Dietary exposure to polychlorinated biphenyls and risk of heart failure - A population-based prospective cohort study.

BACKGROUND: Beneficial effects of fish consumption on heart failure (HF) may be modified by contaminants in fish. Polychlorinated biphenyls (PCBs) are of particular concern as they have been associated with well-established risk factors of HF, but current data are limited. OBJECTIVES: We aimed to assess the association between dietary PCB exposure and risk of HF, accounting for dietary intake of long-chain omega-3 fish fatty acids. DESIGN: We used the prospective population-based research structure SIMPLER (previously the Swedish Mammography Cohort and Cohort of Swedish Men) comprising 32,952 women and 36,546 men, free from cancer, cardiovascular disease and diabetes at baseline in 1997. Validated estimates of dietary PCBs and long-chain omega-3 fish fatty acids [eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] were obtained via a food frequency questionnaire at baseline. Incident cases of HF were ascertained through register linkage. RESULTS: During an average of 12 years of follow-up, we ascertained 2736 and 3128 incident cases of HF in women and men, respectively. In multivariable-adjusted models, mutually adjusted for PCBs and EPA-DHA, the relative risk (RR) for dietary PCB exposure was 1.48 (95% CI 1.12-1.96) in women and 1.42 (95% CI 1.08-1.86) in men, comparing extreme quintiles. Corresponding RRs for EPA-DHA intake were 0.71 (95% CI 0.54-0.93) and 0.82 (95% CI 0.63-1.07), respectively. CONCLUSIONS: Dietary exposure to PCBs was associated with an increased risk of HF in both women and men. EPA-DHA intake was associated with a lower risk of HF in women, with a similar tendency in men.

Dietary polychlorinated biphenyls, long-chain n-3 polyunsaturated fatty acids and incidence of malignant melanoma.

BACKGROUND: For malignant melanoma, other risk factors aside from sun exposure have been hardly explored. Polychlorinated biphenyls (PCBs)-mainly from fatty fish- may affect melanogenesis and promote melanoma progression, while long-chain n-3 polyunsaturated fatty acids seem to exert antineoplastic actions in melanoma cells. OBJECTIVES: We aimed to assess the association of validated estimates of dietary PCB exposure as well as the intake of eicosapentaenoic acid and docosahexaenoic acid (EPA-DHA), accounting for sun habits and skin type, with the risk of malignant melanoma in middle-aged and elderly women. METHODS: We included 20,785 women at baseline in 2009 from the prospective population-based Swedish Mammography Cohort. Validated estimates of dietary PCB exposure and EPA-DHA intake were obtained via a food frequency questionnaire. Incident melanoma cases were ascertained through register-linkage. RESULTS: During 4.5 years of follow-up, we ascertained 67 incident cases of melanoma. After multivariable adjustments, exposure to dietary PCBs was associated with four-fold increased risk of malignant melanoma (hazard ratio [HR], 4.0 [95% confidence interval {CI}, 1.2-13; P for trend = 0.02]), while EPA-DHA intake was associated with 80% lower risk (HR, 0.2 [95% CI, 0.1-0.8; P for trend = 0.03]), comparing the highest exposure tertiles with the lowest. CONCLUSION: While we found a direct association between dietary PCB exposure and risk of melanoma, EPA-DHA intake showed to have a substantial protective association. Question of benefits and risk from fish consumption is very relevant and further prospective studies in the general population verifying these findings are warranted.

Exposure to polychlorinated biphenyls and prostate cancer: population-based prospective cohort and experimental studies.

Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer.

Dietary exposure to polychlorinated biphenyls and risk of breast, endometrial and ovarian cancer in a prospective cohort.

BACKGROUND: Observational studies on polychlorinated biphenyl (PCB) exposure and hormone-related cancer risk are either inconsistent or lacking. We aimed to assess associations of dietary PCB exposure with breast, endometrial and ovarian cancer risk in middle-aged and elderly women. METHODS: We included 36 777 cancer-free women at baseline in 1997 from the prospective population-based Swedish Mammography Cohort. Validated estimates of dietary PCB exposure were obtained via a food frequency questionnaire. Incident cancer cases were ascertained through register linkage. RESULTS: During 14 years of follow-up, we ascertained 1593, 437 and 195 incident cases of breast, endometrial and ovarian cancer. We found no overall association between dietary PCB exposure and any of these cancer forms. The multivariable-adjusted relative risks comparing women in the highest and lowest tertile of PCB exposure were 0.96 (95% confidence interval (CI): 0.75, 1.24), 1.21 (95% CI: 0.73, 2.01) and 0.90 (95% CI: 0.45, 1.79) for breast, endometrial and ovarian cancer. In analyses stratified by factors influencing oestrogen exposure, possibly masking associations with PCBs, indications of higher risks were observed for endometrial cancer. CONCLUSIONS: This study suggests that dietary exposure to PCBs play no critical role in the development of breast, endometrial or ovarian cancer during middle-age and old ages.

