Maria Tellez-Plaza 1, scientist, Eliseo Guallar 2, professor, Ana Navas-Acien 3, professor
Evidence on the role of environmental metals in cardiovascular disease has rapidly increased over the past two decades. In a linked article, Chowdhury and colleagues (doi:10.1136/bmj.k3435) present a comprehensive systematic review and meta-analysis of the associations between the exposure to arsenic, lead, cadmium, mercury, and copper and the risk of cardiovascular disease.1 The first four metals were selected because of widespread population exposure and inclusion in the World Health Organization’s priority list of chemicals of major public health concern. Copper was selected because of previous mechanistic links with atherosclerosis.
Analyses of data from about 350 000 people from 37 countries showed that exposures to arsenic, lead, cadmium, and copper are associated with an increased risk of cardiovascular disease incidence and mortality. This is an important call for attention to an emerging group of risk factors with a high prevalence in populations around the world.
Chowdhury and colleagues paid special attention to the dose-response effect between exposure to metals and cardiovascular disease. Most associations were linear, with no clear lower threshold for toxicity. However, the number of studies in populations with low levels of exposure remains insufficient to reach firm conclusions on the shape of the dose-response curve at low levels. This is critical information for public health authorities and should be a priority for future research.
The study reported no association between mercury exposure and cardiovascular disease. Methylmercury contamination of fish is the primary source of mercury in most populations and these null results must be interpreted carefully, given the complexity of fish intake and the large number of potential confounders of this association. In the current systematic review, some studies relied on self reporting to ascertain seafood intake. More detailed assessments of the intake of potentially beneficial components of fish including n-3 fatty acids would be helpful in future studies. Studies of exposure to other forms of mercury, such as inorganic mercury exposure in communities near coal fire power plants, are also needed.
Experimental studies evaluating the role of metals as disruptors of redox, epigenetic, and endocrine pathways support the causal role of metals in atherosclerosis.234 Other lines of evidence include a double blind randomized trial suggesting that chelation therapy, which increases urinary excretion of heavy metals, may provide some benefit in secondary prevention of cardiovascular disease,5 and a genomic study reporting an association between AS3MT, the major gene involved in arsenic methylation and believed to influence arsenic toxicity, with cardiovascular disease.6
The US conducts nationally representative biomonitoring of arsenic, lead, cadmium, and mercury through regular National Health Nutrition and Examination Surveys (NHANES). These surveys document a marked reduction in population exposure to lead and cadmium (the metals monitored for longest), largely reflecting large scale public health policies on the control of tobacco, reduction of air pollution, remediation of hazardous waste, renovation of drinking water infrastructures, and banning of lead in gasoline.78
Concomitant with these reductions, cardiovascular mortality rates in the US decreased by 43% from 1988-94 to 1999-2004. 9 An analysis that accounted for traditional cardiovascular disease risk factors, showed that 32% of this reduction in cardiovascular mortality could be explained by the decline in lead and cadmium exposures.9 The health impact of recent reductions in arsenic exposure,10 however, has not been evaluated.
Exposure to environmental metals remains substantial because of widespread soil contamination; persistence of past uses (house paint and plumbing for lead); continuing industrial uses (plastics and batteries); and presence in tobacco and tobacco smoke, drinking water and ambient air, and dust near industrial sources and waste sites.78 Cadmium content in fertilizers provide an additional exposure pathway through diet and tobacco since vegetables and grains bioconcentrate cadmium. Emerging tobacco products such as electronic cigarettes also increase metal exposure.11 The main source of metals in electronic cigarettes seems to be the heating coil, from where metals leach into the inhaled aerosol. 11 In low and middle income countries, including many countries in Africa and Asia, exposure to high levels of arsenic and lead is still a serious threat to public health that requires urgent action.121314
Despite widespread distribution of toxic metal contaminants, technical reports from environmental and public health agencies often disregard the mounting evidence of associated cardiovascular risk.1516 Similarly, metal exposures are neglected by the organizations that produce cardiovascular prevention guidelines. The evidence indicates a clear need to minimize unnecessary metal exposures.
In communities affected by disproportionate environmental and occupational exposure, surveillance systems should monitor metal biomarkers and cardiovascular disease events and implement cardiovascular disease prevention programs. Since metals are associated with cardiovascular disease even at relatively low levels of exposure, population wide strategies to minimize exposure can further contribute to overall cardiovascular prevention efforts.
- Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: none.
- Disclaimer: The opinions and views expressed in this editorial are those of the authors and do not necessarily represent the official position of the National Health Institutes Carlos III (Spain).
- Provenance and peer review: Commissioned; not peer reviewed.
- R ChowdhuryA RamondLM O’Keeffe. Environmental toxic metal contaminants and risk of cardiovascular outcomes: systematic review and meta-analysis. BMJ2018;362:k3310
- K JomovaM Valko. Advances in metal-induced oxidative stress and human disease. Toxicology2011;283:65-87. 10.1016/j.tox.2011.03.001 21414382
- A Ruiz-HernandezC-C KuoP Rentero-Garrido. Environmental chemicals and DNA methylation in adults: a systematic review of the epidemiologic evidence. Clin Epigenetics2015;7:55. 10.1186/s13148-015-0055-7 25984247
- I IavicoliL FontanaA Bergamaschi. The effects of metals as endocrine disruptors. J Toxicol Environ Health B Crit Rev2009;12:206-23. 10.1080/10937400902902062 19466673
- GA LamasC GoertzR Boineau. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309(12):1241-50. 10.1001/jama.2013.2107
- CM SchoolingJV HuangJV ZhaoMK KwokSL Au YeungSL Lin. Disconnect Between Genes Associated With Ischemic Heart Disease and Targets of Ischemic Heart Disease Treatments. EBioMedicine. 2018;28:311-5. 10.1016/j.ebiom.2018.01.015
- P MuntnerA MenkeKB DeSalvoFA RabitoV Batuman. Continued decline in blood lead levels among adults in the United States: the National Health and Nutrition Examination Surveys. Arch Intern Med. 2005;165(18):2155-61. 10.1001/archinte.165.18.2155
- M Tellez-PlazaA Navas-AcienKL CaldwellA MenkeP MuntnerE Guallar. Reduction in cadmium exposure in the United States population, 1988-2008: the contribution of declining smoking rates. Environ Health Perspect2012;120:204-9. 10.1289/ehp.1104020 22062584
- A Ruiz-HernandezA Navas-AcienR Pastor-Barriuso. Declining exposures to lead and cadmium contribute to explaining the reduction of cardiovascular mortality in the US population, 1988-2004. Int J Epidemiol2017;46:1903-12. 10.1093/ije/dyx176 29025072
- AE NigraTR Sanchez. The effect of the Environmental Protection Agency maximum contaminant level on arsenic exposure in the USA from 2003 to 2014: an analysis of the National Health and Nutrition Examination Survey (NHANES). The Lancet Public Health. 2017;2(11):PE513-21. 10.1016/S2468-2667(17)30195-0
- P OlmedoW GoesslerS Tanda. Metal Concentrations in e-Cigarette Liquid and Aerosol Samples: The Contribution of Metallic Coils. Environ Health Perspect. 2018;126(2):27010. 10.1289/EHP2175
- M LiJ CaoZ GaoX ShenC Yan. The trend of lead poisoning rate in Chinese population aged 0-18 years old: a meta-analysis. BMC Public Health. 2015;15(1):756. 10.1186/s12889-015-2103-9
- P GottesfeldFH WereL Adogame. Soil contamination from lead battery manufacturing and recycling in seven African countries. Environ Res. 2018;161:609-14. 10.1016/j.envres.2017.11.055
- MF NaujokasB AndersonH Ahsan. The Broad Scope of Health Effects from Chronic Arsenic Exposure: Update on a Worldwide Public Health Problem. Environ Health Perspect. 2013;121(3):295-302. 10.1289/ehp.1205875
- Smolders E, Universiteit Leuven K. Scientific aspects underlying the regulatory framework in the area of fertilisers – state of play and future reforms. 2017. http://www.europarl.europa.eu/RegData/etudes/IDAN/2016/595354/IPOL_IDA(2016)595354_EN.pdf
- GF NordbergA BernardGL DiamondJH DuffusP IllingM Nordberg. Risk assessment of effects of cadmium on human health (IUPAC Technical Report). Pure Appl Chem. 2018;90(4):755-808. 10.1515/pac-2016-0910
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