Invited Perspective: Metal Mixtures and Child Health: The Complex Interplay of Essential and Toxic Elements

Interest in understanding the health effects of chemical mixtures has grown over the past two decades, as evidenced by the acceleration in human health studies across all life stages and increased funding for exposomics research. In parallel, interest in health effects specific to complex mixtures of metals and trace elements has grown. Unique to the consideration of metals and trace elements, perhaps, is the recognition that not all metals are toxic and that, for some elements, there may be optimal levels at which they are beneficial, above and below which they are not.

Studying these complexities in relation to health outcomes necessitates biological understanding of the metals and elements at play. It also requires statistical methodologies that can simultaneously investigate nonlinear associations and interactions between metals and elements whose combined effects may be in opposite directions. In recent years, statistical methods have emerged to address some of these needs, as there is general recognition that the field of environmental epidemiology must move beyond a single-pollutant modeling framework (Keil et al. 2021; Tanner et al. 2020).

Zhang et al. (2021) report that prenatal exposure to the trace elements selenium (Se) and manganese (Mn) was associated with lower systolic blood pressure in children of ages 3–15 y, whereas exposure to the metals lead (Pb), mercury (Hg), and cadmium (Cd) was not associated with either systolic or diastolic blood pressure. The authors used newer statistical methodology—Bayesian kernel machine regression (BKMR) (Bobb et al. 2015, 2018)—to evaluate both nonlinear associations and interactions between metals and trace elements. In so doing, they found an interaction between Cd and Mn. Although Mn was associated overall with lower blood pressure, this apparent protective effect was stronger in mothers with higher Cd concentrations, as measured in red blood cells collected shortly after delivery.

Consistent with the findings for joint exposure to Cd and Mn, the association between Mn and systolic blood pressure differed by maternal smoking, a primary source of Cd (Zhang et al. 2021). Specifically, increasing Mn was associated with lower blood pressure among children whose mothers smoked during pregnancy, but it was not associated with blood pressure in children whose mothers did not smoke. Therefore, the authors suggest that Mn supplementation during pregnancy for mothers who smoke may help protect their children from risk of developing high blood pressure and cardiovascular disease. However, systolic blood pressure was higher in children of mothers who smoked regardless of their Mn level.

The suggestion for nutritional intervention raises an important consideration and avenue for future exploration, although the public health message to not smoke during pregnancy should remain a primary focus. As more evidence emerges showing interactions between trace elements and metals in pregnancy, should we more seriously consider targeted use of essential elements in populations with known high exposures to potentially toxic metals? Might nutritional intervention mitigate risk? We have certainly known for decades that nutritional status can affect the toxicity of some pollutants (Mahaffey and Vanderveen 1979). Other examples of interactions between trace elements and metals related to a variety of child health outcomes also are beginning to emerge (Howe et al. 2020a, 2020b, 2021; Liu et al. 2018). However, in many of these cases, the results suggest that the positive association between the trace element and these outcomes may be attenuated at higher levels of the toxic metal. In such cases, the benefit of potential nutritional intervention is less clear. Hopefully, as the field matures, as we understand the nonlinear relationships between metals and trace elements, and as we apply more sophisticated methodologies to tease apart these complexities, greater clarity will emerge.

The work by Zhang et al. also highlights the potential contribution of metal exposures to adverse cardiovascular health at an early age. In adults, toxic metal exposures are known to be associated with cardiovascular disease risk, even at relatively low levels of exposure (Bulka et al. 2019; Lee et al. 2016; Oliver-Williams et al. 2018; Shiue and Hristova 2014; Wu et al. 2018). Although studies of individual metals have begun to reveal similar relationships among children and adolescents, only a handful of studies have explored associations between metal mixtures and childhood blood pressure, and their results have largely disagreed with one another (Howe et al. 2021; Kupsco et al. 2019; Shih et al. 2021). These disparate results highlight the complexities of mixtures analyses. It is highly likely that the composition of mixtures will vary by population, study context, and timing of exposure assessment, making comparability across studies a challenge. For these very reasons, though, it remains incredibly important to conduct such studies in diverse settings.

The Zhang et al. study was conducted in the Boston Birth Cohort, a large (n = 1,194), diverse prospective birth cohort. This study, which focuses on a racially diverse, low-income population of children, provides unique insight into the impacts of metal mixtures exposures on child health in an urban context, which has not been adequately explored in prior studies. Nonetheless, one important limitation is the lack of exposure data throughout the entire pregnancy. The investigators’ use of red blood cells at delivery reflects third-trimester exposures but misses any potentially important windows of susceptibility in early pregnancy. Another limitation is the lack of information on childhood metal exposure, which could mediate or be independently associated with childhood blood pressure. Indeed, there is evidence that postnatal exposures can sometimes be more strongly related to blood pressure than prenatal exposures (Farzan et al. 2021).

In summary, the work by Zhang et al. highlights some advances and challenges facing researchers interested in understanding metal mixtures and child health. These include a) the likelihood that heterogenous combinations of metals within a given mixture vary by study population, tissue matrix of sampling, exposure window, and time and place of study; b) the likely nonlinearity of at least some relationships between essential elements, toxic metals, and health outcomes; c) the potential for correlations, interactions, or both between trace elements and toxic metals; and d) the need for and emergence of statistical methodologies to address these complexities in metal mixtures.

Despite the challenges, it is clear that a greater understanding of the effects of metal mixtures on early cardiovascular health risk—and corresponding potential interventions that target early elevations in blood pressure—will have positive ramifications for preventing cardiovascular disease over the life course. Child blood pressure is a strong predictor of adult blood pressure, and subclinical cardiovascular effects observed in childhood have increasingly been linked to risk of cardiovascular disease, hypertension, and metabolic disease in later life (Berenson et al. 1989, 1998; Chen and Wang 2008; Davis et al. 2001; Hartiala et al. 2012; Juonala et al. 2005; Knoflach et al. 2009; Lauer and Clarke 1989; Li et al. 2003; Raitakari et al. 2003; Theodore et al. 2015). Given that prevalence of cardiovascular disease has doubled over the last three decades (Roth et al. 2020), insights into modifiable environmental factors and potential interventions to protect public health are more critical than ever.

Refers to https://doi.org/10.1289/EHP8325