Associations of dietary polychlorinated biphenyls and long-chain omega-3 fatty acids with stroke risk.

BACKGROUND: Little is known about joint exposure to polychlorinated biphenyls (PCBs) and long-chain omega-3 fatty acids [eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)], through fish consumption, on cerebrovascular disease risk. OBJECTIVE: To explore associations of dietary PCB exposure and EPA-DHA intake with risk of different stroke subtypes. METHODS: This was assessed in the prospective population-based Cohort of Swedish Men including 39,948, middle-aged and elderly men, who were free of cardiovascular disease and cancer at baseline in 1997. Validated estimates of dietary PCBs and EPA-DHA were obtained via a food frequency questionnaire. RESULTS: During 12years of follow-up, 2286 and 474 incident cases of ischemic stroke and hemorrhagic stroke, respectively, were ascertained through register linkage. Dietary PCB exposure and EPA-DHA intake were associated with hemorrhagic stroke but not ischemic stroke. Men in the highest quartile of dietary PCB exposure (median 412ng/day) had a multivariable- and EPA-DHA-adjusted RR of hemorrhagic stroke of 2.77 [95% confidence interval (CI), 1.48-5.19] compared with men in the lowest quartile (median 128ng/day; p for trend <0.01). The corresponding RRs in men with and without hypertension were 5.45 (95% CI, 1.34-22.1) and 2.37 (95% CI 1.17-4.79), respectively. The multivariable- and PCB-adjusted RR of hemorrhagic stroke for the highest quartile of EPA-DHA intake (median 0.73g/day) versus the lowest quartile (median 0.18g/day) was 0.42 (95% CI, 0.22-0.79). CONCLUSION: Dietary PCB exposure was associated with an increased risk of hemorrhagic stroke, whereas a protective association was observed for dietary EPA-DHA intake.

Dietary exposure to polychlorinated biphenyls and risk of myocardial infarction in men - A population-based prospective cohort study.

BACKGROUND: Major food contaminants such as polychlorinated biphenyls (PCBs) are proposed to play a role in the etiology of cardiovascular disease (CVD), but to date the impact of PCBs on cardiovascular health need to be explored. METHODS AND RESULTS: We assessed the association between validated food frequency questionnaire-based estimates of dietary PCB exposure and risk of myocardial infarction, ascertained through register-linkage, among 36,759 men from the population-based Swedish Cohort of Men, free of cardiovascular disease, diabetes and cancer at baseline (1997). Relative risks were adjusted for known cardiovascular risk factors, long-chain omega-3 fatty acids (eicosapentaenoic and docosahexaenoic acids) and methyl mercury exposure. During 12years of follow-up (433,243 person-years), we ascertained 3005 incident cases of myocardial infarction (654 fatal). Compared with the lowest quintile of dietary PCB exposure (median 113ng/day), men in the highest quintile (median 436ng/day) had multivariable-adjusted relative risks of 1.74 (95% confidence interval [CI], 1.30-2.33; p-trend<0.001) for total and 1.97 (95% CI 1.42-2.75; p-trend<0.001) for non-fatal myocardial infarction. In mutually adjusted models, dietary PCB exposure was associated with an increased risk of myocardial infarction, while the intake of long-chain omega-3 fish fatty acids was associated with a decreased risk. We also observed an effect modification by adiposity on the association between of dietary PCB exposure and myocardial infarction, with higher risk among lean men (p value for interaction =0.03). CONCLUSIONS: Exposure to PCBs via diet was associated with increased risk of myocardial infarction in men.

Oleic acid increases intestinal absorption of the BCRP/ABCG2 substrate, mitoxantrone, in mice.

