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Exploring the link between toxic metal exposure and ADHD: a systematic review of pb and hg

Abstract

Introduction

Attention-Deficit/Hyperactivity Disorder (ADHD) is a recognized neurodevelopmental disorder with a complex, multifactorial origin. Lead (Pb) and mercury (Hg) are highly toxic substances that can potentially impair brain development and have been implicated in the development of ADHD. This systematic review aims to analyze the epidemiological literature regarding the association between Pb and Hg exposure and the diagnosis of ADHD.

Methods

From November 1983 to June 2, 2023, a comprehensive search was conducted in multiple databases and search engines, including PubMed, Web of Science, Scopus, and Google Scholar. Observational studies (case-control, cohort, and cross-sectional) measuring Pb and Hg levels in various biological samples (blood, hair, urine, nail, saliva, teeth, and bone) of children with ADHD or their parents and their association with ADHD symptoms were included.

Results

Out of 2059 studies, 87 met the inclusion criteria and were included in this systematic review. Approximately two-thirds of the 74 studies investigating Pb levels in different biological samples reported associations with at least one subtype of ADHD. However, most studies examining Hg levels in various biological samples found no significant association with any ADHD subtype, although there were variations in exposure periods and diagnostic criteria.

Conclusion

The evidence gathered from the included studies supports an association between Pb exposure and the diagnosis of ADHD, while no significant association was found with Hg exposure. Importantly, even low levels of Pb were found to elevate the risk of ADHD. Further research is needed to explore the comprehensive range of risk factors for ADHD in children, considering its significance as a neurodevelopmental disorder.

Introduction

Attention-Deficit/Hyperactivity Disorder (ADHD) is a well-known neurodevelopmental disorder characterized by symptoms of inattention, impulsivity, and hyperactivity, resulting in significant functional impairment [1]. The condition is particularly important due to its early childhood onset and persistence into adulthood [2]. Children diagnosed with ADHD often struggle with task focus, learning difficulties, and weakened interpersonal skills, leading to self-confidence issues and negative emotional states. Consequently, their personal, academic, and social performance is adversely affected [3].

Globally, ADHD affects approximately 5% of children and adolescents, with an increasing trend observed in recent years [1]. In the United States, the prevalence of diagnosed ADHD cases among children and adolescents has risen from 6.1% in 1998 to 10.2% in 2016 [4]. Furthermore, ADHD is also a concern in adulthood, with persistent cases from childhood and newly symptomatic cases estimated to affect 2.58% and 6.76% of the adult population, respectively [5].

Considering the escalating prevalence of ADHD, it is crucial to explore environmental factors that may contribute to its development. Among these factors, certain metals, known for their neurotoxic effects, have gained attention [6]. Human exposure to these metals can occur through various sources such as industrial sites, soil and air pollution, and dietary intake [7].

Lead (Pb) is a highly dangerous substance, ranked second in terms of hazardousness by the Agency for Toxic Substances and Disease Registry (ATSDR) [8]. Various industrial processes, such as lead ore mining and smelting, pottery production, utilization of lead-lined food and drink containers, lead-based painting, and battery recycling, can result in lead exposure [9, 10]. Even at low concentrations, lead can impair brain development and adversely impact neurobehavioral functions long-term, resulting in poor academic performance and diminished intelligence quotient [11]. Several scientific studies have implicated it as a prevalent risk factor contributing to the development of ADHD in children [12,13,14]. Additionally, there is evidence indicating that lead can traverse the placenta during pregnancy, and elevated prenatal lead levels are associated with deceleration in sensorimotor or visual-motor development in children [15, 16]. Lead is also responsible for structural alterations in neurons, synaptogenesis, myelination, and neuron differentiation [17]. Studies indicate that lead alters neurogenesis and affects cortical neurons, ultimately leading to cognitive disabilities [18]. Traffic continues to be a concern regarding atmospheric lead pollution [19].

