Invited Perspective: Studying Metal Impacts on Neurobehavior during the Critical but Challenging Window of Adolescence

Attention and attention-related behaviors are important predictors of learning outcomes and academic achievement among children and adolescents. Although some positive aspects of attention deficit disorders have been reported,^1,2 the economic burden to individuals and society is substantial, ranging from $\text{USD\hspace{0.17em}}\$12\text{\hspace{0.17em}million}$ to $\text{USD\hspace{0.17em}}\$141\text{\hspace{0.17em}billion}$, depending on the country.³ These costs accumulate from increased interaction with the health care, education, and justice systems for children and adolescents, with additional costs related to wage loss and inefficiency in adults. Notably, individuals with clinical attention deficits are often diagnosed with comorbid psychiatric conditions that manifest in adolescence, suggesting that understanding brain changes in this life stage could be informative for reducing the public health burden of mental illnesses.⁴

The prefrontal cortex contributes to the regulation of attention but does not reach full maturity until early adulthood.⁵ This region of the brain undergoes dramatic changes during adolescence, which reflects a potentially vulnerable period during which metals and other neurotoxicants may adversely affect attention-related behaviors.^6,7 Prior studies have demonstrated that arsenic, lead, and other toxic metals and metalloids (hereafter “metals”) adversely impact neurodevelopmental outcomes, including attention, in early childhood; however, little is currently known about the potential impacts of metal exposures during the vulnerable window of adolescence.^8,9

In this issue of Environmental Health Perspectives, Schildroth et al. addresses this important research gap by investigating how exposure to multiple metals, assessed as a complex mixture, influence attention in a study of adolescents (10–14 years of age) in Brescia, Italy, living near ferroalloy industrial facilities.¹⁰ Using Bayesian kernel machine regression, a flexible method that can assess multiple metal exposures simultaneously, the authors found the metal mixture was associated with worse attention-like behaviors in adolescence. This association was driven by manganese, an essential element with known neurotoxic effects at high concentrations.¹¹

These findings are consistent with several prior epidemiologic studies that have also reported reduced attention in childhood in relation to elevated manganese exposure.^9,12,13 They are also consistent with prior experimental evidence.¹⁴ For example, studies using rodent models have demonstrated that when manganese exposure occurs exclusively during the early postnatal period, impacts on attention are similar to those of lifelong exposure, suggesting that the early postnatal period is a particularly important window of susceptibility for this metal.¹⁴ However, exclusive exposure to manganese during adolescence has not been similarly assessed, possibly owing to the difficulty of studying this life stage.¹⁵

Challenges in studying adolescence arise in part because this is a period of physical, cognitive, and psychological development shaped by intrinsic and extrinsic factors and therefore cannot be defined solely by chronological age.¹⁶ Epidemiologic studies face an additional challenge in trying to determine the individual contributions of environmental contaminant exposures during adolescence, given that many metal exposures are correlated across time.^17,18 Thus, although Schildroth et al. measured manganese exposure during adolescence and reported potential impacts on attention,¹⁰ it is possible that some of the observed associations were driven by manganese exposures occurring earlier in life. Future epidemiologic studies with repeated measures of manganese and other metal exposures across the life course are therefore needed to disentangle the most important windows of exposure.

It is also difficult to assess the precise onset of attentional deficits, particularly during adolescence. Attention deficit/hyperactivity disorder (ADHD) is typically considered a pediatric condition, with the median age of diagnosis between 4 and 7 years of age, depending on severity and access to care.¹⁹ However, ADHD phenotypes vary within individuals over time. In adolescence this variability in disease course can manifest as spikes in symptoms for individuals who had subclinical or mild ADHD symptoms during childhood; this is usually associated with a child’s transition to middle school^20,21 and can lead to a clinical ADHD diagnosis during this window. Some individuals also develop compensatory or masking behaviors, making their observable symptoms less severe in adolescence and adulthood.²² To complicate matters, individuals without ADHD can also experience periods of increased inattention, which may be misclassified as ADHD.²¹ Even when an individual’s symptoms are consistent over time, the severity of these symptoms may be assessed differently depending on the rater. This may occur because the raters themselves change over time (e.g., a student has a different teacher each year) or owing to differences in expectations of neurotypical behavior depending on the child’s age.

Although it is a challenging task, understanding how metal exposures in adolescence exacerbate existing ADHD or lead to new diagnoses during this developmental window is important for designing interventions that reduce the public health burden of attention deficits. However, many epidemiologic studies have assessed attention outcomes at a single time point. This can make it difficult to discern if the observed association between the metal mixture and attention reflects a unique vulnerability during the adolescent window, perhaps related to transient symptoms, or if autocorrelations between both metal mixtures and attention-related behaviors across childhood and adolescence drive some of the relationship. Thus, although challenging to obtain, studies with repeated assessment of both the exposures and outcome will be instrumental in identifying the key windows during which reducing exposure to metals has the greatest impact on reducing risk of inattention.

An additional layer of complexity in studying attention during adolescence is the potential for discrepancies in measures of attention across raters. This was highlighted in the study by Schildroth et al., who reported that the metal mixture was associated with inattention when measured by self-report, but not when using parent- or teacher-reported measures.¹⁰ Several studies have documented the relationship between rater effects (i.e., differences in how an individual’s behavior is scored depending on the relationship between the rater and the individual) and perception of neurobehavior in children and adolescents.²³ Although self-report of behavior by preadolescents ($<12$ years of age) generally aligns with parental report, ratings diverge in adolescence, with teens reporting more internalizing and fewer externalizing symptoms than their parents and teachers. Although teachers are the recommended reporters of externalizing behaviors in adolescence, self-report by adolescents may be more reliable for capturing subclinical inattention.^23,24 Thus, although the discrepancies between self-report and teacher-report observed by Schildroth et al. could be due to sample size differences or chance, they also potentially reflect distinct phenotypes that may be a) more or less sensitive to metal exposures, or b) differentially detected depending on the reporter.²¹ Future epidemiologic studies with repeated measures of inattention by different raters, in addition to objective measures (e.g., continuous performance testing), may provide more insight into these associations.

In conclusion, we commend Schildroth et al. for conducting research on this important and understudied topic. Their finding of reduced attention in relation to metal mixture exposures during adolescence underscores the need for additional epidemiologic studies that collect longitudinal measures of both metal exposures and attention across the life course. This can be challenging to achieve in a single cohort but could be feasible through large collaborative initiatives such as the Environmental Influences on Child Health Outcomes (ECHO) Program, which is collecting repeated measures of different environmental exposures and neurobehavioral data from diverse participants across the United States using a common protocol. Given the specific challenges of assessing attention and other neurobehavioral outcomes during adolescence, there is also a need for studies that obtain detailed measures of attention assessed by different raters; this may be more readily accomplished by individual cohorts that are well positioned to collect these specialized measures. Finally, it is important to acknowledge that adolescence is characterized by dramatic changes across multiple organ systems, as well as changes in behavior that affect diet and other factors that are involved in or modify the absorption, metabolism, and excretion of metals and other contaminants. Given that the timing and tempo of these changes is unique for each individual, adolescence is an especially challenging period during which to study the neurobehavioral impacts of environmental exposures. However, it is also a critical period to focus on, given that changes during this window have the potential to affect lifelong health.

Conclusions and opinions are those of the individual authors and do not necessarily reflect the policies or views of EHP Publishing or the National Institute of Environmental Health Sciences.

Refers to https://doi.org/10.1289/EHP12988