Introduction

The burden of high blood pressure (BP) has remained high in the United States, affecting approximately one-third of American adults in the current century.1 The economic costs associated with hypertension are high for individuals and society. Exposure to environmental chemicals may induce atherosclerosis by increasing oxidative stress or produce reactive oxygen species, such as superoxide ion, hydrogen peroxide and hydroxyl radicals, according to experimental research.2, 3 Previous epidemiological investigations focused on arterial disease, heart disease and cardiovascular disease as end points,4, 5, 6 but the relationship with BP, a strong risk factor for many human chronic diseases as mentioned above, is unclear. Previously, an adverse intrauterine environment was found to be associated with an increased risk for future cardiovascular disease and hypertension. Recent animal models have shown that an elevated BP in offspring could be induced by maternal exposure to toxins.7 In this context, we aimed to examine the relationships of different sets of urine environmental chemical concentrations and high BP in a national, population-based setting.

Methods

Study sample

As described elsewhere,8 the United States National Health and Nutrition Examination Surveys (NHANES) has been a national, population-based, multi-year, cross-sectional study. The study sample is representative of the civilian, non-institutionalized US population. Information on demographics, lifestyle factors and self-reported medical conditions was obtained by household interview using questionnaires. In the current analysis, the 2009–2012 cohorts, the two most recent cohorts, were selected and combined. Informed consent was obtained from participating subjects. BP was measured on all examinees 8 years and older at the household interview and three times (details via: http://www.cdc.gov/nchs/nhanes/nhanes2009-2010/BPX_F.htm). The standard measuring protocol can be found in: http://www.cdc.gov/nchs/nhanes/nhanes20092010/BPX_F.htm#Protocol_and_Procedure. Participants with any of the following on both arms were excluded from the exam according to the standard protocol: rashes, gauze dressings, casts, edema, paralysis, tubes, open sores or wounds, withered arms, a–v shunts and radical mastectomy or if the BP cuff does not fit on the arm. The measurements were taken three times, and in the present study, we used the second BP measurement for the analysis. People with a ⩾140 mm Hg systolic BP and ⩾90 mm Hg diastolic BP were classified as having a high BP.

Biomonitoring

Urine was only collected for selected people (approximately 20–30% of the whole cohort, still representative) to measure environmental chemical concentrations. Urine specimens were processed, stored and shipped to the Division of Laboratory Sciences, National Center for Environmental Health, National Centers for Disease Control and Prevention, Atlanta, Georgia. Urinary environmental chemical concentrations for heavy metals, bisphenols and phthalates were determined by ICP-DRC-MS (inductively coupled plasma dynamic reaction cell mass spectroscopy) or detected using online solid-phase extraction, isotope dilution and high-performance liquid chromatography separation, followed by electrospray ionization and tandem mass spectrometry on those aged 6 years and above.9, 10, 11 Species of parabens in 100 μl urine were hydrolyzed and conjugated using β-glucuronidase/sulfatase (Helix pomatia, H1; Sigma Aldrich Laboratories, St Louis, MO, USA) and were preconcentrated by online solid-phase extraction, separated from other urine components by reversed-phase high-performance liquid chromatography, and detected by atmospheric pressure chemicaionization–isotope dilution/tandem mass spectrometry with peak focusing.12 Pesticides were measured using the isotope dilution technique and tandem mass spectrometry, and details can be found in Hill et al.13, 14 Because urinary environmental chemical concentrations were highly right skewed, they were all log transformed in the analyses.

Statistical analysis

Adults aged 20 years and above were included in the analysis. The effects of urinary environmental chemical concentrations on risk of high BP were examined by t-test and a logistic regression model, with P<0.05 considered to be statistically significant. Covariates including urinary creatinine, age, sex, ratio of family income to poverty (proxy of socioeconomic status) and body mass index (BMI)15 were adjusted. Models were also weighted for the survey design because urinary environmental chemical concentrations were measured in subsamples. The population attributable risk from an indoor temperature below a certain degree, which was to be determined, was calculated based on the formula introduced by Fleiss in 1979.16 In the subsequent analysis, sex differences were assessed. Statistical software STATA version 13.0 (STATA, College Station, TX, USA) was used to perform all of the analyses. Because the present study was only a secondary data analysis, no further ethics approval was required.