The efflux transporter breast cancer resistance protein (BCRP/ABCG2) decrease intestinal absorption of many food toxicants. Oleic acid increases absorption of the specific BCRP substrate mitoxantrone (MXR), and also BCRP gene expression in human intestinal Caco-2 cells, suggesting that oleic acid affect the BCRP function. Here, we investigated the effect of oleic acid on intestinal absorption of MXR in mice. Mice were orally dosed with 2.4g oleic acid/kg b.w. and 1mg MXR/kg b.w., and sacrificed 30, 60, 90 or 120min after exposure, or were exposed to 0.6, 2.4 or 4.8g oleic acid/kg b.w. and 1mg MXR/kg b.w., and sacrificed 90min after exposure. Mice were also treated with Ko143 together with MXR and sacrificed after 60min, as a positive control of BCRP-mediated effects on MXR absorption. Absorption of MXR increased after exposure to oleic acid at all doses, and also after exposure to Ko143. Intestinal BCRP gene expression tended to increase 120min after oleic acid exposure. Our results in mice demonstrate that oleic acid decreases BCRP-mediated efflux, causing increased intestinal MXR absorption in mice. These findings may have implications in humans, concomitantly exposed to oleic acid and food contaminants that, similarly as MXR, are substrates of BCRP.

Dietary exposure to polychlorinated biphenyls and risk of myocardial infarction - a population-based prospective cohort study.

BACKGROUND: Fish consumption may promote cardiovascular health. The role of major food contaminants, such as polychlorinated biphenyls (PCBs) common in fatty fish, is unclear. We assessed the association between dietary PCB exposure and risk of myocardial infarction taking into account the intake of long-chain omega-3 fish fatty acids. METHODS: In the prospective population-based Swedish Mammography Cohort, 33,446 middle-aged and elderly women, free from cardiovascular disease, cancer and diabetes at baseline (1997) were followed-up for 12 years. Validated estimates of dietary PCB exposure and intake of fish fatty acids (eicosapentaenoic acid and docosahexaenoic acid; EPA-DHA) were obtained via a food frequency questionnaire at baseline. RESULTS: During follow-up 1386 incident cases of myocardial infarction were ascertained through register-linkage. Women in the highest quartile of dietary PCB exposure (median 286 ng/day) had a multivariable-adjusted RR of myocardial infarction of 1.21 (95% confidence interval [CI], 1.01-1.45) compared to the lowest quartile (median 101 ng/day) before, and 1.58 (95% CI, 1.10-2.25) after adjusting for EPA-DHA. Stratification by low and high EPA-DHA intake, resulted in RRs 2.20 (95% CI, 1.18-4.12) and 1.73 (95% CI, 0.81-3.69), respectively comparing highest PCB tertile with lowest. The intake of dietary EPA-DHA was inversely associated with risk of myocardial infarction after but not before adjusting for dietary PCB. CONCLUSION: Exposure to PCBs was associated with increased risk of myocardial infarction, while some beneficial effect was associated with increasing EPA and DHA intake. To increase the net benefits of fish consumption, PCB contamination should be reduced to a minimum.

Long-term coffee consumption in relation to fracture risk and bone mineral density in women.

High consumption of coffee has been suggested to reduce the risk of some late-onset diseases and death but also to contribute to the development of osteoporotic fractures. Results of previous fracture studies have been inconsistent, and a comprehensive study is needed. The longitudinal population-based Swedish Mammography Cohort, including 61,433 women born in 1914-1948, was followed up from 1987 through 2008. Coffee consumption was assessed with repeated food frequency questionnaires. During follow-up, 14,738 women experienced fracture of any type, and 3,871 had a hip fracture. In a subcohort (n = 5,022), bone density was measured and osteoporosis determined (n = 1,012). After multivariable adjustment, there was no evidence of a higher rate of any fracture (hazard ratio per 200 mL coffee = 0.99; 95% confidence interval: 0.98, 1.00) or hip fracture (hazard ratio per 200 mL coffee = 0.97, 95% confidence interval: 0.95, 1.00) with increasing coffee consumption. A high coffee intake (≥4 cups daily) versus a low intake (<1 cup daily) was associated with a 2%-4% lower bone density, depending on site (P < 0.001), but the odds ratio for osteoporosis was only 1.28 (95% confidence interval: 0.88, 1.87). Thus, high coffee consumption was associated with a small reduction in bone density that did not translate into an increased risk of fracture.

Prenatal exposure to polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) may influence birth weight among infants in a Swedish cohort with background exposure: a cross-sectional study.

