Lead, Barium, Nickel and Cardiovascular Health: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Karl Kristian Lundin.

Lead (Pb) is a natural part of our environment. In urban areas, lead is predominantly found in housepaint but is also found in the air due to the burning of gasoline with lead additives [2]. Barium (Ba) is ubiquitous in nature in a water-insoluble state as either barium sulfate or barium carbonate [25]. Common exposures include ingestion of barium-containing materials and barium-contaminated water [26]. Human exposure to nickel (Ni) occurs primarily via contamination of drinking water and food; nickel is highly mobile in soil and is, therefore, able to readily contaminate water and food supplies [32]. Environmental pollution from nickel can also occur secondary to industrial processes, fuel burning, and inappropriate disposal of waste products [33].

  • cardiovascular disease
  • metal toxicity
  • metals and cardiovascular disease
  • cardiovascular toxicity
  • cardiovascular metal toxicity
  • barium

1. Lead

Lead exposure routes vary widely based on location; for example, lead exposure due to cosmetics and medications is common in India, whilst lead exposure through glazed ceramics and lead-contaminated utensils or water is more common in Mexico [3][1].
Multiple mechanisms have been proposed whereby lead may impact the cardiovascular system. For example, lead is implicated in the development of reactive oxygen species (ROS). In times of great oxidative stress, the production of excess ROS results in tissue damage and is thought to play a critical part in the development of cardiovascular CVDdisease (CVD) [4,5][2][3]. Gonick and colleagues showed that rats with lead-induced hypertension accumulated lipid peroxidation products and had increased amounts of inducible NO synthase enzymes [6][4]. Lead exposure also appears to have a role in causing vascular constriction through effects on protein kinase C (PKC). Protein Kinase C is involved in many cellular functions, including cell growth, vascular contraction, blood flow, permeability, and overall cell survival [7][5]. In an animal model, Watts and colleagues showed that lead caused the contraction of mesenteric arteries and further found that lead-induced contraction of those arteries was enhanced by a PKC agonist and reduced by a PKC inhibitor [8][6]. In addition, lead exposure activates the nuclear factor-kB (NF-kB) family of transcription factors, which has downstream effects including inflammation, apoptosis, and fibrosis [9][7]. Rodriguez-Itarbe and colleagues showed marked NF-kB activation, tubulointerstitial accumulation of T cells, macrophages, and angiotensin II-expressing cells, increased number of apoptotic cells, and heavy tyrosine nitration in kidneys of rats with lead-induced hypertension (HTN) [10][8]. Bravo and colleagues sought to suppress the inflammatory response in rats with lead-induced hypertension. They found that immunosuppression (via mycophenolate mofetil) prevented HTN, oxidative stress, and NF-κB activation, attenuated tubulointerstitial lymphocyte and macrophage infiltration, and reduced the number of angiotensin II-expressing cells in the lead-exposed animals [11][9].
Lead exposure is also implicated in hormonal alterations that may be harmful to cardiovascular health. Chang and colleagues found that in workers exposed to lead, there were higher levels of circulating plasma norepinephrine levels [12][10]. Likewise, Khalil-Manesh and colleagues found that rats exposed to low levels of lead had increased blood pressure and plasma endothelin-3 concentrations [13][11]. Endothelins are potent vasoconstrictors and have been implicated in CVD [14][12]. Lead exposure may impact the renin–angiotensinogen–aldosterone (RAAS) pathway as well, as evidenced by an animal model conducted by Vander and colleagues [15][13].
Studies conducted by Lustber and Schober linked increasing exposure to lead to an increased risk of CVD-related mortality [16,17][14][15]. Lustber and colleagues used the mortality follow-up data for participants of the Second National Health and Nutrition Examination Survey (NHANES), a national cross-sectional survey of the general population, conducted from 1976 to 1980. They followed 4292 participants aged 30 to 74 years with blood lead measurements through 31 December 1992. After adjustment for potential confounders, individuals with baseline blood lead levels of 20 to 29 microg/dL (1.0–1.4 micromol/L) had a 46% increase in all-cause mortality (rate ratio [RR], 1.46; 95% confidence interval [CI], 1.14–1.86), 39% increase in circulatory mortality (RR, 1.39; 95% CI, 1.01–1.91), and 68% increase in cancer mortality (RR, 1.68; 95% CI, 1.02–2.78) compared with those with blood lead levels of less than 10 microg/dL (<0.5 micromol/L). Muntner and Navas-Acien showed an association between blood lead and peripheral artery disease (PAD) [18,19][16][17]. Munter’s study utilized data from two nationally representative cross-sectional surveys, the Third National Health and Nutrition Examination Survey conducted in 1988–1994 (n = 16,609), and the National Health and Nutrition Examination Survey conducted in 1999–2002 (n = 9961). After multivariable adjustment, persons in the highest quartile (> or = 2.47 microg/dL [> or = 0.12 micromol/L]) compared with those in the lowest quartile (<1.06 microg/dL [<0.05 micromol/L]) of blood lead levels were 1.92 (95% CI, 1.02–3.61) times more likely to have peripheral arterial disease. Some studies show a positive association between higher blood lead levels and increased incidence of coronary artery disease (CAD) or stroke [20[18][19][20],21,22], though this may be attributable to confounding factors, such as cigarette exposure [20][18]. Also, lead may have a role in affecting the electrical conduction system of the heart [23][21]. As shown in a robust meta-analysis conducted by Nacas Acien and colleagues, the underlying basis for lead exposure and CVD seems to be its role in promoting hypertension, one of the strongest risk factors for development of CVD [24][22].
Given the wide-ranging and extensive associations between lead and CVD, it is imperative that prevention strategies are implemented to reduce the general population’s exposure to lead. The United States Environmental Protection Agency (EPA) has guidelines for regulating the amount of lead in air and water, but enforcing these levels has failed at times (as evidenced in the Flint, MI water crisis). Updating housing in areas that use lead-based paint will also serve to decrease exposure to lead.