The central nervous system is the primary target of lead exposure, especially during developmental stages, due to its ability to readily cross the blood-brain barrier [17]. Multiple factors undoubtedly influence the neurotoxicity associated with lead exposure; however, the impacts of lead on the brain can be divided into morphological or pharmacological effects. Morphological effects involve structural alterations in brain cells, influencing crucial processes such as synaptogenesis, myelination, and neuron differentiation. Meanwhile, pharmacological effects involve ion mimicry, wherein Pb2+ competes with essential ions for their functional roles and insertion sites. As a result, Pb2+ is incorporated into the brain, disrupting synaptic neurotransmission, causing mitochondrial dysfunction, and potentially inducing neuroinflammation. Consequently, these mechanisms are responsible for lead intoxication’s neurotoxic effects on the neurobehavioral system [8].

Mercury (Hg) is ranked third in terms of hazardousness, according to ATSDR. The significance of mercury toxicity is not surprising, given the diverse routes of human exposure, such as fish consumption, dental amalgam fillings, and the utilization of mercury-based preservatives like thimerosal (ethylmercury thiosalicylate.) in vaccinations [20, 21]. Due to its ability to cross the placenta and blood-brain barrier, mercury poses a significant risk of neurotoxicity. Notably, the developing brain is particularly vulnerable to these effects, potentially leading to long-lasting consequences [22]. Evidence suggests a potential association between both prenatal and postnatal exposure to mercury and the manifestation of neurodevelopmental complications, including ADHD, diminished cognitive abilities (low IQ), and language impairments [23, 24]. This toxic element inhibits the sulfhydryl-containing enzymes and increases the lipid peroxidation and reactive oxygen species (ROS) levels. Hg is widely discussed for its effect on brain cells through oxidative stress and apoptotic processes [25].

The previous studies emphasize the significance of lead exposure as a potential contributing factor to the development of ADHD. In 2019, a systematic review study [26] was conducted to examine the literature on the impact of lead exposure on children diagnosed with ADHD. This review specifically focused on studies conducted between July 1, 2013, and June 30, 2018. Their findings revealed a significant association between lead exposure and ADHD in 12 out of the 17 studies reviewed [26]. A recent systematic review comprising 31 papers examined the impact of mercury (Hg) on ADHD. The study concluded that the available information regarding the effects of mercury on ADHD is limited [27].

To our knowledge, two similar studies, each with limitations, have been conducted on these toxic and widespread metals.

Previous studies on this matter have been limited to one metal, and we tend to evaluate the effect of two of the most common toxic metals (Pb and Hg) on ADHD. The year of study has also been expanded in our research. We comprehensively reviewed these metals in all available human body samples to better understand their role in ADHD. This systematic review aims to thoroughly evaluate the available evidence on the association between two specific toxic metals, lead (Pb) and mercury (Hg), in various biological specimens (blood, hair, urine, teeth, nails, and bone) and ADHD.

Methods

Design and search strategy

This systematic review study adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A search was conducted in four databases/search engines: PubMed, Scopus, Web of Science, and Google Scholar until June 2, 2023. No restrictions were imposed on the publication dates, and all available studies from the earliest records were considered. To capture relevant studies, we utilized keywords and medical subject headings (MeSH) terms to search for the titles or abstracts of the studies. The search strategies employed in each database are summarized in Table 1. Endnote software was used to facilitate data extraction and management from the databases. The study has been registered in PROSPERO with ID number 557,671.

Table 1 Search strategies in different databases for retrieving the relevant documents

Eligibility criteria for study selection

Inclusion criteria

Human observational studies (case-control, cohort, cross-sectional) that assessed the relationship of ADHD with at least one of the heavy metals of interest, namely lead (Pb) or mercury (Hg), were included in this systematic review. The age restriction for ADHD subjects was set to encompass individuals up to 20 years old, as the review specifically examined the association of heavy metals and attention-deficit/hyperactivity disorder (ADHD) in children. No language or time limitations were imposed, and articles written in English or those with at least one English abstract were considered. Additionally, the reference lists of the included studies were screened for relevant publications.

Exclusion criteria

Experimental research, books, review articles, or letters to the editor were excluded from this systematic review. Studies that did not report relevant results were also excluded at each stage of the document screening process. Initially, the records retrieved from the databases were integrated, and duplicate records were removed. Subsequently, articles were screened based on their titles and abstracts, excluding those not meeting the inclusion criteria. Finally, the full texts of the remaining articles were thoroughly reviewed.