Results

The study cohort in 2009–2012 contained 20 293 participants with 6191 people being classified as having a high BP (30%). Table 1 presents the characteristics of the included participants. The average age was 32 years old (range: 20–80 years); 4380 (21.6%) were identified as overweight (BMI 25–30), while 6879 (33.9%) were classified as obese (BMI 30+). Table 2 shows the associations of urinary heavy metals and high BP. After full adjustments, urinary cesium (odds ratio (OR) 1.52, 95% confidence interval (CI) 1.06–2.18, P=0.026), molybdenum (OR 1.45, 95% CI 1.04–2.02, P=0.029), lead (OR 1.49, 95% CI 1.12–1.98, P=0.009), platinum (OR 1.66, 95% CI 1.14–2.21, P=0.002), antimony (OR 1.44, 95% CI 1.12–1.86, P=0.008) and tungsten (OR 1.48, 95% CI 1.22–1.79, P<0.001) concentrations were observed to be associated with high BP. They accounted for 7.2, 6.3, 6.8, 9.0, 6.2 and 6.7% of the population attributable risk, respectively.

Table 1 Characteristics of included adult participants
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Table 2 Associations between heavy metals and high blood pressure (BP)
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Similarly, in Table 3, associations between industry-associated chemicals and high BP are displayed. To be specific, mono-2-ethyl-5-carboxypentyl (OR 1.29, 95% CI 1.04–1.59, P=0.024), mono-n-butyl (OR 1.36, 95% CI 1.11–1.67, P=0.005), mono-2-ethyl-5-hydroxyhexyl (OR 1.21, 95% CI 1.01–1.46, P=0.041), mono-n-methyl (OR 1.24, 95% CI 1.01–1.46, P=0.014), mono-2-ethyl-5-oxohexyl (OR 1.21, 95% CI 1.01–1.45, P=0.036) and mono-benzyl (OR 1.41, 95% CI 1.15–1.74, P=0.002) phthalate metabolites were found to be related to high BP. They accounted for 4.2, 5.1, 3.1, 3.5, 3.1 and 5.8% of population attributable risks, respectively. In Table 4, only dimethylarsonic acid (OR 1.38, 95% CI 1.08–1.76, P=0.012) and trimethylarsine oxide (OR 2.56, 95% CI 1.29–5.07, P=0.010) were associated with high BP, and they accounted for 5.4 and 19.0% of the population attributable risks.

Table 3 Associations between industry-associated chemicals and high blood pressure (BP)
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Table 4 Associations between pesticide and arsenic and high blood pressure (BP)
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Tables 5 and 6 indicate the potential sex differences associated with urinary heavy metals, phthalate and arsenic and high BP. In men, urinary cobalt, cesium, lead, platinum, antimony, tungsten, mono-n-methyl, mono-benzyl and dimethylarsonic acid concentrations were associated with high BP, while in women, urinary molybdenumm, lead, platinum, antimony, tungsten, mono(carboxynonyl), mono-n-butyl, mono-(3-carboxypropyl), mono-ethyl, mono-benzyl, mono-isobutyl and trimethylarsine oxide concentrations were associated with high BP.

Table 5 Associations of heavy metal and arsenic and high blood pressure (BP) in men (n=10 081)
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Table 6 Associations of heavy metal and arsenic and high blood pressure (BP) in women (n=10 212)
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Discussion

Main findings

In the present national, population-based, multi-year, cross-sectional study, the relationships of different sets of urinary environmental chemical concentrations and high BP were examined. Higher urinary cesium, molybdenum, lead, platinum, antimony, tungsten, mono-2-ethyl-5-carboxypentyl phthalate, mono-n-butyl phthalate, mono-2-ethyl-5-hydroxyhexyl phthalate, mono-n-methyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, mono-benzyl phthalate, dimethylarsonic acid and trimethylarsine oxide concentrations were associated with high BP. Each chemical could account for 3–18% of the population attributable risks for high BP. A small sex difference was found. However, there were no associations between environmental parabens and pesticides and high BP. Several more significant associations were found after covariate adjustments. However, those significant associations disappeared after additionally adjusting for subsample weighting, implying a failure to generalize those potential significant associations to the entire US population.

