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Cadmium affects blood pressure and negatively interacts with obesity: Findings from NHANES 1999–2014
Science of the Total Environment 643 (2018) 270–276
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Cadmium affects blood pressure and negatively interacts with obesity: Findings from NHANES 1999–2014 Qi Wang, Sheng Wei ⁎ Key Laboratory of Environment and Health (HUST), Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubation), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
H I G H L I G H T S
G R A P H I C A L
• Cd exposure is associated with elevated blood pressure and hypertension. • Their associations show discrepancies by sex and ethnicity. • Negative interaction between BCd and obesity affects systolic hypertension.
Blood pressure change (mmHg) (in the left) and OR for hypertension (in the right) in relation to a twofold increase in BCd, stratified by sex and ethnicity, adjusted for age, BMI category, educational background, marital status, poverty index, alcohol consumption, smoking status and serum contents of sodium, potassium, calcium, creatinine, phosphorus, total protein, total cholesterol, glucose, and iron and blood lead concentration. SBP, systolic blood pressure; DBP, diastolic blood pressure; BCd, blood cadmium concentration; BMI, body mass index; CI, confidence interval; OR, odds ratio.
a r t i c l e
a b s t r a c t
i n f o
Article history: Received 6 March 2018 Received in revised form 5 May 2018 Accepted 9 June 2018 Available online xxxx Editor: F.M. Tack Keywords: Cadmium Blood pressure Hypertension Interaction Obesity
A B S T R A C T
Inconsistencies are noted regarding the association between cadmium exposure and blood pressure/hypertension and the interaction between cadmium and body mass index (BMI). This study aims to clarify these inconsistencies in a large sample (n = 32,791) of adults age ≥20 years from eight cycles of the US National Health Examination and Nutrition Survey (NHANES, 1999–2014). The cadmium levels in blood (BCd) and urine (UCd) were used as exposure biomarker. Multiple-linear/logistic regression models were built and stratified by sex, ethnicity and BMI category. The interaction between BCd and BMI was assessed on additive and multiplicative scales. A twofold increase in BCd was associated with 0.54 mm Hg (95% CI: 0.49, 0.58) and 0.05 mm Hg (95% CI: 0.04, 0.06) increases in the systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively, in black women. The SBP and DBP increased by 0.92 mm Hg (95% CI: 0.73, 1.11) and 0.85 mm Hg (95% CI: 0.65, 1.05), respectively, in Mexican-Am women. Significant associations were found between BCd and hypertension in them (systolic risk per twofold BCd, OR = 1.31; 95% CI: 1.07, 1.61; and diastolic risk per twofold BCd, OR = 1.55; 95% CI: 1.17, 2.05). UCd was significantly associated with hypertension in all individuals (OR = 1.14 per twofold; 95% CI: 1.07, 1.21). The associations between cadmium exposure and blood pressure/hypertension showed some discrepancies across BMI categories. A negative interaction was observed between BCd and obesity with regard to their effects on systolic hypertension (RERI = −0.30; 95% CI: −0.56, −0.03; ratio of ORs = 0.55; 95% CI: 0.35, 0.89). Our findings provided evidence for the effect of cadmium on blood pressure and the prevalence of
⁎ Corresponding author at: School of Public Health, Tongji Medical College, Huazhong University of Science of Technology, Wuhan 430030, China. E-mail address: [email protected] (S. Wei).
https://doi.org/10.1016/j.scitotenv.2018.06.105 0048-9697/© 2017 Elsevier B.V. All rights reserved.
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hypertension in American adults. The associations showed discrepancies by sex and ethnicity. The negative interaction between cadmium exposure and obesity influenced systolic hypertension risk. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Cadmium (Cd) is a hazardous heavy metal that is environmentally ubiquitous. Cigarette smoking (even second-hand smoking) is a significant source of Cd exposure for human beings (Messner and Bernhard, 2010). The effect of Cd-containing products via exposure to soil and diet on humans is a major concern (Lalor, 2008). Cd can accumulate progressively in the body and has a long biological half-life of 15–30 years (Satarug and Moore, 2004). Cd concentrations in blood (BCd) and urine (UCd) are established biomarkers of Cd exposure and internal dose, reflecting cumulative exposure; the former also reflects short-term fluctuations in exposure (ATSDR, 2012; Jarup and Akesson, 2009). In vitro studies provide evidence regarding the effect of Cd on vascular endothelium—which plays an important role in various physiologic and pathologic processes such as blood pressure regulation, angiogenesis, and athrosclerosis (Prozialeck et al., 2006). Epidemiologic studies demonstrate that long-term exposure to low levels of Cd contributes to the morbidity and mortality of cardiovascular diseases, atherosclerosis, coronary artery disease, and stroke possibly because of the effect of this metal on elevated blood pressure and hypertension risk (Deering et al., 2018; Eum et al., 2008; Franceschini et al., 2017; Ruiz-Hernandez et al., 2017; Tellez-Plaza et al., 2013b; Tinkov et al., 2018). However, other studies demonstrated null or even negative association between Cd exposure and BP (Gallagher and Meliker, 2010; Mordukhovich et al., 2012; Swaddiwudhipong et al., 2010). In addition, results of previous studies vary in terms of direction or significance that Cd body stores have on blood pressure or hypertension, with results seeming to vary by sex, smoking status, ethnicity, BMI category and medication levels. As a widely known risk factor for higher blood pressure and probability of hypertension, high BMI is reported to be associated with low level of Cd and other heavy metals (Garner and Levallois, 2016; Nie et al., 2016; Padilla et al., 2010). The positive association of BCd and BMI has also been demonstrated (Kim et al., 2015a). A recent study revealed the differential association between Cd exposure, blood pressure and hypertension by BMI category (Garner and Levallois, 2017). Within BMI categories, high urinary Cd levels were associated with significantly high blood pressure among overweight and obese women (Garner and Levallois, 2017). Thus far, the effect of the interaction of Cd and BMI on BP is worthy of further investigation. In this study, we explored the effect of Cd on blood pressure/hypertension and its interaction with BMI by using the 1999–2014 National Health and Nutrition Examination Survey (NHANES) data from American adults aged ≥20 years, representing as a diverse racially sample of the US population. BCd and UCd were used as biomarker of Cd exposure. Adjustment for a number of covariates, including lead concentration in blood (BPb) or urine (UPb), was conducted. 2. Material and methods 2.1. Study population The NHANES 1999–2014 conducted by the U.S. National Center for Health Statistics (NCHS) comprised cross-sectional, nationally representative surveys of the U.S. non-institutionalized civilian population. The NHANES data included in the present study were collected in eight stages, i.e. 1999–2000, 2001–2002, 2003–2004, 2005–2006, 2007–2008, 2009–2010, 2011–2012, and 2013–2014. The survey employed a multistage stratified probability sampling based on selected counties, blocks, households, and persons within households.
Interviews were conducted in participants' homes and extensive physical examinations, which included blood and urine collection, were conducted at mobile exam centers (MEC). We limited the study population to individuals aged ≥20 years who were examined in a MEC and had available BCd concentrations. A total of 43,793 participants (including 21,024 men and 22,769 women) were involved in the study. However, only data from 32,791 participants (including 16,558 men and 16,233 women) were involved in our statistical analysis for the association of Cd exposure with blood pressure or prevalent hypertension risk. Some of the participants were excluded because of missing data. Self-reported ethnicity was categorized as non-Hispanic white (hereafter referred to as Whites), nonHispanic black (hereafter referred to as Blacks), Mexican-American (hereafter referred to as Mexican-Am), and other else. 2.2. Exposure and outcome variables The main exposure variable was BCd, which was determined using an adapted electrothermal atomic absorption method in the surveys of 1999–2000 and 2001–2002 and through inductively coupled plasma mass spectrometry (ICP-MS) in the surveys of the six other cycles (URLs of detailed methods in Supplementary materials). The secondary exposure variable was UCd, which was determined in subsamples (10,691 individuals) of participants by using ICP-MS across all surveys (URLs of detailed methods in Supplementary materials). The UCd was standardized (expressed in μg/g creatinine) by dividing by urinary creatinine concentration. The outcomes included blood pressures of systolic (SBP) and diastolic (DBP) and prevalent hypertension. Blood pressure was reported with an average of ≤3 readings (URLs of detailed methods in Supplementary materials). Prevalent hypertension was defined as the examined SBP ≥140 mm Hg (SHP), DBP ≥90 mm Hg (DHP), or self-reported hypertension case prescribed with antihypertension medication by a physician (URLs of detailed methods in Supplementary materials). 