Systematic review and meta-analysis links autism and toxic metals and highlights the impact of country development status: Higher blood and erythrocyte levels for mercury and lead, and higher hair antimony, cadmium, lead, and mercury

Background: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that affects cognitive and higher cognitive functions. Increasing prevalence of ASD and high rates of related comorbidities has caused serious health loss and placed an onerous burden on the supporting families, caregivers, and health care services. Heavy metals are among environmental factors that may contribute to ASD. However, due to inconsistencies across studies, it is still hard to explain the association between ASD and toxic metals. Therefore the objective of this study was to investigate the difference in heavy metal measures between patients with ASD and control subjects. Methods: We included observational studies that measured levels of toxic metals (antimony, arsenic, cadmium, lead, manganese, mercury, nickel, silver, and thallium) in different specimens (whole blood, plasma, serum, red cells, hair and urine) for patients with ASD and for controls. The main electronic medical database (PubMed and Scopus) were searched from inception through October 2016. Results: 52 studies were eligible to be included in the present systematic review, of which 48 studies were included in the meta-analyses. The hair concentrations of antimony (standardized mean difference (SMD) = 0.24; 95% confidence interval (CI): 0.03 to 0.45) and lead (SMD = 0.60; 95% confidence interval (CI): 0.17 to 1.03) in ASD patients were significantly higher than those of control subjects. ASD patients had higher erythrocyte levels of lead (SMD = 1.55, CI: 0.2 to 2.89) and mercury (SMD = 1.56, CI: 0.42 to 2.70). There were significantly higher blood lead levels in ASD patients (SMD = 0.43, CI: 0.02 to 0.85). Sensitivity analyses showed that ASD patients in developed but not in developing countries have lower hair concentrations of cadmium (SMD = - 0.29, CI: - 0.46 to - 0.12). Also, such analyses indicated that ASD patients in developing but not in developed lands have higher hair concentrations of lead (SMD = 1.58, CI: 0.80 to 2.36) and mercury (SMD = 0.77, CI: 0.31 to 1.23). These findings were confirmed by meta-regression analyses indicating that development status of countries significantly influences the overall effect size of mean difference for hair arsenic, cadmium, lead, and mercury between patients with ASD and controls. Conclusion: The findings help highlighting the role of toxic metals as environmental factors in the etiology of ASD, especially in developing lands. While there are environmental factors other than toxic metals that greatly contribute to the etiology of ASD in developed lands. It would be, thus, expected that classification of ASD includes etiological entities of ASD on the basis of implication of industrial pollutants (developed vs. developing ASD).