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Neurodevelopmental disorders are constantly increasing on a global scale. Some elements like heavy metals are known to be neurotoxic. In this cross-sectional study we assessed the neurobehavioral effect of the exposure to trace elements including lead, mercury, cadmium, manganese, arsenic and selenium and their interactions among 299 schoolchildren residing in the heavily polluted Taranto area in Italy. Whole blood, urine and hair were collected for metal analyses, while the Child Behavior Checklist and the Social Responsiveness Scale, administered to the main teacher and the mothers were considered to identify behavioral problems in children. Blood lead mainly influenced social problems, aggressive behavior, externalizing and total problems. Urinary arsenic showed an impact on anxiety and depression, somatic problems, attention problems and rule breaking behavior. A significant interaction between lead and arsenic was observed, with a synergistic effect of the two metals increasing the risk of attention problems, aggressive behavior, externalizing problems and total problems. Overall, we were able to test that higher blood lead, urinary arsenic concentrations and their interaction increase the risk of neurobehavioral problems. This is in line with the U.S. Environmental Protection Agency’s priority list of hazardous substances where arsenic and lead are ranked as first and second respectively.

The predisposition, severity, and progression of many diseases differ between males and females. Sex-related differences in susceptibility to neurotoxicant exposures may provide insight into the cause of the observed discrepancy. Early adolescence, a period of substantial structural and functional brain changes, may present a critical window of vulnerability to environmental exposures. This study aimed to examine sex-specific associations between co-exposure to multiple metals and visuospatial memory in early adolescence. Manganese (Mn), lead (Pb), chromium (Cr), and copper (Cu) were measured in blood, urine, hair, nails, and saliva of 188 participants (88 girls; 10–14 years of age). Visuospatial memory skills were assessed using a computerized maze task, the virtual radial arm maze (VRAM). Using generalized weighted quantile sum regression, we investigated sex-specific associations between the combined effect of exposure to the metal mixture and visuospatial working memory and determined the contribution of each component to the outcome. The results suggest that sex moderates the association between the metal mixture and visuospatial learning for all outcomes measured. In girls, exposure was associated with slower visuospatial learning and driven by Mn and Cu. In boys, exposure was associated with faster visuospatial learning, and driven by Cr. These results suggest that (a) the effect of metal co-exposure on learning differs in magnitude, and in the direction between sexes, and (b) early adolescence may be a sensitive developmental period for metal exposure.

There is increasing evidence that environmental manganese (Mn) exposure early in life can have negative effects on children's neurodevelopment and increase the risk of behavioral problems, including attention deficit hyperactivity disorder (ADHD). Factors that may contribute to differences in sensitivity to Mn exposure are sex and genetic variation of proteins involved in the regulation of Mn concentrations. Here we investigate if sex and polymorphisms in Mn transporter genes SLC30A10 and SLC39A8 influence the association between Mn exposure and ADHD-related behavioral problems in children.The SNPs rs1776029 and rs12064812 in SLC30A10, and rs13107325 in SLC39A8 were genotyped by TaqMan PCR or pyrosequencing in a population of Italian children (aged 11–14 years; n = 645) with a wide range of environmental Mn exposure. Mn in surface soil was measured in situ using XRF technology or modeled by geospatial analysis. Linear regression models or generalized additive models (GAM) were used for analyzing associations between soil Mn and neurobehavioral problems assessed by the Conners' behavior rating scales (self-, and parent-reported). Gene-environment interactions (Mn transporter genotype x soil Mn) were evaluated using a genetic score in which genotypes for the three SNPs were combined based on their association with blood Mn, as an indication of their influence on Mn regulation.We observed differences in associations between soil Mn and neurobehavior between sexes. For several self-reported Conners' scales, girls showed U-shaped relationships with higher (worse) Conners' scoring at higher soil Mn levels, and several parent-reported scales showed positive linear relationships between increasing soil Mn and higher Conner's scores. For boys, we observed a positive linear relationship with soil Mn for one Conner's outcome only (hyperactivity, parent-reported). We also observed some interactions between soil Mn and the genetic score on Conner's scales in girls and girls with genotypes linked to high blood Mn showed particularly strong positive associations between soil Mn and parent-reported Conners' scales.Our results indicate that sex and polymorphisms in Mn transporter genes contribute to differences in sensitivity to Mn exposure from the environment and that girls that are genetically less efficient at regulating Mn, may be a particularly vulnerable group. Keywords: Manganese exposure, SLC30A10, SLC39A8, Gene-environment interactions, Neurodevelopment, ADHD