2.3. Covariates We obtained the covariate information about age (categorized into three groups: 20–39 years, 40–59 years, and ≥60 years), sex, ethnicity, education (categorized into three groups: 1 = less than 12th grade, 2 = high school Grad/GED or equivalent, and 3 = college or above), marital status (categorized into four groups: 1 = married, 2 = widowed or living with partner, 3 = divorced or separated, and 4 = never married), and poverty index (≤2 vs. N2) from the household interview (URLs of detailed demographics in Supplementary materials). BMI was calculated by dividing the measured weight in kilograms by the measured height in meters squared (URLs of detailed methods for weight and height measurement in Supplementary materials). BMI categories of underweight (i.e., BMI b 18.5), normal weight (i.e., 18.5 ≤ BMI b 25.0), overweight (i.e., 25.0 ≤ BMI b 30.0), and obesity (i.e., BMI ≥ 30.0) were utilized. Data on alcohol consumption (yes = at least 12 alcohol drinks per year or >2 drinking alcohol frequency in the past 12 months vs. no = less than 12 alcohol drinks per year or ≤ 2 drinking alcohol frequency in the past 12 months) and smoking status (yes vs. no) information were obtained by questionnaire interviews (URLs of detailed methods in Supplementary materials). The standard biochemistry profile including serum contents of sodium (mmol/L), potassium (mmol/L), calcium (mg/dl), iron (mg/dl), phosphorus (mg/dl), total protein (g/dl), total cholesterol (mg/dl), glucose (mg/dl), and creatinine (mg/dl) were
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collected from representative laboratory measurements (URLs of detailed methods in Supplementary materials). In particular, serum creatinine was measured by the modified kinetic method of Jaffé and corrected for NHANES 1999–2000 and NHANES 2005–2006 (URLs of detailed methods in Supplementary materials). The following formulas were used to adjust the serum creatinine level to ensure comparability with the standard creatinine level: NHANES 1999–2000 standard creatinine = 0.147 + 1.013 × NHANES 1999–2000 uncalibrated serum creatinine; and NHANES 2005–2006 standard creatinine = −0.016 + 0.978 × NHANES 2005–2006 uncalibrated serum creatinine. With the given serum creatinine concentration, glomerular filtration rate was estimated using the equation reported by Levey et al. (2009). Blood lead (BPb) levels (μg/dl) was simultaneously measured with BCd by using the same methods as mentioned above. The involved covariates were selected with respect to their influence on the regression coefficient of BCd on blood pressure. Covariates were included in the final regression modeling in case of 5% or more change of the effect size of BCd before and/or after adjustment. 2.4. Statistical analysis The analytic guidelines (https://www.cdc.gov/nchs/data/series/sr_ 02/sr02_161.pdf) from NCHS were referred to for statistical analysis. Sample weights were used to account for the complex sampling design and non-response of NHANES. For normally distributed variables, including BMI, SBP, DBP, and serum levels of sodium, potassium, calcium, creatinine, phosphorus, total protein, and total cholesterol, the central tendency and spread of data were reported as mean and standard deviation. For variables such as BCd, BPb, UCd, UPb, and serum levels of glucose and iron, which required logarithmic transformation to approximate normal distribution, the central tendency and spread of data were reported as geometric mean and interquartile range (IQR). Frequency was used to describe enumeration data. Multiple linear/logistic regression modeling in adjustments for the covariates were performed to evaluate the association between Cd exposure and blood pressure/hypertension by using Proc Surveyreg/Surveylogistic. Multiple-variable adjusted blood pressure changes and odds ratios (ORs) of hypertension were calculated by comparing participants with a twofold increase in BCd/UCd for each ethnicity/sex and BMI category groups. In the mentioned association analysis of Cd exposure and blood pressure, data of participants taking antihypertension medication were excluded. The effects of the potential interaction between BCd and BMI on hypertension risk were assessed on additive [with relative excess risk index (RERI) presented] and multiplicative (with ratio of ORs presented) scales (Hosmer and Lemeshow, 1992; Knol and VanderWeele, 2012). All statistical analyses were twosided with a significance of P b 0.05. SAS9.4 (SAS Institute, Cary, NC) was used to conduct statistical analysis. 2.5. Ethics statement Ethical approval for the NHANES study was obtained from the NCHS Research Ethics Review Board. Further ethical approval for the use of NHANES data that are freely available on the web was not required because they were anonymized. Written consent was obtained from all participants.
Mexican-Am ethnic populations. American women had significantly higher BCd and UCd than men (both P b 0.001). 3.2. Association between Cd exposure and blood pressure/hypertension risk, stratified by sex and/or ethnicity The associations between BCd and SBP/DBP were not significant among all individuals (Table 2). Stratified by sex, the BCd and SBP association achieved significance in women but not in men. Increasing BCd (by twofold) was associated with increased SBP (0.40 mm Hg; 95% CI: 0.01, 0.78) in women. Furthermore, a twofold increase in BCd was associated with elevated SBP by 0.54 mm Hg (95% CI: 0.49, 0.58) and 0.92 mm Hg (95% CI: 0.73, 1.11) in Black and Mexican-Am women, respectively. The BCd and DBP associations (β = 0.05 mm Hg per twofold; 95% CI: 0.04, 0.06; and β = 0.85 mm Hg per twofold; 95% CI: 0.65, 1.05) reached significance in the two groups. For hypertension risk referred to as higher blood pressure than the representative thresholds (i.e., 140 mm Hg for SBP, and 90 mm Hg for DBP), increasing BCd was significantly associated with increased hazards of SHP (OR = 1.31 per twofold; 95% CI: 1.07, 1.61) and DHP (OR = 1.55 per twofold; 95% CI: 1.17, 2.05) in Mexican-Am women. The BCd and DHP association also achieved significance in black men (OR = 1.20 per twofold; 95% CI: 1.04, 1.37). With self-reported hypertension cases involved, a twofold increase in BCd level was associated with 28% (95% CI: 8%, 51%) more hazard of hypertension in MexicanAm women. Significant UCd and blood pressure associations were not found either in men or women (Table 2). However, increasing UCd was associated with increased hazard of hypertension risk, referred to as SHP, DHP, or self-reported cases, with twofold UCd-associated OR (95% CI) of 1.14 (1.07, 1.21) in all individuals. 3.3. Association between Cd exposure and blood pressure/hypertension, stratified by BMI category Multiple linear regression modeling revealed non-significant discrepancies of BCd-associated blood pressure changes across BMI categories (Table 3). The discrepancies of BCd-associated hypertension risk showed across BMI categories. The UCd and blood pressure associations did not achieve significance across BMI categories. However, BMIstratification analysis revealed the significant UCd and hypertension association in participants with normal weight (OR = 1.20; 95% CI: 1.07, 1.36) but not in overweight or obese participants. 3.4. Effects of BCd and BMI interaction on hypertension risk To investigate the effect of the potential interaction between BCd and BMI on hypertension risk, we categorized BCd and BMI into two categories (i.e., BCd: ≥ GM vs. bGM; and BMI: ≥ 30 kg/m2 indicating obesity vs. b30 kg/m2 indicating no obesity). On the additive scale, significantly negative interaction between BCd and obesity was found with regard to their effect on SHP (Table 4; RERI = −0.30; 95% CI: −0.56, −0.03). Similar findings were obtained on the multiplicative scale (Table 4; ratio of ORs = 0.55; 95% CI: 0.35, 0.89). The effect of the negative interaction between BCd and obesity on DHP did not achieve significance (RERI = −0.24; 95% CI: −0.67, 0.19; and ratio of ORs = 0.81; 95% CI: 0.56, 1.17).
3. Results
4. Discussion
3.1. Characteristics of participants involved in this study
In this study, American women were found to be exposed to higher levels of Cd than men. The associations showed discrepancies by sex and ethnicity. After controlling for pertinent covariates, high BCd level was independently associated with high blood pressures and risk of hypertension in American women, particularly Mexican-Am. A positive association was found between UCd and hypertension risk (either examined or self-reported) in all individuals. Negative interaction