Data extraction

Relevant data from the included studies were extracted and organized. An electronic data abstraction form was used to document various study characteristics, including the first author’s name, publication year, country where the study was conducted, research design, number of participants, age range, gender distribution, criteria used to diagnose ADHD, specific ADHD symptoms evaluated, and key study results.

Results

From the initial search across various databases and search engines, 2059 studies were identified. After removing duplicates using Endnote Software, 1209 unique studies remained. Applying the pre-defined study inclusion criteria to the titles and abstracts resulted in 120 relevant articles for further examination. Following a thorough assessment of the full texts, 86 articles were included in this systematic review (Fig. 1).

Fig. 1
figure 1

PRISMA Flowchart of the literature search and strategy for selecting relevant documents

The selected studies investigated the measurement of at least one of the metals of interest, lead (Pb) or mercury (Hg), in various biological samples, such as blood, hair, urine, saliva, teeth, or bones, obtained from children diagnosed with ADHD or their parents. Among the selected studies (n = 86), there were 35 case-control studies, 26 cohort studies, and 25 cross-sectional studies. Metal concentrations were predominantly measured in children (66 studies), while ten studies focused on mothers and another ten on mothers and children. In terms of age ranges for ADHD cases, the youngest subject was one year old, while the oldest was 20 years old.

The publication years of the included studies range from 1983 to 2023.

The assessment of heavy metal concentrations primarily utilized techniques such as inductively coupled plasma (ICP) or atomic absorption spectrometry (AAS), although some studies employed methods such as Direct Mercury Analyzer [28,29,30], Anodic Stripping Voltammetry [31, 32], Fluorescence Spectrometry [33, 34], Gas Chromatography and High-resolution Mass Spectrometry [35], or K-shell X-ray Fluorescence [36]. Various questionnaires were employed for the diagnosis of ADHD with determining symptoms (inattention, hyperactivity/impulsivity, or combined), largely based on criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD). Most studies were conducted in China, South Korea, and the United States. Tables 2 and 3 demonstrate the findings of these studies.

Table 2 Characteristics of included studies for assessments of the relationship between lead concentrations in different biological samples and ADHD
Table 3 Characteristics of included studies for assessments of the relationship between mercury concentrations in different biological samples and ADHD

Lead (pb)

Blood

A total of seventy-four studies examined the link between Lead and Attention-Deficit Hyperactivity Disorder (ADHD). Fifty-four studies measured whole blood lead concentrations [12,13,14, 29, 31, 32, 36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82] between 1988 and 2022. Regardless of the ADHD subtype, a total of thirty-four studies found an association between increased lead levels and ADHD occurrences (14 case-control studies, 11 cross-sectional studies, and 9 cohort studies). Twenty-four studies reported that children with a combined ADHD subtype had higher blood lead levels [12,13,14, 31, 32, 40, 44, 50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66], while fourteen studies reported non-significant results (9 case-control studies, and five cross-sectional studies) [14, 29, 36, 43, 67,68,69, 71, 72, 77,78,79,80,81]. The Inattention subtype of ADHD was positively associated with blood lead levels in nine studies [12,13,14, 31, 37,38,39,40,41]. In contrast, nineteen studies found no significant association between the inattention subtype and blood lead levels (9 case-control studies, seven cross-sectional studies, and 3 cohort studies) [29, 36, 37, 42, 43, 46, 47, 49, 50, 57, 58, 67,68,69,70,71,72,73,74]. The increasing impact of blood lead concentrations on ADHD hyperactivity was documented in thirteen studies [13, 14, 37, 39,40,41,42, 44,45,46,47,48,49], while thirteen reported non-significant results (6 case-control studies, five cross-sectional studies, and 2 cohort studies) [14, 31, 36, 37, 50, 67,68,69, 71,72,73, 75, 76]. Conversely, Lucchini et al. (2012) reported that all three subtypes of ADHD are associated with lower blood lead levels [82]. Furthermore, Huang et al. (2016) found a positive correlation between lower blood lead levels and an increased risk of the hyperactivity subtype in children with ADHD [43]. Table 2 shows the findings of these studies in alphabetical order.

