) rise in Lden. The OR for central obesity among those exposed to road traffic noise ≥45 dB(A) was 1.18 (95% CI 1.03 to 1.34) in comparison to those exposed below this level. Similar results were seen for waist–hip ratio (OR 1.29; 95% CI 1.14 to 1.45) but not for BMI (OR 0.89; 95% CI 0.76 to 1.04). Central obesity was also associated with exposure to railway and aircraft noise, and a particularly high risk was seen for combined exposure to all three sources of traffic noise (OR 1.95; 95% CI 1.24 to 3.05). Conclusions Our results suggest that traffic noise exposure can increase the risk of central obesity. Combined exposure to different sources of traffic noise may convey a particularly high risk.

Dietary cadmium exposure and risk of epithelial ovarian cancer in a prospective cohort of Swedish women

Background:The proposed cadmium-induced oestrogen mimicking effects in reproductive tissues, suggest a role of this widespread food contaminant in the development of hormone-dependent malignancies.Methods:We prospectively evaluated the association between tertiles of dietary cadmium exposure and epithelial ovarian cancer in 60 889 women from the population-based Swedish Mammography Cohort. Dietary cadmium was estimated using a food-frequency questionnaire at baseline (1987–1990) and in 1997. Multivariable-adjusted rate ratios (RR) were evaluated using Cox proportional hazards models.Results:During a mean follow-up of 18.9 years (1 149 470 person-years), we identified 409 incident cases of epithelial ovarian cancer, including 215 serous, 27 mucinous, 62 endometrioid and 12 clear cell tumours. We found no association between dietary cadmium exposure and the risk of ovarian cancer. Compared with the lowest tertile of cadmium exposure, the multivariable-adjusted RR for the highest tertile was 0.90 (95% confidence interval (CI): 0.71–1.15) for total epithelial ovarian cancer. Likewise, no association was observed in subtypes modelled with continuous dietary cadmium exposure; multivariable RR for each 1 μg per day increment of cadmium: 0.97 (95% CI: 0.93–1.02) for serous tumours, 0.94 (95% CI: 0.82–1.07) for mucinous tumours and 1.00 (95% CI: 0.92–1.08) for endometrioid and clear cell tumours.Conclusion:Our study suggests that dietary cadmium exposure is not likely to have a substantial role in ovarian cancer development.

Exposure to cadmium from food and risk of cardiovascular disease in men: a population-based prospective cohort study

Cadmium is a widely dispersed toxic metal that accumulates in the human body owing to its long biological halflife (10–30 years). Levels in food are elevated as result of farmland having become contaminated both by atmospheric deposition and the use of cadmium-containing fertilizers and sewage sludge [1]. Recently, this metal has emerged as a potential risk factor for cardiovascular disease (CVD). The diet is the main source of cadmium exposure [1]. Influenced both by the concentrations in food and by consumption patterns, dietary cadmium exposure can vary greatly between and within populations. Exposure to cadmium in the diet takes place over a lifetime and therefore even in areas with no particular cadmium contamination and where levels in food are generally low, exposure levels may be sufficient to be of public health concern. In western societies, foods such as cereals, potatoes and vegetables account for the bulk of dietary cadmium exposure owing to the frequency of their consumption. At the same time, some of these foods— especially wholegrain and vegetables—have been proposed to protect against heart-related diseases. Average dietary cadmium exposure in Sweden is similar to that observed in other parts of Europe and the US (8–25 lg/day), where no particular cadmium contamination has been reported. In Asia (Japan and China), exposure levels are commonly much higher due to the high intake of rice grown on soil contaminated by industrial processes [1]. Tobacco smoking, one of the most important CVD risk factors, also contributes to cadmium exposure due to the elevated levels in tobacco leaves and high rate of absorption from the lungs. Cadmium accumulates in endothelium and vascular smooth muscle cells, causes endothelial dysfunction in vitro and can promote atherosclerosis in vitro, in vivo and in human studies [2]. Only one previous study has assessed total cadmium exposure (measured in urine) and incident CVD, this study observed modest positive associations [3]. Two prospective studies on CVD mortality indicate some positive associations with biomarkers (blood and/or urine) of total cadmium exposure [4, 5], but overall, results are inconsistent particularly with respect to differences between the sexes. There is, therefore, a need for further studies that explore the relationship between cadmium exposure and incident CVD events in men and women separately. In addition, the risks associated with cadmium from the diet alone, remain to be assessed. We prospectively examined whether low-level dietary cadmium exposure was associated with incidence of total and specific CVD (myocardial infarction; MI and stroke) in a population-based prospective cohort of men and assessed whether tobacco smoking modified the associations. The cohort of Swedish men (COSM) has been described elsewhere [6]. In brief, 48,850 men aged 45–79 years at baseline were recruited in 1997 (response rate 49 %). Dietary intake and lifestyle data (such as education level, smoking status, height, weight, physical activity and alcohol consumption) was assessed at baseline using a selfadministered questionnaire. The validity of the food frequency questionnaire (FFQ) has been assessed in a random population-based sample of 248 men who were aged between 40 and 74 years and who lived in the study area. Each man completed the FFQ and 14 repeated 24-h recalls during a 1-year period. For macronutrients, the mean Spearman’s rank correlation coefficient was 0.65 [7]. The B. Julin (&) A. Wolk L. D. Thomas A. Åkesson Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden e-mail: bettina.julin@ki.se