Total of 32,791 participants were involved in our analysis (Table 1). The Whites (n = 16,016), Blacks (n = 6681), Mexican-Ams (n = 5612) and others else (n = 4492) accounted to 48.8%, 20.4%, 17.1% and 13.7% of the participants, respectively. Significant differences were observed in almost all variables, except BMI of men, across the White, Black and
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Table 1 Characteristics of the involved participants from NHANES 1999–2014. Characteristic
Men⁎
P
Women⁎
P
White
Black
Mexican-Am
White
Black
Mexican-Am
N = 8140
N = 3320
N = 2915
N = 7876
N = 3361
N = 2697
2453 (17.1) 2524 (17.6) 3163 (22.0)
1133 (7.9) 1103 (7.7) 1084 (7.5)
1141 (7.9) 957 (6.6) 817 (5.7)
b0.0001
2259 (16.2) 2511 (18.0) 3106 (22.3)
1081 (7.6) 1205 (8.6) 1075 (7.7)
962 (6.9) 893 (6.4) 842 (6.0)
b0.0001
1425 (9.9) 2120 (14.7) 4595 (32.0)
1008 (7.0) 879 (6.1) 1433 (10.0)
1660 (11.5) 549 (3.8) 706 (4.9)
b0.0001
1230 (8.8) 2052 (14.7) 4594 (33.0)
892 (6.4) 772 (5.5) 1697 (12.2)
1460 (10.5) 460 (3.3) 777 (5.6)
b0.0001
5118 (35.6) 933 (6.5) 857 (6.0) 1232 (8.6)
1477 (10.3) 478 (3.3) 514 (3.6) 851 (5.9)
1896 (13.2) 332 (2.3) 246 (1.7) 441 (3.1)
b0.0001
4163 (30.0) 1622 (11.6) 1189(8.5) 902 (6.5)
1009 (7.2) 658 (4.7) 755 (5.4) 939 (6.7)
1465 (10.5) 507 (3.6) 389 (2.8) 336 (2.4)
b0.0001
2924 (20.3) 5216 (36.3)
1582 (11.0) 1738 (12.1)
1825 (12.7) 1090 (7.6)
b0.0001
3313 (22.3) 4763 (34.2)
1817 (13.0) 15,449 (11.1)
1744 (12.5) 953 (6.8)
b0.0001
1139 (7.9) 7001 (48.7)
690 (4.8) 2630 (18.3)
323 (2.2) 2592 (18.0)
b0.0001
2294 (16.4) 5582 (40.0)
1458 (10.5) 1903 (13.6)
1224 (8.8) 1473 (10.6)
b0.0001
3269 (22.8) 4868 (33.9)
1538 (10.7) 1776 (12.4)
1317 (9.2) 1596 (11.1)
4163 (29.9) 3712 (26.6)
2155 (15.5) 1205 (8.6)
1954 (14.0) 741 (5.3)
6650 (47.1) 1364 (9.7)
2451 (17.4) 782 (5.5)
2395 (17.0) 464 (3.3)
b0.0001
6197 (45.7) 1486 (11.0)
2477 (18.3) 763 (5.6)
2140 (15.8) 489 (3.6)
b0.0001
7489 (53.4) 481 (3.4)
2856 (20.4) 360 (2.6)
2689 (19.2) 158 (1.1)
b0.0001
7391 (54.9) 242 (1.8)
2984 (22.2) 235 (1.7)
2519 (18.7) 97 (0.7)
b0.0001
4826 (34.0) 3232 (22.8)
1707 (12.0) 1560 (11.0)
2014 (14.2) 862 (6.1)
b0.0001
4619 (33.7) 3148 (22.9)
1593 (11.6) 1715 (12.5)
1729 (12.6) 918 (6.7)
b0.0001
Mean of measurements (±SD) BMI, kg/m2 Sodium (serum), mmol/L Potassium (serum), mmol/L Calcium (serum), mg/dl Creatinine (serum), mg/dl eGFR, ml/min/1.73 m2 Phosphorus (serum), mg/dl Total protein (serum), g/dl Cholesterol (serum), mg/dl SBP, mmHg DBP, mmHg PBP, mmHg
28.4 ± 5.80 139.3 ± 2.32 4.1 ± 0.34 9.5 ± 0.36 1.0 ± 0.34 90.1 ± 21.67 3.7 ± 0.58 7.2 ± 0.46 195.5 ± 41.53 123.5 ± 17.1 72.3 ± 13.23 50.8 ± 17.59
28.8 ± 6.46 139.5 ± 2.21 4.0 ± 0.35 9.5 ± 0.39 1.2 ± 0.77 85.2 ± 25.42 3.7 ± 0.59 7.4 ± 0.53 188.1 ± 40.67 127.0 ± 18.31 73.3 ± 14.58 55.2 ± 17.38
28.7 ± 5.00 139.2 ± 2.36 4.0 ± 0.32 9.4 ± 0.35 0.9 ± 0.41 105.5 ± 20.6 3.7 ± 0.57 7.4 ± 0.47 198.1 ± 41.87 121.5 ± 17.70 71.2 ± 12.88 50.2 ± 17.04
0.0799 0.0013 b0.0001 b0.0001 b0.0001 b0.0001 0.0044 b0.0001 b0.0001 b0.0001 0.0001 b0.0001
28.3 ± 6.92 139.0 ± 2.37 4.0 ± 0.34 9.4 ± 0.38 0.8 ± 0.27 89.4 ± 22.87 3.8 ± 0.54 7.0 ± 0.45 202.0 ± 41.94 120.9 ± 21.11 69.6 ± 13.20 50.9 ± 21.35
32.1 ± 8.06 139.1 ± 2.42 3.9 ± 0.35 9.4 ± 0.40 0.9 ± 0.56 89.0 ± 28.02 3.7 ± 0.55 7.3 ± 0.51 190.1 ± 41.04 125.0 ± 21.82 71.2 ± 14.09 53.3 ± 20.74
29.8 ± 6.22 138.8 ± 2.26 3.9 ± 0.32 9.3 ± 0.37 0.7 ± 0.30 106.8 ± 22.22 3.8 ± 0.54 7.3 ± 0.46 194.2 ± 39.18 117.7 ± 21.52 68.6 ± 12.50 48.9 ± 20.24
b0.0001 0.0036 b0.0001 b0.0001 b0.0001 b0.0001 0.0002 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001
GM (IQR) Glucose (serum), mg/dl Iron (serum), mg/dl BCd, μg/L BPb, μg/dl Ucr, mg/dl UCd, μg/g Ucr UPb μg/dl
97.6 (18.0) 88.3 (44.0) 0.4 (0.5) 1.6 (1.4) 111.5 (100.0) 1.9 (3.0) 0.6 (0.7)
98.5 (19.0) 78.4 (39.0) 0.4 (0.6) 1.7 (1.8) 158.7 (119.0) 1.8 (2.9) 0.7 (0.9)
101.6 (19.0) 92.3 (46.0) 0.3 (0.3) 1.6 (1.7) 118,9 (97.0) 1.6 (2.3) 0.7 (1.3)
0.0004 b0.0001 b0.0001 0.015 b0.0001 b0.0001 b0.0001
93.9 (17.0) 75.0 (41.0) 0.4 (0.4) 1.1 (1.1) 73.3 (87.0) 2.9 (3.8) 0.4 (0.6)
96.9 (19.0) 62.1 (37.0) 0.4 (0.4) 1.2 (1.2) 122.3 (112.0) 2.8 (3.5) 0.6 (0.6)
99.0 (19.0) 67.3 (42.0) 0.3 (0.3) 1.0 (1.1) 83.5 (94.0) 2.6 (3.4) 0.5 (0.8)
b0.0001 b0.0001 b0.0001 0.0005 b0.0001 0.0154 b0.0001
No. (%) Age (yrs.) 20–39 40–59 60– Educational background Less than 12th grade High school grad/GED or equivalent Some college or above Marital status Married Widowed/living with partner Divorced/separated Never married Poverty index ≤2 N2 Alcohol consumption No Yes Smoking status No Yes SHP No Yes DHP No Yes HP No Yes
b0.0001
b0.0001
SBP, systolic blood pressure; DBP, diastolic blood pressure; PBP, pulse blood pressure; SHP, systolic hypertension, defined as examined SBP ≥140 mm Hg; DHP, diastolic hypertension, defined as examined DBP ≥90 mm Hg; HP, hypertension of SHP or DHP or self-reported cases prescribed with anti-hypertension medication by a physician; eGFR, estimated glomerular filtration rate; BCd, blood cadmium concentration; BPb, blood lead concentration; UCd, urinary cadmium concentration; UPb, urinary lead concentration; Ucr, urinary creatinine concentration; GM, geometric mean; IQR, interquartile range. ⁎ Data of men (n = 2183) and women (n = 2299) of ethnicity other than non-Hispanic white, non-Hispanic black and Mexican-American were not shown.
between BCd and obesity was observed in their effects on systolic hypertension risk. The higher Cd exposure levels of women than men are consistent with previous reports (Adams and Newcomb, 2014; Garner and Levallois, 2016; Garner and Levallois, 2017; Kim et al., 2015b; Lee and Kim, 2014). Choudhury et al. (Choudhury et al., 2001) proposed that women absorbed a longer proportion of ingested Cd because of their lower iron storage. In the present study, American men had higher serum iron content than American women. The association between
iron storage and Cd levels was also reported by other researchers (Berglund et al., 1994; Meltzer et al., 2010). Women, especially Mexican-Am, seem to be more susceptible to Cdrelated BP effects than men. Scinicariello et al. (Scinicariello et al., 2011) analyzed data from NHANES 1999–2006 and reported that increasing BCd was associated with higher blood pressures in American women and higher hypertension risk in Caucasian and Mexican-Am women. However, the BCd and hypertension risk association in Black women and men of the three ethnic groups (i.e., Caucasian, Black, and
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Table 2 Blood pressure changes (mmHg) and hypertension risks in relation to a twofold increase in Cd exposure measurements, stratified by sex and/or ethnicity. β (95% CI)
Stratification
OR (95% CI)
SBPa
DBPa
SHPa
DHPa
HP
Non-Hispanic white women Non-Hispanic black women Mexican-Am women All participants⁎
−0.09 (−0.43, 0.25) −0.16 (−0.56, 0.25) 0.31 (−0.23, 0.86) −0.00 (−0.04, 0.04) 0.40 (0.01, 0.78) 0.30 (−0.15, 0.74) 0.54 (0.49, 0.58) 0.92 (0.73, 1.11) 0.14 (−0.14, 0.41)
−0.02 (−0.28, 0.25) −0.09 (−0.40, 0.22) 0.41 (−0.01, 0.82) 0.09 (−0.00, 0.19) 0.08 (−0.20, 0.36) 0.03 (−0.28, 0.34) 0.05 (0.04, 0.06) 0.85 (0.65, 1.05) 0.02 (−0.19, 0.23)
0.98 (0.92, 1.04) 0.95 (0.87, 1.04) 1.00 (0.91, 1.14) 1.09 (0.96, 1.24) 1.06 (0.99, 1.14) 1.02 (0.92, 1.13) 1.08 (0.96, 1.23) 1.31 (1.07, 1.61) 1.01 (0.96, 1.06)
1.06 (0.98, 1.16) 1.02 (0.91, 1.14) 1.20 (1.04, 1.37) 1.10 (0.87, 1.39) 1.09 (0.96, 1.24) 1.00 (0.85, 1.18) 1.27 (1.02, 1.59) 1.55 (1.17, 2.05) 1.07 (0.98, 1.16)
0.96 (0.92, 1.02) 0.94 (0.88, 1.01) 1.06 (0.96, 1.16) 1.08 (0.94, 1.24) 1.01 (0.95, 1.08) 0.98 (0.91, 1.06) 1.06 (0.92, 1.21) 1.28 (1.08, 1.51) 0.98 (0.94, 1.03)
A twofold increase in UCd Men⁎ Women⁎ All participants⁎
−0.05 (−0.60, 0.49) −0.08 (−0.58, 0.42) −0.07 (−0.44, 0.30)
−0.06 (−0.53, 0.40) −0.09 (−0.49, 0.32) −0.08 (−0.38, 0.23)
1.04 (0.93, 1.16) 1.02 (0.92, 1.14) 1.03 (0.95, 1.12)
1.11 (0.96, 1.29) 0.92 (0.77, 1.10) 1.04 (0.92, 1.16)
1.18 (1.08, 1.30) 1.09 (0.99, 1.19) 1.14 (1.07, 1.21)
A twofold increase in BCd Men⁎ Non-Hispanic white men Non-Hispanic black men Mexican-Am men Women⁎
CI, confidence interval; BMI, body mass index; BCd, blood cadmium concentration; SBP, systolic blood pressure; DBP, diastolic blood pressure; SHP, systolic hypertension defined as examined SBP ≥140 mm Hg; DHT, diastolic hypertension defined as examined DBP ≥90 mm Hg; HP: hypertension of SHP or DHP or self-reported cases with medical prescription from a physician. Bold indicates statistically significant. ⁎ Data of men (n = 2183) and/or women (n = 2299) of ethnicity other than non-Hispanic white, non-Hispanic black and Mexican-American were also included. a Participants reported taking antihypertension medications were excluded. Estimates were adjusted for age, BMI category, educational background, marital status, poverty index, alcohol consumption, smoking status, serum contents of sodium, potassium, calcium, phosphorus, total protein, total cholesterol, glucose, and iron, estimated glomerular filtration rate, and blood lead concentration.
