Abstract
Background: A link between environmental chemicals and human health has emerged but not complete in risk factors. This work aimed to study the relationships of different sets of urinary environmental chemical concentrations and risk of high blood pressure (BP) in a national, population-based study. Methods: Data was retrieved from United States National Health and Nutrition Examination Surveys, 2009–2010, including demographics, BP readings and urinary environmental chemical concentrations. Analyses included t-test and survey-weighted logistic regression models. Results: Urinary mercury concentrations were not associated with high BP (OR = 1.19, 95% CI 0.97–1.48, p = 0.095). Urinary cobalt (OR = 1.35, 95% CI 1.01–1.81, p = 0.044), lead (OR = 1.77, 95% CI 1.31–2.38, p = 0.001), antimony (OR = 1.37, 95% CI 1.09–1.72, p = 0.010) and tungsten (OR = 1.52, 95% CI 1.27–1.81, p < 0.001) concentrations were observed to increase the risk of high BP. There are no clear associations between environmental parabens and high BP. The effect of environmental bisphenol A (OR = 1.14, 95% CI 1.00–1.30, p = 0.051) disappeared after additionally adjusting for subsample weighting (OR = 1.12, 95% CI 0.93–1.35, p = 0.225). People with higher urinary mono-2-ethyl-5-carboxypentyl phthalate (OR = 1.26, 95% CI 1.00–1.58, p = 0.051), mono-n-butyl phthalate (OR = 1.19, 95% CI 1.01–1.41, p = 0.042) and mono-n-methyl phthalate metabolites (OR = 1.16, 95% CI 1.03–1.32, p = 0.021) tended to have high BP. Moreover, urinary o-phenyl phenol concentrations (OR = 1.49, 95% CI 1.25–1.77, p < 0.001) and dimethylarsonic acid concentrations (OR = 1.35, 95% CI 1.06–1.73, p = 0.019) were also seen to be associated with high BP. Conclusions: Urinary environmental chemical concentrations were associated with risk of high BP, although the causal effect cannot be established. Elimination of environmental chemicals in humans would need to be continued.
Introduction
The burden of high blood pressure (BP) has remained high in the USA, with about one third of American adults in the current century (Citation1). The economic costs associated with hypertension are high for both individuals and the society. Exposure to environmental chemicals may induce atherosclerosis by increasing oxidative stressors or produce reactive oxygen species as superoxide ions, hydrogen peroxide and hydroxyl radical, according to experimental research (Citation2,Citation3). Previous epidemiological investigations focused on arterial disease, heart disease and cardiovascular disease (CVD) as endpoints (Citation4–6), but the relationship with BP, a strong risk contributor for many human chronic diseases as mentioned above in the pathway, is unclear. Previously, adverse intrauterine environments were found to be associated with an increased risk of later CVD and obesity (i.e. weight gain in animals at low doses), leading to a population epidemic (Citation7). Recent animal models have shown that elevated offspring BP could be induced by maternal exposure to toxicants (Citation8). Experimental human research has also shown chemicals with estrogenic- or endocrine-disrupting activity and that exposure to these chemicals during critical stages of differentiation may have permanent long-lasting consequences, some of which may not be expressed or detected until later in life (Citation9). Following this context, it was aimed to examine the relationships of different sets of urine environmental chemical concentrations and risk of high BP in a national and population-based setting.
Methods
Study sample
As described elsewhere (Citation10), United States National Health and Nutrition Examination Surveys (NHANES) have been national, population-based, multi-year, cross-sectional studies. The study samples are representative samples 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 2009–2010 cohort as the most recent cohort was selected. Informed consents were obtained from participating subjects. BP was measured on all examinees 8 years and older at the household interview, three times (details via: http://www.cdc.gov/nchs/nhanes/nhanes2009-2010/BPX_F.htm). The standard measuring protocol can be found here: 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 BP cuff does not fit on the arm. The measurements were taken three times, and in the present study we considered the second BP measurement in the analysis. People with ≥ 140 mmHg systolic BP and ≥ 90 mmHg diastolic BP were classified as high BP.
