Toxic Metals: The Poisons that are "Killing Us Softly"

Lamas and colleagues and the American Heart Association deserve praise for publishing the Scientific Statement on Contaminant Metals as Cardiovascular Risk Factors. Along with other recent high-profile discussions of similar topics¹, the Statement hopefully signals a turning point in the recognition of environmental exposures to toxic metals as risk factors for cardiovascular disease that are widespread, preventable, and potentially treatable, with major implications for policy and clinical practice, world-wide.

 Three of the eight authors of the Statement had previously published a 2021 Viewpoint in these pages² that set forth the proposition that the burden of proof has been met for lead and cadmium as cardiovascular risk factors. In the current Statement, the evidence for these two toxic metals--as well as arsenic-- are reviewed in depth, showcasing a body of evidence that has reached a crescendo. The combination of in vivo and in vitro studies demonstrating oxidative stress, impaired vascular endothelial function, chronic inflammation, disturbances of lipid metabolism and myocardial function, and other abnormalities, together with well-conducted prospective epidemiological studies demonstrating hypertension, epigenetic dysregulation, dyslipidemia, subclinical atherosclerosis, coronary artery/ischemic heart disease, and death from cardiovascular disease is difficult to ignore.

Aspects of some of these relationships had been previously confirmed by panels of experts; for example, the relationship of low-level lead exposure to increased blood pressure and hypertension was deemed to be causal based on systematic reviews of the evidence published in 2007 by experts convened by the Association of Occupational and Environmental clinics³ and in 2012 by the Office of Health Assessment and Translation of the National Toxicology Program⁴. However, neither lead nor any other toxic metal is mentioned, let alone discussed, as a risk factor in chapters on hypertension in the most current editions of widely read clinical textbooks (such as Harrison's Principles of Internal Medicine⁵).

 Some points made in the Scientific Statement could use further explication. Lamas et al. correctly prioritize for discussion lead, cadmium and arsenic based on their widespread global distribution and the accumulation of evidence for their cardiovascular toxicity. However, as noted in a recent systematic review⁶, a strong argument could be made to add mercury to the list based on the same parameters. A source of exposure to toxic metals that is not mentioned but that is widely pervasive in middle- and low-income countries is toxic waste, particularly from metal mining and informal industries involved in the recycling of lead-acid batteries and electronic waste⁷ (which, notably, originate mostly from high-income countries). The impact of toxic metals on cardiovascular disease may begin with prenatal exposures. For example, prospective birth cohort studies have shown that prenatal exposure to lead is associated with higher blood pressures among the offspring during late childhood/adolescence⁸,⁹, which, in turn, has been shown to be a predictor of adult hypertension¹⁰. Lamas et al. note that exposures to all three toxic metals have been shown to be more prevalent in communities of color, raising the twin issues of environmental racism as well as the methodological issue of potential confounding of epidemiological studies linking metals with cardiovascular disease by lower socioeconomic status (SES) and/or exposure to psychosocial stressors including systemic racism. However, it is also true that social factors such as race and stress may interact with metals exposure to amplify the adverse cardiovascular effects of both classes of risks. For example, research using 2001-2008 data from the National Health and Nutrition Examination Survey (NHANES) found that the relationship between blood lead levels and higher systolic blood pressure was higher for Black men and women v. Whites, and particularly among Blacks of low SES¹¹ or high depressive symptoms¹². Toxic metals may interact with common co-morbidities to amplify cardiovascular disease risks, as suggested by the accentuated salutary effects of chelation among diabetics in the TACT 1 trial.

 In terms of research gaps, Lamas, et al. mention the continuing need to identify the best biological markers for each metal contaminant and best treatment strategies. While measuring substances in blood and urine are standard practice in clinical medicine for electrolytes and toxics like illicit drugs, there are nuances that need to be appreciated when it comes to toxic metals. For example, unlike TACT1, the TACT2 trial includes the measurement of lead and cadmium both prior to and after provocation with EDTA. Since EDTA stimulates the mobilization and excretion of metals from organs where they accumulate, such tests serve to measure cumulative body metal burdens. The trial will thus demonstrate whether the benefit of chelation occurs mostly or only in those individuals who have higher metal burdens, which if true, may underscore the value of measuring metals provoked by chelation as useful biological markers of cumulative exposures (compared to blood and urine metal levels, which mostly reflect recent exposures).

 Lamas et al. note the growing interest in the potential impact of metal mixtures¹³,¹⁴. More research is also needed to understand the potential for toxic metals to interact with genetic traits and other environmental, nutritional, and behavioral factors to greatly increase adverse impacts, i.e., synergy. Some such studies exist. For example, lead exposure has been associated with (a) lengthening of the Q-T interval, especially among individuals carrying gene variants related to iron metabolism¹⁵; (b) widening pulse pressure (a measure of arterial stiffness), especially among individuals carrying gene variants related to Vitamin D metabolism¹⁶; (c) abnormalities in heart rate variability, especially among individuals with metabolic syndrome¹⁷; and (d) increased incidence of coronary heart disease, especially among individuals adhering to a Western (v. Mediterranean) diet¹⁸. These insights arguably contribute to the goal of advancing "precision medicine", i.e., clinical approaches tailored to individuals. Overall, however, such interactions remain under-explored, in part because epidemiological studies that can address interactions need large population sizes to meet the statistical power requirements of research on interactions. Nevertheless, exposure to multiple risk factors, including mixtures of metals, is the norm for populations in real life.