Hair

Ten studies were conducted to assess lead concentrations in the hair of children with ADHD. Seven types of research found elevated Pb levels in hair associated with ADHD between 1998 and 2023, regardless of subtype (5 case-control studies and two cross-sectional studies) [33, 83,84,85,86,87,88]. Six studies found an association between hair Pb levels and Combined ADHD subtype [33, 83,84,85,86,87], While no significant result was found between the three studies [81, 89, 90]. In three research studies, higher hair Pb levels have been linked to inattention ADHD [83, 85, 88]. One reported no significant association between the hair Pb levels and the inattention subtype [89]. There is a positive correlation between higher hair Pb levels and the hyperactivity subtype of ADHD, according to Amgalan et al. [83], whereas Perham et al. (2020) did not find a significant association [89]. Table 2 shows details of these studies in alphabetical order.

Urine

Pb levels in urine were measured in six studies between 1983 and 2023. Two studies reported elevated Pb levels in urine are associated with combined ADHD (2 cross-sectional studies) [86, 91]. Wang et al. (2019) did not find any significant association [81]. According to Lee (2018), there is a positive correlation between the inattention and hyperactivity subtypes of ADHD and Urinary Pb levels [92], while Gittelman et al. (1983) found no significant correlation [93]. Table 2 shows the findings of these studies in alphabetical order.

Teeth

A total of two studies measured lead concentrations in teeth, but only one found an association between higher levels of Pb and inattention and hyperactivity subtypes of ADHD (a cohort study) [94]. In contrast, the other found no relation with any of the three subtypes [95]. Table 2 presents the results of these studies listed in alphabetical order.

Nail

Lead concentration in nails was measured in two studies. One reported that higher Pb nail levels are correlated with the combined ADHD subtype (a case-control study) [96]. In contrast, the other did not report significant results (a cross-sectional study) [81]. Table 2 shows the findings of these studies in alphabetical order.

Bone

Lin et al. (2017) measured Pb concentrations in bone but found no significant correlation between bone Pb levels and ADHD [36]. Table 2 shows the findings of this study in alphabetical order.

Cord blood

Seven studies measured the level of lead in cord blood. Fraser et al. (2006) could not detect Pb levels in cord blood [47]. In four studies, Pb levels in cord blood were unrelated to the hyperactivity subtype of ADHD (4 cohort studies). In contrast, in two studies, they were positively correlated (1 cross-sectional study and 1 cohort study). Three studies found no significant association between cord blood Pb levels and ADHD inattention. As opposed to that, Ethier (2015) discovered that high cord blood Pb levels are associated with inattention ADHD [73]. Table 2 presents the results of these studies in alphabetical sequence.

Maternal blood

A lead level was measured in the blood of mothers of ADHD children in two studies. Neugebauer found that greater Pb levels in maternal blood increase the risk of hyperactivity and combined ADHD [35], whereas Skogheim (2021) did not report any significant association between maternal blood Pb levels and combined ADHD [97]. Table 2 shows the findings of these studies in alphabetical order.

Maternal urine

The lead level in the urine of ADHD children’s mothers has been examined in one study. However, no significant correlation has been found [98]. Table 2 shows the findings of this study in alphabetical order.

Mercury (hg)

Blood

The relationship between Mercury level and attention deficit hyperactivity disorder was examined in twenty-nine studies between 2009 and 2021. Mercury blood levels in children with ADHD were examined in ten studies. Six reported non-significant results between blood Hg level and combined ADHD (4 case-control studies, one cross-sectional study, and 1 cohort study) [40, 53, 55, 60, 69, 78]. Six found no correlation between Hg level and Inattention ADHD (1 case-control study, one cross-sectional study, and 4 cohort studies) [40, 41, 49, 69, 73, 99]. Five more studies found no link between blood Hg level and hyperactive subtype (1 cross-sectional study and 4 cohort studies) [40, 41, 49, 73, 99]. In contrast, only Sehgal (2020) discovered a link between blood Hg level and hyperactivity subtype [69]. Table 3 presents the results of these studies listed in alphabetical order.

Hair

Five studies assessed the Mercury level in the hair between 2012 and 2020. Tabatadze et al. (2018) discovered that increased hair Hg levels are connected with the combined subtype of ADHD [33]. However, three other studies showed no significant connection (one case-control study, one cross-sectional study, and one cohort study) [28, 29, 89]. Three studies found no conclusive link between hair Hg levels and the inattention subtype (two case-control studies and one cross-sectional study) [29, 88, 89]. Table 3 shows the findings of these studies in alphabetical order.