Mexican-Am) did not reach statistical significance (Scinicariello et al., 2011). In the KNHANES 2008–2013, Lee et al. reported that increasing BCd was associated with increased hypertension risk in men; the positive association was even stronger in women, given that women had higher mean BCd level than men (Lee et al., 2016). Independent and positive associations between Cd exposure (even at low levels) and blood pressure/hypertension were revealed in this study. The associations remained statistically significant in adjustments for many blood pressure-related covariates. According to Tellez-plaza et al.'s study (Tellez-Plaza et al., 2008), BCd was associated with SBP and DBP at low levels (mean BCd 0.42 μg/L, which is similar to the BCd value in this study); however, no association was found between BCd and hypertension. We supposed the large number of participants in our study could be a possible explanatory, contributing to the statistic power of finding difference. In this study, UCd was detected for some participants (subsamples consisting of 10,691 individuals). Significant associations between UCd and hypertension risk were found in all individuals but were not detected in sex stratifications. The exact biological mechanisms that link Cd exposure and elevated blood pressure and hypertension risk remain uncertain. Cd may have direct vascular effects. Cd can inhibit endothelial nitric oxide synthase in
blood vessels, thereby suppressing acetylcholoine-induced vascular relaxation and ultimately inducing hypertension (Yoopan et al., 2008). At the molecular level, the effects of Cd on the endothelium could be due to actions at multiple sites including cell adhesion molecules, metal ion transporters and protein kinase signaling pathways, leading to detrimental changes in the cell structure and significantly elevated level of apoptosis (Messner et al., 2016; Prozialeck et al., 2006; Tang et al., 2017). The nephrotoxic effects of Cd may contribute too (Eum et al., 2008; Satarug et al., 2005; Satarug et al., 2006). In renal cells, the Cdmetallothionein complex enters the lysosomes, which release Cd into the cytosol and degrade the metallothionein into its component amino acids. Cd that is not bound to metallothionein can injure the renal tubules; this phenomenon can lead to salt retention, volume overload, and eventually hypertension. Cd-induced kidney toxicity can proceed concurrently through renal tubular and glomerular damage even under a low exposure (Akesson et al., 2005). Individuals with decreased kidney function are at increased risk of hypertension (Kalra, 2007). Moreover, kidney damage may also be sequelae of hypertension (Kazancioglu, 2013). The current study included estimated glomerular filtration rate as an indicator of chronic kidney disease in regression models to account for this relationship.
Table 3 Blood pressure changes (mmHg) and hypertension risks in relation to a twofold increase in Cd exposure measurements, stratified by BMI category. BMI category
β (95% CI)
OR (95% CI)
SBPa
DBPa
SHPa
DHPa
HP
A twofold increase in BCd Normal Overweight Obese Subtotal⁎
0.36 (−0.05, 0.78) 0.32 (−0.10, 0.72) −0.12 (−0.61, 0.36) 0.21 (−0.06, 0.47)
0.14 (−0.18, 0.46) 0.23 (−0.12, 0.59) −0.10 (−0.46, 0.25) 0.10 (−0.11, 0.31)
1.05 (0.95, 1.17) 1.05 (0.97, 1.13) 0.96 (0.89, 1.04) 1.02 (0.97, 1.07)
1.02 (0.87, 1.20) 1.08 (0.95, 1.24) 0.96 (0.87, 1.07) 1.07 (0.99, 1.16)
1.05 (0.97, 1.14) 1.00 (0.93, 1.07) 0.94 (0.88, 1.00) 0.98 (0.94, 1.03)
A twofold increase in UCd Normal Overweight Obese Subtotal⁎
0.11 (−0.52, 0.74) −0.09 (−0.74, 0.56) −0.29 (−1.17, 0.60) −0.17 (−0.61, 0.28)
−0.49 (−1.03, 0.06) −0.35 (−0.88, 0.18) −0.01 (−0.67, 0.65) 0.29 (−0.62, 0.04)
1.11 (0.97, 1.27) 0.96 (0.83, 1.09) 0.98 (0.86, 1.11) 1.03 (0.95, 1.12)
1.00 (0.81, 1.22) 0.84 (0.70, 1.01) 0.98 (0.82, 1.16) 1.03 (0.92, 1.16)
1.20 (1.07, 1.36) 1.06 (0.94, 1.20) 1.07 (0.97, 1.18) 1.13 (1.06, 1.21)
BMI, body mass index; BCd, blood cadmium concentration; UCd, urinary cadmium concentration; SBP, systolic blood pressure; DBP, diastolic blood pressure; SHP, systolic hypertension defined as examined SBP ≥140 mm Hg; DHP, diastolic hypertension defined as examined DBP ≥90 mm Hg; HP, hypertension of SHP or DHP or self-reported hypertension cases with prescribed anti-hypertension medication; CI, confidence interval. Bold indicates statistically significant. ⁎ Data of participants with a BMI of b18.5 were excluded. a Participants reported taking antihypertension medications were excluded. Estimates were adjusted for age, ethnicity, educational background, marital status, poverty index, alcohol consumption, smoking status, serum contents of sodium, potassium, calcium, phosphorus, total protein, total cholesterol, glucose, and iron, estimated glomerular filtration rate, and blood lead concentration.
Q. Wang, S. Wei / Science of the Total Environment 643 (2018) 270–276 Table 4 Effect of interaction between BCd and obesity on systolic hypertension risk. BMI
Competing financial interests The authors have no conflict of interest to declare.
OR (95% CI) BCd
18.5–29.9 ≥30.0 Within strata of BCd
275
Within strata of BMI
Lower 50%
Upper 50%
1.0 1.45 (1.24, 1.70) 1.45 (1.24, 1.70)
1.11 (0.97, 1.26) 2.06 (1.61, 2.64) 1.16 (1.04, 1.31)
1.11 (0.97, 1.26) 1.03 (0.87, 1.21)
Measure of interaction on additive scale: RERI (95% CI) = −0.30 (−0.56, −0.03). Measure of interaction on multiplicative scale: ratio of ORs (95% CI) = 0.55 (0.35, 0.89). ORs are adjusted for age, ethnicity, education, marital status, marital status, poverty index, alcohol consumption, smoking status, serum contents of sodium, potassium, calcium, phosphorus, total protein, total cholesterol, glucose, and iron, estimated glomerular filtration rate, and blood lead concentration. BMI, body mass index; BCd, blood cadmium concentration; OR, odds ratio; CI, confidence interval.
Similar to previous reports, the present study findings showed some discrepancies of the effect of Cd on SBP and DBP. Eum et al. (Eum et al., 2008) reported that BCd was positively associated with SBP when BCd was ranged from 1.29 to 5.52 μg/L; and BCd was positively associated with DBP when BCd ranged from 1.87 to 5.52 μg/L; hence, SBP may be more easily influenced by Cd exposure. Chen et al. (Chen et al., 2015) evaluated the reference level of BCd for hypertension by using the benchmark dose approach and found the BCd reference level for systolic hypertension was lower (0.95 μg/L and 1.02 μg/L for women and men, respectively) than that for diastolic hypertension (1.8 μg/L and 1.66 μg/L for women and men, respectively). In the present study, BCd-associated SBP increment seemed to be slightly higher than DBP increment in women and slightly more obvious in Mexican-Am. However, the conclusion of higher susceptibility of SBP to Cd exposure than DBP cannot be drawn yet considering the overlap of the effect-size confidence intervals. Interestingly, our findings suggested the effect of the negative interaction between BCd and BMI (and only that of obesity but not overweight) on systolic hypertension risk. Previous data from the human studies on the interaction between Cd exposure and BMI/obesity are rather controversial, varying from negative to positive; such data also demonstrated that Cd exposure may be both negatively and positively associated with overweight/obesity (Tinkov et al., 2017). Significant negative association between Cd exposure and BMI was demonstrated in some reports (Riederer et al., 2013; Rignell-Hydbom et al., 2009; Son et al., 2015; Tellez-Plaza et al., 2013a); by contrast, null to positive association between the two were reported in other studies (Ahn et al., 2017; Berglund et al., 2015; Gonzalez-Reimers et al., 2014). The blood pressure-related factors other than those adjusted for in our multiple-linear/logistic regression modeling may contribute to the negative interaction to some extent. Additionally, potential biological mechanisms underlying the Cd exposure and BMI/obesity interaction in their effects on blood pressures are worthy of further investigation. The main limitation of our study is its cross-sectional design. Hence, casual inference was limited for Cd exposure and blood pressure or hypertension. Prospective evidence in such field is still needed in the future. 5. Conclusions Cd exposure is a risk factor for elevated blood pressure and hypertension risk in American adults. The Cd-associated blood pressure and hypertension effects show discrepancies by sex and ethnicity. The negative interaction between blood cadmium concentration and obesity influences systolic hypertension risk. Acknowledgments The work was supported by the National Natural Science Foundation of China (81573235), and the Fundamental Research Funds for the Central Universities (HUST:2016YXMS223).
Authors' roles Study design: SW and QW. Study conduct, data collection, data analysis, data interpretation, and draft manuscript: QW. Revising manuscript content: SW. Approving final version of manuscript: QW and SW. SW takes responsibility for the integrity of the data analysis. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.scitotenv.2018.06.105.