Biomonitoring
Urine was only collected in selected people (for about 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 such as heavy metals, bisphenols and phthalates are 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 and above (Citation11–13). Species of parabens in 100 μl urine were hydrolyzed then conjugated by use of β-glucuronidase/sulfatase (Helix pomatia, H1; Sigma Aldrich Laboratories, Inc., St. Louis, MO), 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 chemical ionization–isotope dilution/tandem mass spectrometry with peak focusing (Citation14). Pesticides were measured using an isotope dilution technique and tandem mass spectrometry, and details can be found in Hill et al. (Citation15,Citation16). As urinary environmental chemicals concentrations were highly right-skewed, they were all log-transformed in the analyses.
Statistical analysis
Adults aged 20 and above were included in the analysis. The effects of urinary environmental chemical concentrations on the risk of high BP were examined by t-test and logistic regression model, with p < 0.05 considered statistically significant. Covariates including age, sex, ethnicity and body mass index (BMI) (Citation17) were adjusted. Models were also weighted for the survey design. Statistical software STATA version 12.0 (STATA, College Station, Texas, USA) was used to perform all the analyses. As the present study was only a secondary data analysis, no further ethics approval is required.
Results
The study cohort in 2009–2010 contained 10,537 participants with 3156 people classified as having high BP (30%). presents the characteristics of included participants. About 22% were identified as overweight while 35% were classified as obese. shows the effects of urinary heavy metals and mercury concentrations on risk of high BP. After full adjustments (including age at examination, sex, ethnicity and BMI) and subsample weighting (following the biomonitoring examination in a small proportion of the study population), urinary mercury concentrations were not associated with high BP (OR = 1.19, 95% CI 0.97–1.48, p = 0.095). Among 12 heavy metals, urinary cobalt (OR = 1.35, 95% CI 1.01–1.81, p = 0.044), lead (OR = 1.77, 95% CI 1.31–2.38, p = 0.001), antimony (OR = 1.37, 95% CI 1.09–1.72, p = 0.010) and tungsten (OR = 1.52, 95% CI 1.27–1.81, p < 0.001) concentrations were observed to be related to the risk of high BP.
Table I. Characteristics of participants.
Table II. Associations between heavy metals and high blood pressure.
In , associations between industry- associated chemicals and high BP were demonstrated. The effect of environmental bisphenol A (OR = 1.14, 95% CI 1.00–1.30, p = 0.051) went from significant to non-significant after additionally adjusting for subsample weighting (OR = 1.12, 95% CI 0.93–1.35, p = 0.225), while no clear associations were observed between environmental parabens and risk of high BP. On the other hand, associations with a few urinary phthalates metabolites were found. For example, people with higher urinary mono-2-ethyl-5-carboxypentyl phthalate concentrations (OR = 1.26, 95% CI 1.00–1.58, p = 0.051), mono-n-butyl phthalate concentrations (OR = 1.19, 95% CI 1.01–1.41, p = 0.042) and mono-n-methyl phthalate concentrations (OR = 1.16, 95% CI 1.03–1.32, p = 0.021) tended to have high BP. Moreover, people with higher urinary o-phenyl phenol concentrations (OR = 1.49, 95% CI 1.25–1.77, p < 0.001) and dimethylarsonic acid concentrations (OR = 1.35, 95% CI 1.06–1.73, p = 0.019) were also likely to have high BP ().
Table III. Associations between industry-associated chemicals and high blood pressure.
Table IV. Associations between pesticide and arsenic and high blood pressure.