The impact on adult cardiovascular disease states of early life exposures to toxic metals needs more research, particularly since pregnancy is associated with changes in physiology that are known to increase the mobilization of accumulated stores of lead¹⁹ and possibly other toxicants. In addition, organs are known to be especially vulnerable to toxicants during fetal and early childhood²⁰, with evidence growing for the developing heart as a target²¹.

From a population and global health perspective, given that ischemic heart disease and stroke have been the leading causes of death world-wide since at least 2000²², understanding the contribution of toxic metals to the burden of disease in and within each country is critically needed by policy makers working to prioritize and address health issues. In the latest iteration of the global burden of disease (GBD) study, lead exposure was estimated to have been responsible for 0.9 million deaths worldwide in 2019²³, the majority of which are accounted for by cardiovascular disease. Individual estimates were made for each country along with sub-national estimates for large countries. However, a recent study²⁴ using data from NHANES suggests that the magnitude of the impact of lead exposure on cardiovascular mortality may be substantially larger than that associated with the risk estimates used in the GBD calculations. Moreover, the GBD has yet to attempt to account for the impacts of arsenic, cadmium, mercury or other toxic metals²⁵--research that is needed to provide policy-makers with a full picture.

 The implications for clinical practice and policies of the evidence on toxic metals and cardiovascular disease are potentially profound. From a patient care perspective, pediatricians have been sensitized for decades to the need for screening for and intervening in cases of childhood lead poisoning, and occupational physicians have been trained to screen for and manage cases of occupational lead poisoning (although, as noted by Lamas et al., exposure limits promulgated by the U.S. Occupational Safety and Health Administration remain too high). Going forward, adult primary care practitioners, cardiologists, and other clinicians may need to become familiar with environmental sources of exposure to lead as well as other toxic metals, take appropriate histories, have a low threshold for suspecting toxic metals as a risk factor for cardiovascular disease, consider ordering the appropriate laboratory tests, and help patients reduce exposure. Even though trends in data from NHANES suggest that overall national levels for toxic metals in blood like lead and cadmium are declining, significant exposures continue for subpopulations based on sources such as those mentioned by Lamas et al. as well as contamination incidents such as the Flint lead in drinking water crisis²⁶. Moreover, depending on the results of the TACT2 trial, it may be important for clinicians to use chelation mobilization or similar tests to check for toxic metals burdens. Such burdens are known to persist for decades²⁷ (e.g., the lead stored in the skeleton of almost all middle-aged and elderly adults²⁸,²⁹) and the TACT2 results may provide indications for treatment.

A limitation is that except for suspected lead exposure (for which guidelines on testing and management for children and adults are mostly well-established,³⁰,³¹), it is unclear whether current clinical reference values for tests of toxic metals and associated management strategies are appropriate given the results of the most recent research. Quantitative risk assessments such as those conducted by the U.S. Environmental Protection Agency and the CDC that include attention to clinical parameters are needed for clinical practice as well as policy. Ironically, the recommendations that eventually ensue may bring clinical practice a step closer to that which has been pursued for years by alternative and complementary medicine practitioners, who, for example, were likely responsible for most of the over 100,000 chelations that occurred among U.S. adults in 2007³², typically given for any of a wide variety of chronic medical conditions. In 2013, the American College of Medical Toxicology correctly noted that, unless used for treating acute metal toxicity, the prevailing scientific evidence at the time did not provide support for the administration of such chelations³³. An updated assessment may soon be needed, however.

 Finally, in terms of policy, it is critical for regulatory agencies to review the accumulating evidence of the impacts of toxic metals on cardiovascular disease (and other end points), consider revisions to existing standards, and establish standards where none exist as they pertain to toxic metal levels in air, water, food, and consumer products. This can and should be done now even as research proceeds, in the name of prevention, with more attention to enforcement than is currently being paid. Industry needs to consider alternatives to the use of toxic metals in manufacturing, with, for example, a shift away from the production and recycling of automobile lead-acid batteries to other forms of energy storage and recycling with less toxic consequences³⁴. Legacy sources of pollutants need to be addressed, such as the millions of residences in the U.S. that still have lead paint and lead plumbing³⁵. In low and middle-income countries with legacy pollutants and few resources to pursue clean-up, some improvements are being advanced by non-governmental organizations such as Pure Earth³⁶, which sponsors initiatives that safely dispose of toxic waste. Going forward, as all governments continue to pursue the United Nations Sustainable Development Goals³⁷, consideration must be given on how to avoid industrialization involving toxic metals and leapfrog to clean and sustainable industry practices.

 In conclusion, a critical mass of evidence has emerged indicating that toxic metals are responsible for a major portion of cardiovascular disease. It is time for clinicians as well as policy makers to incorporate the associated insights into the practice of medicine, healthcare, and policies, even as research continues to fully elucidate best approaches to surveillance, screening, diagnosis, treatments, and management. After all, we now know that these truly are silent but pervasive threats that are "killing us softly".