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Science of the Total Environment journal homepage: www.elsevier.com/locate/scitotenv
Cadmium affects blood pressure and negatively interacts with obesity: Findings from NHANES 1999–2014 Qi Wang, Sheng Wei ⁎ Key Laboratory of Environment and Health (HUST), Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubation), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
H I G H L I G H T S
G R A P H I C A L
• Cd exposure is associated with elevated blood pressure and hypertension. • Their associations show discrepancies by sex and ethnicity. • Negative interaction between BCd and obesity affects systolic hypertension.
Blood pressure change (mmHg) (in the left) and OR for hypertension (in the right) in relation to a twofold increase in BCd, stratified by sex and ethnicity, adjusted for age, BMI category, educational background, marital status, poverty index, alcohol consumption, smoking status and serum contents of sodium, potassium, calcium, creatinine, phosphorus, total protein, total cholesterol, glucose, and iron and blood lead concentration. SBP, systolic blood pressure; DBP, diastolic blood pressure; BCd, blood cadmium concentration; BMI, body mass index; CI, confidence interval; OR, odds ratio.
a r t i c l e
a b s t r a c t
i n f o
Article history: Received 6 March 2018 Received in revised form 5 May 2018 Accepted 9 June 2018 Available online xxxx Editor: F.M. Tack Keywords: Cadmium Blood pressure Hypertension Interaction Obesity
A B S T R A C T
Inconsistencies are noted regarding the association between cadmium exposure and blood pressure/hypertension and the interaction between cadmium and body mass index (BMI). This study aims to clarify these inconsistencies in a large sample (n = 32,791) of adults age ≥20 years from eight cycles of the US National Health Examination and Nutrition Survey (NHANES, 1999–2014). The cadmium levels in blood (BCd) and urine (UCd) were used as exposure biomarker. Multiple-linear/logistic regression models were built and stratified by sex, ethnicity and BMI category. The interaction between BCd and BMI was assessed on additive and multiplicative scales. A twofold increase in BCd was associated with 0.54 mm Hg (95% CI: 0.49, 0.58) and 0.05 mm Hg (95% CI: 0.04, 0.06) increases in the systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively, in black women. The SBP and DBP increased by 0.92 mm Hg (95% CI: 0.73, 1.11) and 0.85 mm Hg (95% CI: 0.65, 1.05), respectively, in Mexican-Am women. Significant associations were found between BCd and hypertension in them (systolic risk per twofold BCd, OR = 1.31; 95% CI: 1.07, 1.61; and diastolic risk per twofold BCd, OR = 1.55; 95% CI: 1.17, 2.05). UCd was significantly associated with hypertension in all individuals (OR = 1.14 per twofold; 95% CI: 1.07, 1.21). The associations between cadmium exposure and blood pressure/hypertension showed some discrepancies across BMI categories. A negative interaction was observed between BCd and obesity with regard to their effects on systolic hypertension (RERI = −0.30; 95% CI: −0.56, −0.03; ratio of ORs = 0.55; 95% CI: 0.35, 0.89). Our findings provided evidence for the effect of cadmium on blood pressure and the prevalence of
⁎ Corresponding author at: School of Public Health, Tongji Medical College, Huazhong University of Science of Technology, Wuhan 430030, China. E-mail address: [email protected] (S. Wei).
https://doi.org/10.1016/j.scitotenv.2018.06.105 0048-9697/© 2017 Elsevier B.V. All rights reserved.
Q. Wang, S. Wei / Science of the Total Environment 643 (2018) 270–276
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hypertension in American adults. The associations showed discrepancies by sex and ethnicity. The negative interaction between cadmium exposure and obesity influenced systolic hypertension risk. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Cadmium (Cd) is a hazardous heavy metal that is environmentally ubiquitous. Cigarette smoking (even second-hand smoking) is a significant source of Cd exposure for human beings (Messner and Bernhard, 2010). The effect of Cd-containing products via exposure to soil and diet on humans is a major concern (Lalor, 2008). Cd can accumulate progressively in the body and has a long biological half-life of 15–30 years (Satarug and Moore, 2004). Cd concentrations in blood (BCd) and urine (UCd) are established biomarkers of Cd exposure and internal dose, reflecting cumulative exposure; the former also reflects short-term fluctuations in exposure (ATSDR, 2012; Jarup and Akesson, 2009). In vitro studies provide evidence regarding the effect of Cd on vascular endothelium—which plays an important role in various physiologic and pathologic processes such as blood pressure regulation, angiogenesis, and athrosclerosis (Prozialeck et al., 2006). Epidemiologic studies demonstrate that long-term exposure to low levels of Cd contributes to the morbidity and mortality of cardiovascular diseases, atherosclerosis, coronary artery disease, and stroke possibly because of the effect of this metal on elevated blood pressure and hypertension risk (Deering et al., 2018; Eum et al., 2008; Franceschini et al., 2017; Ruiz-Hernandez et al., 2017; Tellez-Plaza et al., 2013b; Tinkov et al., 2018). However, other studies demonstrated null or even negative association between Cd exposure and BP (Gallagher and Meliker, 2010; Mordukhovich et al., 2012; Swaddiwudhipong et al., 2010). In addition, results of previous studies vary in terms of direction or significance that Cd body stores have on blood pressure or hypertension, with results seeming to vary by sex, smoking status, ethnicity, BMI category and medication levels. As a widely known risk factor for higher blood pressure and probability of hypertension, high BMI is reported to be associated with low level of Cd and other heavy metals (Garner and Levallois, 2016; Nie et al., 2016; Padilla et al., 2010). The positive association of BCd and BMI has also been demonstrated (Kim et al., 2015a). A recent study revealed the differential association between Cd exposure, blood pressure and hypertension by BMI category (Garner and Levallois, 2017). Within BMI categories, high urinary Cd levels were associated with significantly high blood pressure among overweight and obese women (Garner and Levallois, 2017). Thus far, the effect of the interaction of Cd and BMI on BP is worthy of further investigation. In this study, we explored the effect of Cd on blood pressure/hypertension and its interaction with BMI by using the 1999–2014 National Health and Nutrition Examination Survey (NHANES) data from American adults aged ≥20 years, representing as a diverse racially sample of the US population. BCd and UCd were used as biomarker of Cd exposure. Adjustment for a number of covariates, including lead concentration in blood (BPb) or urine (UPb), was conducted. 2. Material and methods 2.1. Study population The NHANES 1999–2014 conducted by the U.S. National Center for Health Statistics (NCHS) comprised cross-sectional, nationally representative surveys of the U.S. non-institutionalized civilian population. The NHANES data included in the present study were collected in eight stages, i.e. 1999–2000, 2001–2002, 2003–2004, 2005–2006, 2007–2008, 2009–2010, 2011–2012, and 2013–2014. The survey employed a multistage stratified probability sampling based on selected counties, blocks, households, and persons within households.
Interviews were conducted in participants' homes and extensive physical examinations, which included blood and urine collection, were conducted at mobile exam centers (MEC). We limited the study population to individuals aged ≥20 years who were examined in a MEC and had available BCd concentrations. A total of 43,793 participants (including 21,024 men and 22,769 women) were involved in the study. However, only data from 32,791 participants (including 16,558 men and 16,233 women) were involved in our statistical analysis for the association of Cd exposure with blood pressure or prevalent hypertension risk. Some of the participants were excluded because of missing data. Self-reported ethnicity was categorized as non-Hispanic white (hereafter referred to as Whites), nonHispanic black (hereafter referred to as Blacks), Mexican-American (hereafter referred to as Mexican-Am), and other else. 2.2. Exposure and outcome variables The main exposure variable was BCd, which was determined using an adapted electrothermal atomic absorption method in the surveys of 1999–2000 and 2001–2002 and through inductively coupled plasma mass spectrometry (ICP-MS) in the surveys of the six other cycles (URLs of detailed methods in Supplementary materials). The secondary exposure variable was UCd, which was determined in subsamples (10,691 individuals) of participants by using ICP-MS across all surveys (URLs of detailed methods in Supplementary materials). The UCd was standardized (expressed in μg/g creatinine) by dividing by urinary creatinine concentration. The outcomes included blood pressures of systolic (SBP) and diastolic (DBP) and prevalent hypertension. Blood pressure was reported with an average of ≤3 readings (URLs of detailed methods in Supplementary materials). Prevalent hypertension was defined as the examined SBP ≥140 mm Hg (SHP), DBP ≥90 mm Hg (DHP), or self-reported hypertension case prescribed with antihypertension medication by a physician (URLs of detailed methods in Supplementary materials). 