2. Barium

Barium toxicity was associated with gastrointestinal side effects as well as hypokalemia, ST changes, and ventricular extrasystoles in one series of case reports involving 39 cases and 226 human subjects [27][23]. Unfortunately, there have not been many studies investigating the role of Barium on CVD. One study conducted by Wones and colleagues investigated the role increasing levels of barium in water had on an individual’s risk factors for cardiovascular disease. They enrolled 11 men in a 10-week study where they increased the Barium in drinking water from 0 ppm to 5 ppm to 10 ppm. They found that there was no change in systolic or diastolic blood pressure, cholesterol, potassium, glucose, or urine catecholamine levels. There was a borderline statistically significant increase in serum calcium levels, but this was of uncertain clinical significance. Thus, at least from this restudyearch, barium did not seem to have much of an effect on the development of CVD risk factors [28][24]. However, in an animal model, exposure to increased concentrations of barium resulted in an increase in blood pressure and a decrease in cardiac contractility and electrical excitability in the heart [29][25]. A retrospective study conducted by Brenniman and colleagues investigated the differences between Illinois communities with high barium levels in water (2–10 mg/liter) compared to Illinois communities with low barium levels in the water. Results of this mortality study revealed that the high barium communities had significantly higher (p < 0.05) death rates for “all cardiovascular diseases” and “heart disease” compared to the low barium communities [30][26].
The EPA has recommended that barium concentrations not exceed 2 mg/liter of water [31][27]. WResearchers have not been able to locate studies showing that 2 mg/liter of water is a specific threshold for barium toxicity, but there is some evidence to suggest that higher levels of barium are detrimental. More studies are needed to determine the safe level of exposure to barium and guide the formation of public health measures to reduce exposure to toxic levels of this metal.

3. Nickel

Nickel seems to exert cardiotoxic effects through the generation of free radicals. Novelli and colleagues discovered that increased nickel exposure increased the lipoperoxide and lipid concentrations in the cardiac tissue of male Wistar rats, with the superoxide radical (O2−) being central to the cardiac damage [34][28].
A study conducted by Zhang and colleagues in China provided some evidence of an association between nickel exposure and congenital heart disease. Based on 490 controls and almost 400 cases, they were able to conclude that there seemed to be an association between nickel exposure and the development of congenital heart disease [35][29]. One proposed explanation is that nickel causes mutations in the mitotic apparatus, precipitating premature cell death during fetal development [36][30]. Nickel may also cause epigenetic alterations and/or produce reactive oxygen species [37,38][31][32]. A recent study published by Cheek and colleagues sought to address the impact of nickel exposure on cardiovascular disease. Using the National Health and Nutrition Examination Survey from 2017–2020, urinary nickel concentration was measured in individuals with a diagnosis of CVD. They found that independent of traditional CVD risk factors, nickel exposure was associated with CVD [39][33]. Nickel exposure was also shown to be related to the number of carotid arteries with plaques in a Swedish cross-sectional study [40][34]. Finally, a dose-dependent association between nickel exposure and hypertension was observed by Shi and colleagues in a study conducted in China [41][35]. In this restudyearch, they recruited 940 participants from six factories in northeastern China and measured the urinary concentrations of 19 metals. They then used Bayesian kernel machine regression (BKMR) to explore associations between metal co-exposure and hypertension. The BKMR model indicated a hermetic dose-response relationship between eight urinary metals (Cobalt (Co), Chromium (Cr), Ni, Cadmium (Cd), Arsenic (As), Iron (Fe), Zinc (Zn), and Pb) and hypertension risk.
The Occupational Safety and Health Administration (OSHA) has set a guideline of 1 mg/m3 of nickel compounds in work-room air during an 8 h shift to protect workers. In addition, the EPA has set a guideline of 0.1 mg per liter of nickel in drinking water for the general public [42][36]. More robust data may be needed to validate these guidelines and determine the exact nickel levels associated with an increased risk of CVD.

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