Background Metal exposure is a public health hazard due to neurocognitive effects starting in early life. Poor socio-economic status, adverse home and family environment can enhance the neurodevelopmental toxicity due to chemical exposure. Disadvantaged socio-economic conditions are generally higher in environmentally impacted areas although the combined effect of these two factors has not been sufficiently studied. Methods The effect of co-exposure to neurotoxic metals including arsenic, cadmium, manganese, mercury, lead, selenium, and to socio-economic stressors was assessed in a group of 299 children aged 6–12 years, residing at incremental distance from industrial emissions in Taranto, Italy. Exposure was assessed with biological monitoring and the distance between the home address and the exposure point source. Children’s cognitive functions were examined using the Wechsler Intelligence Scale for Children (WISC) and the Cambridge Neuropsychological Test Automated Battery (CANTAB). Linear mixed models were chosen to assess the association between metal exposure, socio-economic status and neurocognitive outcomes. Results Urinary arsenic, cadmium and hair manganese resulted inversely related to the distance from the industrial emission source (β − 0.04; 95% CI -0.06, − 0.01; β − 0.02; 95% CI -0.05, − 0.001; β − 0.02 95% CI -0.05, − 0.003) while the WISC intellectual quotient and its sub-scores (except processing speed index) showed a positive association with distance. Blood lead and urinary cadmium were negatively associated with the IQ total score and all sub-scores, although not reaching the significance level. Hair manganese and blood lead was positively associated with the CANTAB between errors of spatial working memory (β 2.2; 95% CI 0.3, 3.9) and the reaction time of stop signal task (β 0.05; 95% CI 0.02, 0.1) respectively. All the other CANTAB neurocognitive tests did not show to be significantly influenced by metal exposure. The highest socio-economic status showed about five points intellectual quotient more than the lowest level on average (β 4.8; 95% CI 0.3, 9.6); the interaction term between blood lead and the socio-economic status showed a significant negative impact of lead on working memory at the lowest socio-economic status level (β − 4.0; 95% CI -6.9, − 1.1). Conclusions Metal exposure and the distance from industrial emission was associated with negative cognitive impacts in these children. Lead exposure had neurocognitive effect even at very low levels of blood lead concentration when socio-economic status is low, and this should further address the importance and prioritize preventive and regulatory interventions.

Residential proximity to ferroalloy production has been associated with increased manganese exposure, which can adversely affect health, particularly among children. Little is known, however, about which environmental samples contribute most to internal levels of manganese and other ferroalloy metals. We aimed to characterize sources of exposure to metals and evaluate the ability of internal biomarkers to reflect exposures from environmental media. In 717 Italian adolescents residing near ferromanganese industry, we examined associations between manganese, lead, chromium, and copper in environmental samples (airborne particles, surface soil, indoor/outdoor house dust) and biological samples (blood, hair, nails, saliva, urine). In multivariable regression analyses adjusted for child age and sex, a 10% increase in soil Mn was associated with increases of 3.0% (95% CI: 1.1%, 4.9%) in nail Mn and 1.6% (95% CI: -0.2%, 3.4%) in saliva Mn. Weighted-quantile-sum (WQS) regression estimated that higher soil and outdoor dust Mn accounted for most of the effect on nail Mn (WQS weights: 0.61 and 0.22, respectively, out of a total of 1.0). Higher air and soil Mn accounted for most of the effect on saliva Mn (WQS weights: 0.65 and 0.29, respectively). These findings can help inform biomarker selection in future epidemiologic studies and guide intervention strategies in exposed populations.

Manganese (Mn) is an essential element that can become neurotoxic through various exposure windows over the lifespan. While there is clear evidence of Mn neurotoxicity in pediatric and adult occupational populations, little is known about effects in the elderly who may exhibit enhanced susceptibilities due to compromised physiology compared to younger adults. In the province of Brescia, Italy, the Valcamonica area has been the site of three ferroalloy plants operating from 1902 to 2001. Metal emissions of Mn and to a lesser extent lead (Pb) have impacted the surrounding environment, where a high prevalence of Parkinsonism was previously observed. This study aimed to assess neurocognitive and motor functions in healthy elderly subjects residing for most of their lifetime in Valcamonica or in a reference area unimpacted by ferroalloy plant activity.Subjects were enrolled for extensive neurobehavioral assessment of motor, cognitive and sensory functions. Exposure was assessed with 24h personal air sampling for PM10 airborne particles, surface soil and tap water measurement at individual households, Mn levels in blood and urine and Pb in blood. Dose-response relationships between exposure indicators and biomarkers and health outcomes were analyzed with generalized (linear and logistic) additive models (GAM).A total of 255 subjects (55% women) were examined; most (52.9%) were within the 65-70 years age class. Average airborne Mn was 26.41 ng/m(3) (median 18.42) in Valcamonica and 20.96 ng/m(3) (median 17.62) in the reference area. Average Mn in surface soil was 1026 ppm (median 923) in Valcamonica and 421 ppm (median 410) in the reference area. Manganese in drinking water was below the LDL of 1 μg/L. The GAM analysis showed significant association between airborne Mn (p=0.0237) and the motor coordination tests of the Luria Nebraska Neuropsychological Battery. The calculation of the Benchmark Dose using this dose-response relationship yielded a lower level confidence interval of 22.7 ng/m(3) (median 26.4). For the odor identification score of the Sniffin Stick test, an association was observed with soil Mn (p=0.0006) and with a significant interaction with blood Pb (p=0.0856). Significant dose-responses resulted also for the Raven's Colored Progressive Matrices with the distance from exposure point source (p=0.0025) and Mn in soil (p=0.09), and for the Trail Making test, with urinary Mn (p=0.0074). Serum prolactin (PRL) levels were associated with air (p=0.061) and urinary (p=0.003) Mn, and with blood Pb (p=0.0303). In most of these associations age played a significant role as an effect modifier.Lifelong exposure to Mn was significantly associated with changes in odor discrimination, motor coordination, cognitive abilities and serum PRL levels. These effects are consistent with the hypothesis of a specific mechanism of toxicity of Mn on the dopaminergic system. Lead co-exposure, even at very low levels, can further enhance Mn toxicity.