2.3. Covariates We obtained the covariate information about age (categorized into three groups: 20–39 years, 40–59 years, and ≥60 years), sex, ethnicity, education (categorized into three groups: 1 = less than 12th grade, 2 = high school Grad/GED or equivalent, and 3 = college or above), marital status (categorized into four groups: 1 = married, 2 = widowed or living with partner, 3 = divorced or separated, and 4 = never married), and poverty index (≤2 vs. N2) from the household interview (URLs of detailed demographics in Supplementary materials). BMI was calculated by dividing the measured weight in kilograms by the measured height in meters squared (URLs of detailed methods for weight and height measurement in Supplementary materials). BMI categories of underweight (i.e., BMI b 18.5), normal weight (i.e., 18.5 ≤ BMI b 25.0), overweight (i.e., 25.0 ≤ BMI b 30.0), and obesity (i.e., BMI ≥ 30.0) were utilized. Data on alcohol consumption (yes = at least 12 alcohol drinks per year or >2 drinking alcohol frequency in the past 12 months vs. no = less than 12 alcohol drinks per year or ≤ 2 drinking alcohol frequency in the past 12 months) and smoking status (yes vs. no) information were obtained by questionnaire interviews (URLs of detailed methods in Supplementary materials). The standard biochemistry profile including serum contents of sodium (mmol/L), potassium (mmol/L), calcium (mg/dl), iron (mg/dl), phosphorus (mg/dl), total protein (g/dl), total cholesterol (mg/dl), glucose (mg/dl), and creatinine (mg/dl) were
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collected from representative laboratory measurements (URLs of detailed methods in Supplementary materials). In particular, serum creatinine was measured by the modified kinetic method of Jaffé and corrected for NHANES 1999–2000 and NHANES 2005–2006 (URLs of detailed methods in Supplementary materials). The following formulas were used to adjust the serum creatinine level to ensure comparability with the standard creatinine level: NHANES 1999–2000 standard creatinine = 0.147 + 1.013 × NHANES 1999–2000 uncalibrated serum creatinine; and NHANES 2005–2006 standard creatinine = −0.016 + 0.978 × NHANES 2005–2006 uncalibrated serum creatinine. With the given serum creatinine concentration, glomerular filtration rate was estimated using the equation reported by Levey et al. (2009). Blood lead (BPb) levels (μg/dl) was simultaneously measured with BCd by using the same methods as mentioned above. The involved covariates were selected with respect to their influence on the regression coefficient of BCd on blood pressure. Covariates were included in the final regression modeling in case of 5% or more change of the effect size of BCd before and/or after adjustment. 2.4. Statistical analysis The analytic guidelines (https://www.cdc.gov/nchs/data/series/sr_ 02/sr02_161.pdf) from NCHS were referred to for statistical analysis. Sample weights were used to account for the complex sampling design and non-response of NHANES. For normally distributed variables, including BMI, SBP, DBP, and serum levels of sodium, potassium, calcium, creatinine, phosphorus, total protein, and total cholesterol, the central tendency and spread of data were reported as mean and standard deviation. For variables such as BCd, BPb, UCd, UPb, and serum levels of glucose and iron, which required logarithmic transformation to approximate normal distribution, the central tendency and spread of data were reported as geometric mean and interquartile range (IQR). Frequency was used to describe enumeration data. Multiple linear/logistic regression modeling in adjustments for the covariates were performed to evaluate the association between Cd exposure and blood pressure/hypertension by using Proc Surveyreg/Surveylogistic. Multiple-variable adjusted blood pressure changes and odds ratios (ORs) of hypertension were calculated by comparing participants with a twofold increase in BCd/UCd for each ethnicity/sex and BMI category groups. In the mentioned association analysis of Cd exposure and blood pressure, data of participants taking antihypertension medication were excluded. The effects of the potential interaction between BCd and BMI on hypertension risk were assessed on additive [with relative excess risk index (RERI) presented] and multiplicative (with ratio of ORs presented) scales (Hosmer and Lemeshow, 1992; Knol and VanderWeele, 2012). All statistical analyses were twosided with a significance of P b 0.05. SAS9.4 (SAS Institute, Cary, NC) was used to conduct statistical analysis. 2.5. Ethics statement Ethical approval for the NHANES study was obtained from the NCHS Research Ethics Review Board. Further ethical approval for the use of NHANES data that are freely available on the web was not required because they were anonymized. Written consent was obtained from all participants.
Mexican-Am ethnic populations. American women had significantly higher BCd and UCd than men (both P b 0.001). 3.2. Association between Cd exposure and blood pressure/hypertension risk, stratified by sex and/or ethnicity The associations between BCd and SBP/DBP were not significant among all individuals (Table 2). Stratified by sex, the BCd and SBP association achieved significance in women but not in men. Increasing BCd (by twofold) was associated with increased SBP (0.40 mm Hg; 95% CI: 0.01, 0.78) in women. Furthermore, a twofold increase in BCd was associated with elevated SBP by 0.54 mm Hg (95% CI: 0.49, 0.58) and 0.92 mm Hg (95% CI: 0.73, 1.11) in Black and Mexican-Am women, respectively. The BCd and DBP associations (β = 0.05 mm Hg per twofold; 95% CI: 0.04, 0.06; and β = 0.85 mm Hg per twofold; 95% CI: 0.65, 1.05) reached significance in the two groups. For hypertension risk referred to as higher blood pressure than the representative thresholds (i.e., 140 mm Hg for SBP, and 90 mm Hg for DBP), increasing BCd was significantly associated with increased hazards of SHP (OR = 1.31 per twofold; 95% CI: 1.07, 1.61) and DHP (OR = 1.55 per twofold; 95% CI: 1.17, 2.05) in Mexican-Am women. The BCd and DHP association also achieved significance in black men (OR = 1.20 per twofold; 95% CI: 1.04, 1.37). With self-reported hypertension cases involved, a twofold increase in BCd level was associated with 28% (95% CI: 8%, 51%) more hazard of hypertension in MexicanAm women. Significant UCd and blood pressure associations were not found either in men or women (Table 2). However, increasing UCd was associated with increased hazard of hypertension risk, referred to as SHP, DHP, or self-reported cases, with twofold UCd-associated OR (95% CI) of 1.14 (1.07, 1.21) in all individuals. 3.3. Association between Cd exposure and blood pressure/hypertension, stratified by BMI category Multiple linear regression modeling revealed non-significant discrepancies of BCd-associated blood pressure changes across BMI categories (Table 3). The discrepancies of BCd-associated hypertension risk showed across BMI categories. The UCd and blood pressure associations did not achieve significance across BMI categories. However, BMIstratification analysis revealed the significant UCd and hypertension association in participants with normal weight (OR = 1.20; 95% CI: 1.07, 1.36) but not in overweight or obese participants. 3.4. Effects of BCd and BMI interaction on hypertension risk To investigate the effect of the potential interaction between BCd and BMI on hypertension risk, we categorized BCd and BMI into two categories (i.e., BCd: ≥ GM vs. bGM; and BMI: ≥ 30 kg/m2 indicating obesity vs. b30 kg/m2 indicating no obesity). On the additive scale, significantly negative interaction between BCd and obesity was found with regard to their effect on SHP (Table 4; RERI = −0.30; 95% CI: −0.56, −0.03). Similar findings were obtained on the multiplicative scale (Table 4; ratio of ORs = 0.55; 95% CI: 0.35, 0.89). The effect of the negative interaction between BCd and obesity on DHP did not achieve significance (RERI = −0.24; 95% CI: −0.67, 0.19; and ratio of ORs = 0.81; 95% CI: 0.56, 1.17).
3. Results
4. Discussion
3.1. Characteristics of participants involved in this study
In this study, American women were found to be exposed to higher levels of Cd than men. The associations showed discrepancies by sex and ethnicity. After controlling for pertinent covariates, high BCd level was independently associated with high blood pressures and risk of hypertension in American women, particularly Mexican-Am. A positive association was found between UCd and hypertension risk (either examined or self-reported) in all individuals. Negative interaction