BACKGROUND: Prenatal exposure to persistent organic pollutants, e.g. polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) has been suggested to negatively affect birth weight although epidemiological evidence is still inconclusive. We investigated if prenatal exposure to PCBs and PBDEs is related to birth weight in a Swedish population with background exposure. METHODS: Breast milk was sampled during the third week after delivery from first-time mothers in Uppsala county, Sweden 1996-2010 (POPUP cohort) (N = 413). Samples were analysed for di-ortho PCBs (CB-138, 153, 180) and tetra- to hexa- brominated PBDEs (BDE-47, 99, 100, 153). Simple and multiple linear regression models were used to investigate associations between lipid-adjusted, ln-transformed PCB and PBDE concentrations, and birth weight. Covariates included in the multivariate regression model were PCB and PBDE exposure, maternal age, pre-pregnancy BMI, weight gain during pregnancy, education, smoking, gender of the infant and gestational length. The effect of including fish consumption was also investigated. RESULTS: In the multivariate model, prenatal exposure to di-ortho PCBs was significantly associated with increased birth weight (ß = 137; p = 0.02). The result did not change when gestational length was added to the model. An inverse association between PBDE(4) (sum of BDE-47, -99, -100 and -153) and birth weight was observed in the multivariate model including gestational length (ß = -106; p = 0.04). Maternal pre-pregnancy BMI and weight gain during pregnancy were important confounders of the association between di-ortho PCBs and birth weight. The associations were not alleviated after adjustment for fish consumption, a major source of PCB and PBDE exposure. The observed associations were stronger for boys than for girls. CONCLUSIONS: Our results indicate that prenatal exposure to di-ortho PCBs and PBDE(4) may influence birth weight in different directions, i.e. PCB exposure was associated with higher birth weight and PBDE exposure with lower birth weight. Maternal pre-pregnancy BMI and weight gain during pregnancy were important confounders that may hide positive association between di-ortho PCB exposure and birth weight if they are not included in the statistical model. We speculate that even small PCB- and PBDE-induced shifts in the distribution of birth weight may influence future public health in populations with background exposure.

Validation of questionnaire-based long-term dietary exposure to polychlorinated biphenyls using biomarkers.

SCOPE: The health consequences of lifelong low-level exposure to polychlorinated biphenyls (PCBs) via food are largely unknown, mainly due to the lack of large population-based prospective studies addressing this issue. We validated long-term food frequency questionnaire (FFQ)-based dietary PCB exposure against concentrations of six PCB congeners in serum. METHODS AND RESULTS: Dietary PCB exposure was estimated in the Swedish Mammography Cohort by constructing a recipe-based database of CB-153, an indicator for total PCBs in food. The Spearman rank correlation (adjusted for within-person variability) was assessed between concurrent (2004-2006), past (1997), and long-term (mean of 1997 and 2004-2006) FFQ-based dietary PCB exposure, respectively, and the following serum PCB congeners, CB-118, CB-138, CB-153, CB-156, CB-170, and CB-180, in women (56-85 years of age, n = 201). The correlation between FFQ-based dietary PCB exposure and serum CB-153 was 0.41 (p < 0.001) for the concurrent (median 1.6 ng/kg body weight) and 0.34 (p < 0.05) for the past (median 2.6 ng/kg body weight) exposure assessment. Long-term validity of FFQ-based PCB estimates and the six serum PCB congeners ranged from 0.30 to 0.58 (p < 0.05). CONCLUSION: FFQ-based PCB exposure estimates show acceptable validity in relation to PCB concentrations in serum, justifying their use in large-scale epidemiological studies.

Oleic acid decreases BCRP mediated efflux of mitoxantrone in Caco-2 cell monolayers.

Breast cancer resistance protein (BCRP) efflux restricts intestinal absorption of substances like heterocyclic amines, mycotoxins and certain human and veterinary drugs. Fat rich meals seem to increase absorption of drugs which are BCRP substrates or inhibitors. We therefore hypothesize that absorption of toxicants normally effluxed by BCRP are increased by fatty acids in food. Transport across and accumulation of 3H-Mitoxantrone (MXR) in Caco-2 cell monolayers were measured after 60 min exposure to emulsions of 3H-MXR (1µM) and oleic acid (0.5-5 mM). In addition, BCRP gene expression (RT-PCR) and the amount of BCRP protein (Western blot) were measured in oleic acid exposed Caco-2 cells. Oleic acid increased transport of MXR in a concentration dependent manner and 2 mM oleic acid or higher increased accumulation of MXR in cells, without any signs of cytotoxicity. Gene expression of BCRP was increased after exposure to oleic acid for 6 h, but the amount of BCRP protein was not increased. In conclusion, oleic acid clearly induced BCRP gene expression and reduced BCRP mediated efflux, although the amount of BCRP in cells was not affected. Consequently, effects of fatty acids on BCRP mediated efflux are important to consider in risk assessment of toxicants in food.