Manganese (Mn) is an essential metal that plays a fundamental role for brain development and functioning. Environmental exposure to Mn may lead to accumulation in the basal ganglia and development of Parkinson-like disorders. The most recent research is focusing on early-life overexposure to Mn and the potential vulnerability of younger individuals to Mn toxicity also in regard to cognitive and executive functions through the involvement of the frontal cortex.Neurodevelopmental disturbances are increasing in the society, and understanding the potential role of environmental determinants is a key for prevention. Therefore, assessing the environmental sources of Mn exposure and the mechanisms of developmental neurotoxicity and defining appropriate biomarkers of exposure and early functional alterations represent key issues to improve and address preventive strategies. These themes will be reviewed in this chapter.

Background Release of ambient metals during ferroalloy production may be an important source of environmental exposure for nearby communities and exposure to these metals has been linked to adverse respiratory outcomes. We sought to characterize the association between personal air levels of metals and respiratory health in Italian adolescents living in communities with historic and current ferroalloy activity. Methods As part of a study in the industrial province of Brescia, Italy, 410 adolescents aged 11–14 years were recruited. Participants were enrolled from three different communities with varying manganese (Mn) levels: Bagnolo Mella which has current ferroalloy activity, Valcamonica, which has historic ferroalloy activity and Garda Lake which has no history of ferroalloy activity. Particulate matter

Ferroalloy production can release a number of metals into the environment, of which manganese (Mn) is of major concern. Other elements include lead, iron, zinc, copper, chromium, and cadmium. Manganese exposure derived from settled dust and suspended aerosols can cause a variety of adverse neurological effects to chronically exposed individuals. To better estimate the current levels of exposure, this study quantified metal levels in dust collected inside homes (n=85), outside homes (n=81), in attics (n=6), and in surface soil (n=252) in an area with historic ferroalloy production. Metals contained in indoor and outdoor dust samples were quantified using inductively coupled plasma optical emission spectroscopy while attic and soil measurements were made with a XRF instrument. Mean Mn concentrations in soil (4600 μg/g) and indoor dust (870 μg/g) collected within 0.5 km of a plant exceeded levels previously found in suburban and urban areas, but did decrease outside 1.0 km to the upper end of background concentrations. Mn concentrations in attic dust were approximately 120 times larger than other indoor dust levels, consistent with historical emissions that yielded high airborne concentrations in the region. Considering the potential health effects that are associated with chronic manganese inhalation and ingestion exposure, remediation of soil near the plants and frequent, on-going hygiene indoors may decrease residential exposure and the likelihood of adverse health effects.

Adolescents living in communities with ferromanganese alloy plant activity have been shown to exhibit deficits in olfactory and fine motor function. Household dust may serve as an important manganese (Mn) exposure pathway to children, though dust Mn concentrations have not previously been measured to assess household contamination from ferromanganese alloy plant emissions. Here we determined the association between dust concentrations and surface loadings of Mn and other metals (Al, Cd, Cr, Cu, Fe, Pb, and Zn) in indoor and outdoor household dust from three Italian communities that differ by history of ferromanganese alloy plant activity: Bagnolo Mella, with an active ferromanganese alloy plant (n=178 households); Valcamonica, with historically active plants (n=166); and Garda Lake, with no history of ferromanganese plant activity (n=99). We also evaluated Mn levels in other environmental (soil, airborne particulates) and candidate biomarker (blood, hair, saliva, fingernails) samples from children within the households. Household dust Mn concentrations and surface loadings were significantly different between the three sites, with levels highest in Bagnolo Mella (outdoor median Mn concentration = 4620, range 487 – 183,000 µg/g), intermediate in Valcamonica (median = 876, range 407 – 8240 µg/g), and lowest in Garda Lake (median = 407, range 258 – 7240 µg/g). Outdoor dust Mn concentrations in Bagnolo Mella, but not the other communities, were significantly inversely related with distance from the plant (R2=0.6630, P