Total of 32,791 participants were involved in our analysis (Table 1). The Whites (n = 16,016), Blacks (n = 6681), Mexican-Ams (n = 5612) and others else (n = 4492) accounted to 48.8%, 20.4%, 17.1% and 13.7% of the participants, respectively. Significant differences were observed in almost all variables, except BMI of men, across the White, Black and
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Table 1 Characteristics of the involved participants from NHANES 1999–2014. Characteristic
Men⁎
P
Women⁎
P
White
Black
Mexican-Am
White
Black
Mexican-Am
N = 8140
N = 3320
N = 2915
N = 7876
N = 3361
N = 2697
2453 (17.1) 2524 (17.6) 3163 (22.0)
1133 (7.9) 1103 (7.7) 1084 (7.5)
1141 (7.9) 957 (6.6) 817 (5.7)
b0.0001
2259 (16.2) 2511 (18.0) 3106 (22.3)
1081 (7.6) 1205 (8.6) 1075 (7.7)
962 (6.9) 893 (6.4) 842 (6.0)
b0.0001
1425 (9.9) 2120 (14.7) 4595 (32.0)
1008 (7.0) 879 (6.1) 1433 (10.0)
1660 (11.5) 549 (3.8) 706 (4.9)
b0.0001
1230 (8.8) 2052 (14.7) 4594 (33.0)
892 (6.4) 772 (5.5) 1697 (12.2)
1460 (10.5) 460 (3.3) 777 (5.6)
b0.0001
5118 (35.6) 933 (6.5) 857 (6.0) 1232 (8.6)
1477 (10.3) 478 (3.3) 514 (3.6) 851 (5.9)
1896 (13.2) 332 (2.3) 246 (1.7) 441 (3.1)
b0.0001
4163 (30.0) 1622 (11.6) 1189(8.5) 902 (6.5)
1009 (7.2) 658 (4.7) 755 (5.4) 939 (6.7)
1465 (10.5) 507 (3.6) 389 (2.8) 336 (2.4)
b0.0001
2924 (20.3) 5216 (36.3)
1582 (11.0) 1738 (12.1)
1825 (12.7) 1090 (7.6)
b0.0001
3313 (22.3) 4763 (34.2)
1817 (13.0) 15,449 (11.1)
1744 (12.5) 953 (6.8)
b0.0001
1139 (7.9) 7001 (48.7)
690 (4.8) 2630 (18.3)
323 (2.2) 2592 (18.0)
b0.0001
2294 (16.4) 5582 (40.0)
1458 (10.5) 1903 (13.6)
1224 (8.8) 1473 (10.6)
b0.0001
3269 (22.8) 4868 (33.9)
1538 (10.7) 1776 (12.4)
1317 (9.2) 1596 (11.1)
4163 (29.9) 3712 (26.6)
2155 (15.5) 1205 (8.6)
1954 (14.0) 741 (5.3)
6650 (47.1) 1364 (9.7)
2451 (17.4) 782 (5.5)
2395 (17.0) 464 (3.3)
b0.0001
6197 (45.7) 1486 (11.0)
2477 (18.3) 763 (5.6)
2140 (15.8) 489 (3.6)
b0.0001
7489 (53.4) 481 (3.4)
2856 (20.4) 360 (2.6)
2689 (19.2) 158 (1.1)
b0.0001
7391 (54.9) 242 (1.8)
2984 (22.2) 235 (1.7)
2519 (18.7) 97 (0.7)
b0.0001
4826 (34.0) 3232 (22.8)
1707 (12.0) 1560 (11.0)
2014 (14.2) 862 (6.1)
b0.0001
4619 (33.7) 3148 (22.9)
1593 (11.6) 1715 (12.5)
1729 (12.6) 918 (6.7)
b0.0001
Mean of measurements (±SD) BMI, kg/m2 Sodium (serum), mmol/L Potassium (serum), mmol/L Calcium (serum), mg/dl Creatinine (serum), mg/dl eGFR, ml/min/1.73 m2 Phosphorus (serum), mg/dl Total protein (serum), g/dl Cholesterol (serum), mg/dl SBP, mmHg DBP, mmHg PBP, mmHg
28.4 ± 5.80 139.3 ± 2.32 4.1 ± 0.34 9.5 ± 0.36 1.0 ± 0.34 90.1 ± 21.67 3.7 ± 0.58 7.2 ± 0.46 195.5 ± 41.53 123.5 ± 17.1 72.3 ± 13.23 50.8 ± 17.59
28.8 ± 6.46 139.5 ± 2.21 4.0 ± 0.35 9.5 ± 0.39 1.2 ± 0.77 85.2 ± 25.42 3.7 ± 0.59 7.4 ± 0.53 188.1 ± 40.67 127.0 ± 18.31 73.3 ± 14.58 55.2 ± 17.38
28.7 ± 5.00 139.2 ± 2.36 4.0 ± 0.32 9.4 ± 0.35 0.9 ± 0.41 105.5 ± 20.6 3.7 ± 0.57 7.4 ± 0.47 198.1 ± 41.87 121.5 ± 17.70 71.2 ± 12.88 50.2 ± 17.04
0.0799 0.0013 b0.0001 b0.0001 b0.0001 b0.0001 0.0044 b0.0001 b0.0001 b0.0001 0.0001 b0.0001
28.3 ± 6.92 139.0 ± 2.37 4.0 ± 0.34 9.4 ± 0.38 0.8 ± 0.27 89.4 ± 22.87 3.8 ± 0.54 7.0 ± 0.45 202.0 ± 41.94 120.9 ± 21.11 69.6 ± 13.20 50.9 ± 21.35
32.1 ± 8.06 139.1 ± 2.42 3.9 ± 0.35 9.4 ± 0.40 0.9 ± 0.56 89.0 ± 28.02 3.7 ± 0.55 7.3 ± 0.51 190.1 ± 41.04 125.0 ± 21.82 71.2 ± 14.09 53.3 ± 20.74
29.8 ± 6.22 138.8 ± 2.26 3.9 ± 0.32 9.3 ± 0.37 0.7 ± 0.30 106.8 ± 22.22 3.8 ± 0.54 7.3 ± 0.46 194.2 ± 39.18 117.7 ± 21.52 68.6 ± 12.50 48.9 ± 20.24
b0.0001 0.0036 b0.0001 b0.0001 b0.0001 b0.0001 0.0002 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001
GM (IQR) Glucose (serum), mg/dl Iron (serum), mg/dl BCd, μg/L BPb, μg/dl Ucr, mg/dl UCd, μg/g Ucr UPb μg/dl
97.6 (18.0) 88.3 (44.0) 0.4 (0.5) 1.6 (1.4) 111.5 (100.0) 1.9 (3.0) 0.6 (0.7)
98.5 (19.0) 78.4 (39.0) 0.4 (0.6) 1.7 (1.8) 158.7 (119.0) 1.8 (2.9) 0.7 (0.9)
101.6 (19.0) 92.3 (46.0) 0.3 (0.3) 1.6 (1.7) 118,9 (97.0) 1.6 (2.3) 0.7 (1.3)
0.0004 b0.0001 b0.0001 0.015 b0.0001 b0.0001 b0.0001
93.9 (17.0) 75.0 (41.0) 0.4 (0.4) 1.1 (1.1) 73.3 (87.0) 2.9 (3.8) 0.4 (0.6)
96.9 (19.0) 62.1 (37.0) 0.4 (0.4) 1.2 (1.2) 122.3 (112.0) 2.8 (3.5) 0.6 (0.6)
99.0 (19.0) 67.3 (42.0) 0.3 (0.3) 1.0 (1.1) 83.5 (94.0) 2.6 (3.4) 0.5 (0.8)
b0.0001 b0.0001 b0.0001 0.0005 b0.0001 0.0154 b0.0001
No. (%) Age (yrs.) 20–39 40–59 60– Educational background Less than 12th grade High school grad/GED or equivalent Some college or above Marital status Married Widowed/living with partner Divorced/separated Never married Poverty index ≤2 N2 Alcohol consumption No Yes Smoking status No Yes SHP No Yes DHP No Yes HP No Yes
b0.0001
b0.0001
SBP, systolic blood pressure; DBP, diastolic blood pressure; PBP, pulse blood pressure; SHP, systolic hypertension, defined as examined SBP ≥140 mm Hg; DHP, diastolic hypertension, defined as examined DBP ≥90 mm Hg; HP, hypertension of SHP or DHP or self-reported cases prescribed with anti-hypertension medication by a physician; eGFR, estimated glomerular filtration rate; BCd, blood cadmium concentration; BPb, blood lead concentration; UCd, urinary cadmium concentration; UPb, urinary lead concentration; Ucr, urinary creatinine concentration; GM, geometric mean; IQR, interquartile range. ⁎ Data of men (n = 2183) and women (n = 2299) of ethnicity other than non-Hispanic white, non-Hispanic black and Mexican-American were not shown.
between BCd and obesity was observed in their effects on systolic hypertension risk. The higher Cd exposure levels of women than men are consistent with previous reports (Adams and Newcomb, 2014; Garner and Levallois, 2016; Garner and Levallois, 2017; Kim et al., 2015b; Lee and Kim, 2014). Choudhury et al. (Choudhury et al., 2001) proposed that women absorbed a longer proportion of ingested Cd because of their lower iron storage. In the present study, American men had higher serum iron content than American women. The association between
iron storage and Cd levels was also reported by other researchers (Berglund et al., 1994; Meltzer et al., 2010). Women, especially Mexican-Am, seem to be more susceptible to Cdrelated BP effects than men. Scinicariello et al. (Scinicariello et al., 2011) analyzed data from NHANES 1999–2006 and reported that increasing BCd was associated with higher blood pressures in American women and higher hypertension risk in Caucasian and Mexican-Am women. However, the BCd and hypertension risk association in Black women and men of the three ethnic groups (i.e., Caucasian, Black, and
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Table 2 Blood pressure changes (mmHg) and hypertension risks in relation to a twofold increase in Cd exposure measurements, stratified by sex and/or ethnicity. β (95% CI)
Stratification
OR (95% CI)
SBPa
DBPa
SHPa
DHPa
HP
Non-Hispanic white women Non-Hispanic black women Mexican-Am women All participants⁎
−0.09 (−0.43, 0.25) −0.16 (−0.56, 0.25) 0.31 (−0.23, 0.86) −0.00 (−0.04, 0.04) 0.40 (0.01, 0.78) 0.30 (−0.15, 0.74) 0.54 (0.49, 0.58) 0.92 (0.73, 1.11) 0.14 (−0.14, 0.41)
−0.02 (−0.28, 0.25) −0.09 (−0.40, 0.22) 0.41 (−0.01, 0.82) 0.09 (−0.00, 0.19) 0.08 (−0.20, 0.36) 0.03 (−0.28, 0.34) 0.05 (0.04, 0.06) 0.85 (0.65, 1.05) 0.02 (−0.19, 0.23)
0.98 (0.92, 1.04) 0.95 (0.87, 1.04) 1.00 (0.91, 1.14) 1.09 (0.96, 1.24) 1.06 (0.99, 1.14) 1.02 (0.92, 1.13) 1.08 (0.96, 1.23) 1.31 (1.07, 1.61) 1.01 (0.96, 1.06)
1.06 (0.98, 1.16) 1.02 (0.91, 1.14) 1.20 (1.04, 1.37) 1.10 (0.87, 1.39) 1.09 (0.96, 1.24) 1.00 (0.85, 1.18) 1.27 (1.02, 1.59) 1.55 (1.17, 2.05) 1.07 (0.98, 1.16)
0.96 (0.92, 1.02) 0.94 (0.88, 1.01) 1.06 (0.96, 1.16) 1.08 (0.94, 1.24) 1.01 (0.95, 1.08) 0.98 (0.91, 1.06) 1.06 (0.92, 1.21) 1.28 (1.08, 1.51) 0.98 (0.94, 1.03)
A twofold increase in UCd Men⁎ Women⁎ All participants⁎
−0.05 (−0.60, 0.49) −0.08 (−0.58, 0.42) −0.07 (−0.44, 0.30)
−0.06 (−0.53, 0.40) −0.09 (−0.49, 0.32) −0.08 (−0.38, 0.23)
1.04 (0.93, 1.16) 1.02 (0.92, 1.14) 1.03 (0.95, 1.12)
1.11 (0.96, 1.29) 0.92 (0.77, 1.10) 1.04 (0.92, 1.16)
1.18 (1.08, 1.30) 1.09 (0.99, 1.19) 1.14 (1.07, 1.21)
A twofold increase in BCd Men⁎ Non-Hispanic white men Non-Hispanic black men Mexican-Am men Women⁎
CI, confidence interval; BMI, body mass index; BCd, blood cadmium concentration; SBP, systolic blood pressure; DBP, diastolic blood pressure; SHP, systolic hypertension defined as examined SBP ≥140 mm Hg; DHT, diastolic hypertension defined as examined DBP ≥90 mm Hg; HP: hypertension of SHP or DHP or self-reported cases with medical prescription from a physician. Bold indicates statistically significant. ⁎ Data of men (n = 2183) and/or women (n = 2299) of ethnicity other than non-Hispanic white, non-Hispanic black and Mexican-American were also included. a Participants reported taking antihypertension medications were excluded. Estimates were adjusted for age, BMI category, educational background, marital status, poverty index, alcohol consumption, smoking status, serum contents of sodium, potassium, calcium, phosphorus, total protein, total cholesterol, glucose, and iron, estimated glomerular filtration rate, and blood lead concentration.