Saliva

Two studies examined the quantity of mercury in saliva. Both studies revealed a link between higher Hg levels in saliva and children with comorbid ADHD [34, 100]. Table 3 shows more details of these studies in alphabetical order.

Teeth

Mercury levels in teeth were measured in two studies. Hg level in teeth could not be detected by Chan [95]. Additionally, Lin and colleagues (2017) did not discover a connection between combined ADHD and teeth Hg level [101]. Table 3 shows the findings of these studies in alphabetical order.

Urine

Lee et al. (2018) measured the mercury level in urine [92]. Furthermore, there was a significant connection between elevated urine Hg level and the Hyperactivity subtype of ADHD, but not with the Inattention subtype [92]. Table 3 shows details of this study in alphabetical order.

Maternal hair

Two studies assessed the mercury content of the mothers’ hair of ADHD children. Additionally, both studies found higher amounts of Hg in the maternal hair of ADHD offspring (2 cohort studies), which is associated with all subtypes of the disorder [23, 30]. The table presents the results of these studies, which are listed alphabetically.

Maternal blood

The Mercury level in maternal blood was measured in two studies. One did not find any significant correlation between maternal blood Hg level and hyperactivity/inattention ADHD subtypes [99]. Whereas, Skogheim et al. (2021) reported that decreased Hg levels in maternal blood are related to combined ADHD [97]. Table 3 shows the findings of these studies in alphabetical order.

Maternal saliva

One study looked into the association between mercury concentration in maternal saliva and child ADHD and concluded that higher Hg levels are linked to the combined subtype of ADHD [34]. Another study examined the link between maternal amalgam filling and child ADHD but found no significant results [102]. Table 3 shows the findings of these studies in alphabetical order.

Cord blood

The Mercury level in cord blood was measured in three studies. Two studies did not discover any significant result [41, 73], while Boucher 2012 found a correlation between elevated cord blood Hg level and inattention ADHD [49]. Table 3 shows the findings of these studies in alphabetical order.

Vaccination

Five studies were conducted to investigate the link between Thimerosal vaccination exposure and ADHD. Four of them found that a higher vaccine dosage is linked to ADHD [103,104,105]. In contrast, Andrews discovered a decreasing trend in ADHD by immunization dosage in 2004 [106]. Table 3 shows details of these studies in alphabetical order.

Discussion

The outcomes of this systematic review reveal a substantial correlation between lead exposure and ADHD, as evidenced by nearly two-thirds of the seventy-four studies that examined lead levels in various biological samples being associated with at least one of the ADHD subtypes.

In our systematic review, we took a more comprehensive approach by encompassing a broader range of literature published from 1983 to 2023. Our analysis expanded to include more diverse biological samples, including blood, urine, nails, hair, and teeth. By doing so, we aimed to enhance the overall comprehensiveness of our investigation into the association between lead exposure and ADHD in children. Also, we include studies on maternal lead levels and the occurrence of ADHD in their children. Our systematic review findings were mixed regarding the maternal and cord blood lead levels and the occurrence of ADHD, which underscores more studies in this field. According to scientific investigation, it has been firmly established that lead can cross the placental barrier and enter the fetal circulation as early as the 12th week of gestation, maintaining its presence throughout the entirety of the developmental process until birth [107, 108].

The human body can be exposed to lead through various pathways, including ingesting contaminated food, water consumption from contaminated supply systems, contact with lead-based paint, exposure to secondhand smoke, and inhaling air pollutants. Children are especially susceptible to lead poisoning [19]. Lead contamination in food is the primary source of nonoccupational lead exposure, originating from diverse sources encompassing soil, air, and water pollutants and agricultural processes throughout various stages, such as harvesting, processing, packaging, and preparation [19, 109]. Passive tobacco smoking represents a significant source of lead exposure. In a study conducted by Serdar et al. [110], it was observed that children living in households with smokers had hair lead levels that were more than double those of children in households without smokers. Children who play with toys are at a high risk of lead exposure, particularly from PVC toys, which contain lead as a component. This risk is further exacerbated when the toys are coated with lead-based paints. The issue becomes more severe when children habitually chew, suck, or lick these toys, leading to the ingestion of significant amounts of lead [111]. In addition to the ways mentioned above, leaded gasoline was previously identified as an important source of lead exposure. However, removing leaded gasoline has reduced airborne lead pollutants [112]. Nevertheless, the amount of time spent in.