Previous studies and possible mechanisms

Cobalt is widely distributed in the environment, accounting for 0.001% of the Earth’s crust. Cobalt forms bivalent and trivalent compounds, those of biological interest being bivalent.17 In animal models, exposure to excess cobalt was found to have a toxic effect on the heart, including an elevated BP and may result in cardiomyopathy, although one study in rats showed the opposite.18, 19, 20, 21 Cesium was previously found in people exposed to Chernobyl radiation,22 and animal models in rats, dogs, rabbits, and in vivo have also observed that the cardiovascular system or coronary blood flow could be impaired after long-term contamination with cesium in drinking water.23, 24, 25, 26, 27 Lead was previously observed to enhance B-cell activity, impair host resistance to several bacterial and viral infections, and differentially modify cytokine production in vitro and in vivo.28 Lead exposure was found to result in a marked elevation in BP, a significant reduction in urinary nitric oxide metabolites (NO(chi)) excretion, and upregulation of endothelial and inducible nitric oxide synthase in the kidneys (which could impact filtration rate and normalization using creatinine), aorta, and heart and neuronal nitric oxide synthase in the cerebral cortex and brain stem in animals.29 Tungsten is thrombogenic and proinflammatory, but its toxicity and carcinogenicity in cardiovascular health is not well examined.30, 31 Tungsten coils were prevalent in clinical use for occluding intracranial aneurysms, varicocele veins and other abnormal vascular connections.32 Therefore, people with intracranial aneurysms after the treatment may experience higher tungsten volumes in the body than people without them. In subsequent analysis, after additionally excluding people with a history of a stroke, its effect on the risk for high BP has remained significant (data not shown). Antimony has long been related to pneumoconiosis and dermatitis (acute effect)33 and previously was also found to be correlated with cardiovascular end points in smelter workers and those with gastrointestinal disorders (chronic effect by inhalation).34, 35, 36

Phthalates, considered to be chemical estrogens, are widely used in the food packaging industry, leaching from the polymers into food and water under normal conditions37 and can be detected in human urine. They can migrate out of the plastic product and into the environment and are suspected to act as hormone mimics and endocrine-disrupting compounds.38, 39 Animal studies have shown that chronic exposure to these compounds, even at a low dose, can alter some biological end points.40, 41 Other evidence further showed that mono-butyl phthalate disturbs the glycolytic pathway and can suppress other proteins that are involved in DNA transcription, RNA biogenesis and protein synthesis.6 These compounds have been hypothesized to contribute to cardiovascular disease and highlight the need to eliminate these potential risks to prevent disease prevention. In recent meta-analyses, the pooled effect estimates of arsenic concentrations were found to be from 1.19 (95% CI 1.2–3.0) to 1.27 (95%CI 1.09–1.47).42, 43 In the present study, although the total arsenic concentration was not significantly associated with the risk of high BP, dimethylarsonic acid and trimethylarsine oxide concentrations were observed to be related to an increased risk of high BP, which is similar to a previous study using NHANES 2003–2008 data.44 Animal studies have also suggested that the chemical propensity of arsenic to oxidize vicinal thiols could potentially affect a number of cellular proteins with reactive thiols, including endothelial nitric oxide synthase.45 In the current analysis, there was somewhat of a sex difference, indicating that men might be more prone to exposure to heavy metals, while women might be more vulnerable to phthalates. The biological mechanism is unclear and requires future research.

Strengths and limitations

There are a few strengths and limitations worthy of being discussed. First, this study was conducted in a large, nationally representative human sample with mixed ethnicities. Moreover, different sets of chemicals were able to be included for examination. However, there could be still other chemicals in the environment that we might not yet be known and would need future research to identify and examine. Causality cannot be established in the present study due to the cross-sectional study design. Future studies with a longitudinal study design to confirm or refute the current findings and to understand the persisting risk throughout life from the above-mentioned environmental chemicals should be considered.

Conclusion

In summary, we have provided evidence for the association of urinary cesium, molybdenum, lead, platinum, antimony, tungsten, phthalates, and arsenic concentrations and high BP using a very recent, national, population-based human study sample with multiple ethnicities. Each chemical could account for 3–18% of the population attributable risk for high BP. There was also a small sex difference. Elimination of environmental chemicals should still be prioritized to aim for disease prevention and benefit population health in the coming decades. Future research with a longitudinal design to understand the persisting risk from the above-mentioned environmental chemicals is also recommended.