Mexican-Am) did not reach statistical significance (Scinicariello et al., 2011). In the KNHANES 2008–2013, Lee et al. reported that increasing BCd was associated with increased hypertension risk in men; the positive association was even stronger in women, given that women had higher mean BCd level than men (Lee et al., 2016). Independent and positive associations between Cd exposure (even at low levels) and blood pressure/hypertension were revealed in this study. The associations remained statistically significant in adjustments for many blood pressure-related covariates. According to Tellez-plaza et al.'s study (Tellez-Plaza et al., 2008), BCd was associated with SBP and DBP at low levels (mean BCd 0.42 μg/L, which is similar to the BCd value in this study); however, no association was found between BCd and hypertension. We supposed the large number of participants in our study could be a possible explanatory, contributing to the statistic power of finding difference. In this study, UCd was detected for some participants (subsamples consisting of 10,691 individuals). Significant associations between UCd and hypertension risk were found in all individuals but were not detected in sex stratifications. The exact biological mechanisms that link Cd exposure and elevated blood pressure and hypertension risk remain uncertain. Cd may have direct vascular effects. Cd can inhibit endothelial nitric oxide synthase in
blood vessels, thereby suppressing acetylcholoine-induced vascular relaxation and ultimately inducing hypertension (Yoopan et al., 2008). At the molecular level, the effects of Cd on the endothelium could be due to actions at multiple sites including cell adhesion molecules, metal ion transporters and protein kinase signaling pathways, leading to detrimental changes in the cell structure and significantly elevated level of apoptosis (Messner et al., 2016; Prozialeck et al., 2006; Tang et al., 2017). The nephrotoxic effects of Cd may contribute too (Eum et al., 2008; Satarug et al., 2005; Satarug et al., 2006). In renal cells, the Cdmetallothionein complex enters the lysosomes, which release Cd into the cytosol and degrade the metallothionein into its component amino acids. Cd that is not bound to metallothionein can injure the renal tubules; this phenomenon can lead to salt retention, volume overload, and eventually hypertension. Cd-induced kidney toxicity can proceed concurrently through renal tubular and glomerular damage even under a low exposure (Akesson et al., 2005). Individuals with decreased kidney function are at increased risk of hypertension (Kalra, 2007). Moreover, kidney damage may also be sequelae of hypertension (Kazancioglu, 2013). The current study included estimated glomerular filtration rate as an indicator of chronic kidney disease in regression models to account for this relationship.
Table 3 Blood pressure changes (mmHg) and hypertension risks in relation to a twofold increase in Cd exposure measurements, stratified by BMI category. BMI category
β (95% CI)
OR (95% CI)
SBPa
DBPa
SHPa
DHPa
HP
A twofold increase in BCd Normal Overweight Obese Subtotal⁎
0.36 (−0.05, 0.78) 0.32 (−0.10, 0.72) −0.12 (−0.61, 0.36) 0.21 (−0.06, 0.47)
0.14 (−0.18, 0.46) 0.23 (−0.12, 0.59) −0.10 (−0.46, 0.25) 0.10 (−0.11, 0.31)
1.05 (0.95, 1.17) 1.05 (0.97, 1.13) 0.96 (0.89, 1.04) 1.02 (0.97, 1.07)
1.02 (0.87, 1.20) 1.08 (0.95, 1.24) 0.96 (0.87, 1.07) 1.07 (0.99, 1.16)
1.05 (0.97, 1.14) 1.00 (0.93, 1.07) 0.94 (0.88, 1.00) 0.98 (0.94, 1.03)
A twofold increase in UCd Normal Overweight Obese Subtotal⁎
0.11 (−0.52, 0.74) −0.09 (−0.74, 0.56) −0.29 (−1.17, 0.60) −0.17 (−0.61, 0.28)
−0.49 (−1.03, 0.06) −0.35 (−0.88, 0.18) −0.01 (−0.67, 0.65) 0.29 (−0.62, 0.04)
1.11 (0.97, 1.27) 0.96 (0.83, 1.09) 0.98 (0.86, 1.11) 1.03 (0.95, 1.12)
1.00 (0.81, 1.22) 0.84 (0.70, 1.01) 0.98 (0.82, 1.16) 1.03 (0.92, 1.16)
1.20 (1.07, 1.36) 1.06 (0.94, 1.20) 1.07 (0.97, 1.18) 1.13 (1.06, 1.21)
BMI, body mass index; BCd, blood cadmium concentration; UCd, urinary cadmium concentration; SBP, systolic blood pressure; DBP, diastolic blood pressure; SHP, systolic hypertension defined as examined SBP ≥140 mm Hg; DHP, diastolic hypertension defined as examined DBP ≥90 mm Hg; HP, hypertension of SHP or DHP or self-reported hypertension cases with prescribed anti-hypertension medication; CI, confidence interval. Bold indicates statistically significant. ⁎ Data of participants with a BMI of b18.5 were excluded. a Participants reported taking antihypertension medications were excluded. Estimates were adjusted for age, ethnicity, educational background, marital status, poverty index, alcohol consumption, smoking status, serum contents of sodium, potassium, calcium, phosphorus, total protein, total cholesterol, glucose, and iron, estimated glomerular filtration rate, and blood lead concentration.
Q. Wang, S. Wei / Science of the Total Environment 643 (2018) 270–276 Table 4 Effect of interaction between BCd and obesity on systolic hypertension risk. BMI
Competing financial interests The authors have no conflict of interest to declare.
OR (95% CI) BCd
18.5–29.9 ≥30.0 Within strata of BCd
275
Within strata of BMI
Lower 50%
Upper 50%
1.0 1.45 (1.24, 1.70) 1.45 (1.24, 1.70)
1.11 (0.97, 1.26) 2.06 (1.61, 2.64) 1.16 (1.04, 1.31)
1.11 (0.97, 1.26) 1.03 (0.87, 1.21)
Measure of interaction on additive scale: RERI (95% CI) = −0.30 (−0.56, −0.03). Measure of interaction on multiplicative scale: ratio of ORs (95% CI) = 0.55 (0.35, 0.89). ORs are adjusted for age, ethnicity, education, marital status, marital status, poverty index, alcohol consumption, smoking status, serum contents of sodium, potassium, calcium, phosphorus, total protein, total cholesterol, glucose, and iron, estimated glomerular filtration rate, and blood lead concentration. BMI, body mass index; BCd, blood cadmium concentration; OR, odds ratio; CI, confidence interval.
Similar to previous reports, the present study findings showed some discrepancies of the effect of Cd on SBP and DBP. Eum et al. (Eum et al., 2008) reported that BCd was positively associated with SBP when BCd was ranged from 1.29 to 5.52 μg/L; and BCd was positively associated with DBP when BCd ranged from 1.87 to 5.52 μg/L; hence, SBP may be more easily influenced by Cd exposure. Chen et al. (Chen et al., 2015) evaluated the reference level of BCd for hypertension by using the benchmark dose approach and found the BCd reference level for systolic hypertension was lower (0.95 μg/L and 1.02 μg/L for women and men, respectively) than that for diastolic hypertension (1.8 μg/L and 1.66 μg/L for women and men, respectively). In the present study, BCd-associated SBP increment seemed to be slightly higher than DBP increment in women and slightly more obvious in Mexican-Am. However, the conclusion of higher susceptibility of SBP to Cd exposure than DBP cannot be drawn yet considering the overlap of the effect-size confidence intervals. Interestingly, our findings suggested the effect of the negative interaction between BCd and BMI (and only that of obesity but not overweight) on systolic hypertension risk. Previous data from the human studies on the interaction between Cd exposure and BMI/obesity are rather controversial, varying from negative to positive; such data also demonstrated that Cd exposure may be both negatively and positively associated with overweight/obesity (Tinkov et al., 2017). Significant negative association between Cd exposure and BMI was demonstrated in some reports (Riederer et al., 2013; Rignell-Hydbom et al., 2009; Son et al., 2015; Tellez-Plaza et al., 2013a); by contrast, null to positive association between the two were reported in other studies (Ahn et al., 2017; Berglund et al., 2015; Gonzalez-Reimers et al., 2014). The blood pressure-related factors other than those adjusted for in our multiple-linear/logistic regression modeling may contribute to the negative interaction to some extent. Additionally, potential biological mechanisms underlying the Cd exposure and BMI/obesity interaction in their effects on blood pressures are worthy of further investigation. The main limitation of our study is its cross-sectional design. Hence, casual inference was limited for Cd exposure and blood pressure or hypertension. Prospective evidence in such field is still needed in the future. 5. Conclusions Cd exposure is a risk factor for elevated blood pressure and hypertension risk in American adults. The Cd-associated blood pressure and hypertension effects show discrepancies by sex and ethnicity. The negative interaction between blood cadmium concentration and obesity influences systolic hypertension risk. Acknowledgments The work was supported by the National Natural Science Foundation of China (81573235), and the Fundamental Research Funds for the Central Universities (HUST:2016YXMS223).
Authors' roles Study design: SW and QW. Study conduct, data collection, data analysis, data interpretation, and draft manuscript: QW. Revising manuscript content: SW. Approving final version of manuscript: QW and SW. SW takes responsibility for the integrity of the data analysis. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.scitotenv.2018.06.105.
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