PCDD/F, PCB, PBDE, HBCD and chlorinated pesticides in a Swedish market basket from 2005--levels and dietary intake estimations.

Based on consumption data statistics, food items from four regions in Sweden were sampled in a so-called market basket study. Food items from five food groups, i.e. fish, meat, dairy products, eggs and fat/oils, were analyzed for persistent organic pollutants (POPs) followed by per capita intake calculations. The highest levels of PCDD/F, PCB, PBDE, HBCD and chlorinated pesticides were found in the fish/fish products. The estimated market basket per capita intake of PCDD/F and dl-PCB was 0.7pg WHO-TEQ kg bw(-1) d(-1) (TEFs from 1998). The intake of ∑PCB was estimated to 4.9 ng kg bw(-1) d(-1) and fish was found to be the major contributor with 64%. The intake of ∑PBDE was found to be 0.7 ng kg bw(-1) d(-1). Fish (38%) and dairy products (31%) were the largest contributors to the total PBDE intake. The intake of HBCD was estimated to 0.14 ng kg bw(-1) d(-1). HBCD mainly came from fish (65%), but also dairy products (24%) and meat (10%) contributed. Also regarding the chlorinated pesticides, fish was found to be the major contributor, with 51% of the ∑DDT coming from fish. The intake of ∑DDT, ∑HCH and HCB was 4.0, 1.0 and 1.1 ng kg bw(-1) d(-1), respectively. Most of the ∑HCH and HCB originate from dairy products (43% and 55%, respectively). This study shows that the levels, and intake, of different POPs from food of animal origin in the market basket of 2005 seem to have decreased since the market basket study in 1999.

Polybrominated diphenyl ethers in breast milk from Uppsala County, Sweden.

The breast milk concentrations of polybrominated diphenyl ethers (PBDEs; sum of five congeners: BDE-47, -99, -100, -153, and -154) were determined (by GC-ECD) in samples from 93 primiparous women collected from 1996 to 1999 in Uppsala County, Sweden. Dietary and lifestyle factors were also recorded. The mean PBDE concentration was 4.0 ng/g fat and the distribution of samples was skewed with few high values (maximum 28.2 ng/g fat). BDE-47 was the major congener and constituted 59% of the mean concentration of PBDEs. No significant relationship was found between breast milk concentrations of PBDEs and dietary intake of PBDE, age, body mass index, alcohol consumption, or computer usage. After adjustments for these factors, a weak but significant association between PBDE concentrations and smoking was observed. The dietary intake of PBDE for these women was estimated at 27 ng/day, of which fish contributed almost half. After inclusion of 31 additional samples, collected from 2000 to 2001, time trends were studied. The changes in breast milk PBDE levels between 1996 and 2001, similar to the results from another Swedish study on milk from Stockholm mothers, suggest a peak in PBDE concentrations around 1998 and thereafter decreasing levels. However, far-reaching conclusions about PBDE time trends in milk cannot be drawn from this short study.

Organochlorines in Swedish women: determinants of serum concentrations.

We studied associations between lifestyle/medical factors and lipid-adjusted serum concentrations of seven polychlorinated biphenyl (PCB) congeners and five chlorinated pesticides/metabolites among 205 Swedish women (54-75 years old). Serum concentrations were significantly associated with age, body mass index, body weight change, diabetes mellitus, consumption of fatty fish, and place of residence. The findings suggest that lifestyle/medical factors may confound results in epidemiologic studies when they are related to both serum concentrations and disease. Moreover, disease itself may influence serum concentrations of some organochlorines, as indicated by the negative associations between recent weight change and serum concentrations of some PCB congeners, p,p -dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) and the positive association between diabetes mellitus and HCB concentrations. Age was the only determinant that showed a consistent association with all compounds studied (positive); otherwise associations with single determinants varied among compounds even within the PCB group. This shows that the studied organochlorines should not be treated as a homogeneous group of compounds in epidemiologic studies.