Discussion
Main findings
In the present national, population-based, cross- sectional study, the effects of different sets of urinary environmental chemicals concentrations on the risk of high BP were examined. It was observed that higher urinary cobalt, lead, antimony, tungsten, mono- 2-ethyl-5-carboxypentyl phthalate, mono-n-butyl phthalate, mono-n-methyl phthalate, o-phenyl phenol and dimethylarsonic acid concentrations were significantly associated with increased risk of high BP in the general adult population, although the causality cannot be established in the current cross-sectional study design. There were a few more significant associations after covariate adjustments. However, those significant associations disappeared (such as bisphenol A (Citation16), certain heavy metals, certain phthalate metabolites, and certain arsenic concentrations) after additionally adjusting for subsample weighting, implying the failure to generalize those masked significant associations to the whole US population.
Possible mechanisms
Cobalt is widely distributed in the environment, accounting for 0.001% of the earth's crust. It forms bivalent and trivalent compounds, those of biological interest being bivalent (Citation18). In animal models, exposure to excess cobalt was found to have a toxic effect on the heart, including elevated BP, and may result in cardiomyopathy, although one study in rats showed the opposite (Citation19–22). It was previously observed that lead could cause enhanced B cell activities and impairs host resistance to several bacterial and viral infections, and can differentially modifies cytokine production in vitro and in vivo (Citation23). Lead exposure was found to result in a marked elevation of BP, a significant reduction in urinary NO metabolites (NO(chi)) excretion, and up-regulations of endothelial and inducible NOS abundance in the kidney (which could impact filtration rates and normalization using creatinine), aorta and heart, and of neuronal NOS in the cerebral cortex and brain stem in animals (Citation24). Tungsten is thrombogenic and proinflammatory but its toxicity and carcinogenicity on cardiovascular health has not been well examined (Citation25,Citation26). Tungsten coils were prevalent in the clinical use for the occlusion of intracranial aneurysms, varicocele veins and other abnormal vascular connections (Citation27). Therefore, people with intracranial aneurysms after the treatment may experience higher tungsten volumes in the body than people without. In the subsequent analysis, after additionally excluding people who had ever experienced a stroke (n = 227), its effect on risk of high BP has remained significant (data not shown). Antimony has long been related to pneumoconiosis and dermatitis (acute effect) (Citation28), and previously it was also found to be correlated with cardiovascular endpoints in smelter workers and in gastrointestinal disorders (chronic effect) by inhalation (Citation29–31).
Phthalates and bisphenol A, two chemical estrogens widely used in the food packaging industry, leach from the polymers into food and water under normal conditions (Citation32), 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) (Citation33,Citation34). Animal studies have shown that chronic exposure to these, even at low dose, can alter some biological endpoints (Citation35,Citation36). 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 (Citation6). They are hypothesized to contribute to the cardiovascular disease pathway and highlight the need for new disease prevention by eliminating these potential risks. 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) (Citation37,Citation38). In the present study, although the total arsenic concentrations were not significantly associated with risk of high BP, dimethylarsonic acid concentrations were observed to be related to an increased risk of high BP (OR = 1.35) (Citation39). Animal studies have suggested that the chemical propensity of arsenic to oxidize vicinal thiols could potentially affect a number of cellular proteins with reactive thiols including endothelial NO synthase (Citation40). NHANES data in 1999–2002 once elucidated the potential link between pesticides and hypertension in the general population (Citation41). However, the possible mechanism is still less clear (Citation42), although BP was previously found to be elevated and persisted after injection of pesticides in rats (Citation43).
Strengths and limitations
There are a few strengths and limitations worthy of being discussed. First, this study was conducted in a nationally representative human sample in the recent years. Moreover, different sets of chemicals were able to be included for examination. However, there could be still emerging chemicals from the environment that we might not know and would need future research to identify and examine. The causality effect in nature 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, if at all, to understand the persisting risk effects from those environmental chemicals mentioned above is suggested.
Conclusion
In sum, evidence on the associations of urinary cobalt, lead, antimony, tungsten, arsenic and phthalate concentrations, and the risk of high BP using a very recent, national, population-based human study sample with mixed ethnicities was provided. Elimination of environmental chemicals should still be prioritized to in terms of disease prevention and for the benefit of the population health in the coming decades.
Acknowledgements
IS is supported by the Global Platform for Research Leaders scheme.
Conflict of interest: None.
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