Our findings indicate that most included studies reported no association between pre and postnatal mercury exposure and any ADHD symptoms. However, it is important to note that the available evidence on the impact of prenatal and postnatal mercury exposure on the prevalence of ADHD is limited. Due to this limitation and the heterogenicity of the studies, it is challenging to reach any conclusive findings or draw definite conclusions from the results. These findings are consistent with the study conducted by Tapia et al. in 2023, which examined the correlation between mercury exposure and neurodevelopmental diseases among children [27].

There are several sources of mercury exposure, particularly methylmercury, the most hazardous form of Hg. The primary source for human populations is fish consumption.

In the past, mercury exposure posed a significant concern due to the widespread use of mercury dental amalgam fillings. However, these have now been replaced by alternative materials [113]. A study conducted by Ulukapi analyzed mercury levels in the urine of individuals with amalgam fillings and found that their levels fell within the normal range [114]. It is important to note that the mercury concentration in the air is generally low and does not pose a significant risk to human health [22]. Currently, the main concern regarding mercury exposure stems from the discharge of mercury into waterways by industries and occupational exposure [115].

Our study reveals that exposure to mercury through the preservative Thimerosal poses a risk factor for the diagnosis of ADHD. Thimerosal contains ethylmercury and has historically been included in various vaccines since the 1930s. It is still used in several childhood vaccines, including tetanus toxoid, Hib, HBV, DTP, DT, and influenza [116]. Ethylmercury, produced when Thimerosal-containing vaccines break down, can traverse the BBB. However, the half-life of ethylmercury is shorter, leading to lower peak concentrations in the blood upon repeated exposure [117]. Although studies on the toxicity of Thimerosal in the human population are limited, existing research has indicated no notable differences in toxicity between methylmercury and ethylmercury. It has been demonstrated that the accumulation of Hg2+ in the brain is greater following exposure to ethylmercury than methylmercury exposure [22].

Limitations

Our study’s literature review revealed some potential limitations. A significant limitation is that many studies relied on questionnaires filled out by parents or teachers to diagnose ADHD, which could introduce the risk of misdiagnosis or biases. A more appropriate approach to reduce this risk and improve diagnostic accuracy would have been for physicians to use a medical diagnosis of ADHD based on established diagnostic criteria, such as the ICD or DSM, thereby decreasing the likelihood of misdiagnosis. Additionally, various biological materials, including blood, hair, urine, teeth, and bone, have been analyzed by researchers in this particular field. There may be notable variations in the outcomes observed across different laboratories utilizing distinct techniques. Consequently, interpreting these findings can present a challenge due to the biological samples’ inherent characteristics. Specifically, the distribution of elements within a tooth is not uniform, and their levels differ depending on the type of tooth, which correlates with its age [118]. Urine cannot reflect long-term metal exposure either [98].

Additionally, it is important to highlight that the studies examined in our review employed varying observation and exposure times, which needed to be more consistent across all research investigations. These studies also encompassed different age groups, adding to the heterogeneity of the findings. This review included studies spanning several decades; we observed consistent findings on metal levels’ effects across the older and more recent publications. Future longitudinal analyses examining the potential impact of evolving environmental regulations and industrial practices on metal exposures could provide valuable insights into the temporal trends of these contaminants and their relationship with ADHD.

Variations in methodologies and the considerable heterogeneity within the literature should be considered when interpreting our findings. Also, studies did not report the concentration of these metals in their studies, and the lack of numerical data prevented us from executing a meta-analysis on this matter. Another notable issue is that studies should have mentioned the isotope of Hg and Pb in which they have been measured. Therefore, we could not organize the studies using their isotope.

Data availability

No datasets were generated or analysed during the current study.

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Farmani, R., Mehrpour, O., Kooshki, A. et al. Exploring the link between toxic metal exposure and ADHD: a systematic review of pb and hg. J Neurodevelop Disord 16, 44 (2024). https://doi.org/10.1186/s11689-024-09555-8

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