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BACKGROUND: Exposure to environmental metals has been consistently associated with attention and behavioral deficits in children, and these associations may be modified by coexposure to other metals or iron (Fe) status. However, few studies have investigated Fe status as a modifier of a metal mixture, particularly with respect to attention-related behaviors. METHODS: We used cross-sectional data from the Public Health Impact of Metals Exposure study, which included 707 adolescents (10–14 years of age) from Brescia, Italy. Manganese, chromium, and copper were quantified in hair samples, and lead was quantified in whole blood, using inductively coupled plasma mass spectrometry. Concentrations of Fe status markers (ferritin, hemoglobin, transferrin) were measured using immunoassays or luminescence assays. Attention-related behaviors were assessed using the Conners Rating Scales Self-Report Scale–Long Form, Parent Rating Scales Revised–Short Form, and Teacher Rating Scales Revised–Short Form. We employed Bayesian kernel machine regression to examine associations of the metal mixture with these outcomes and evaluate Fe status as a modifier. RESULTS: Higher concentrations of the metals and ferritin were jointly associated with worse self-reported attention-related behaviors: metals and ferritin set to their 90th percentiles were associated with 3.0% [&#946= 0.03; 95% credible interval (CrI): -0.01, 0.06], 4.1% (&#946= 0.04; 95% CrI: 0.00, 0.08), and 4.1% (β= 0.04; 95% CrI: 0.00, 0.08) higher T-scores for self-reported attention deficit/hyperactivity disorder (ADHD) index, inattention, and hyperactivity, respectively, compared with when metals and ferritin were set to their 50th percentiles. These associations were driven by hair manganese, which exhibited nonlinear associations with all self-reported scales. There was no evidence that Fe status modified the neurotoxicity of the metal mixture. The metal mixture was not materially associated with any parent-reported or teacher-reported scale. CONCLUSIONS: The overall metal mixture, driven by manganese, was adversely associated with self-reported attention-related behavior. These findings suggest that exposure to multiple environmental metals impacts adolescent neurodevelopment, which has significant public health implications. [ABSTRACT FROM AUTHOR]

BACKGROUND: Research on the health effects of chemical mixtures has focused mainly on early life rather than adolescence, a potentially important developmental life stage. OBJECTIVES: We examined associations of a metal mixture with general cognition in a cross-sectional study of adolescents residing near ferromanganese industry, a source of airborne metals emissions. METHODS: We measured manganese (Mn), lead (Pb), copper (Cu), and chromium (Cr) in hair, blood, urine, nails, and saliva from 635 Italian adolescents 10–14 years of age. Full-scale, verbal, and performance intelligence quotient (FSIQ, VIQ, PIQ) scores were assessed using the Wechsler Intelligence Scale for Children-III. Multivariable linear regression and Bayesian kernel machine regression (BKMR) were used to estimate associations of the metal mixture with IQ. In secondary analyses, we used BKMR’s hierarchical variable selection option to inform biomarker selection for Mn, Cu, and Cr. RESULTS: Median metal concentrations were as follows: hair Mn, 0.08 µg/g; hair Cu, 9.6 µg/g; hair Cr, 0.05 µg/g; and blood Pb, 1.3 µg/dL. Adjusted models revealed an inverted U-shaped association between hair Cu and VIQ, consistent with Cu as an essential nutrient that is neurotoxic in excess. At low levels of hair Cu (10th percentile, 5.4 µg/g), higher concentrations (90th percentiles) of the mixture of Mn, Pb, and Cr (0.3 µg/g, 2.6 µg/dL, and 0.1 µg/g, respectively) were associated with a 2.9 (95% CI: -5.2, -0.5)–point decrease in VIQ score, compared with median concentrations of the mixture. There was suggestive evidence of interaction between Mn and Cu. In secondary analyses, saliva Mn, hair Cu, and saliva Cr were selected as the biomarkers most strongly associated with VIQ score DISCUSSION: Higher adolescent levels of Mn, Pb, and Cr were associated with lower IQ scores, especially at low Cu levels. Findings also support further investigation into Cu as both beneficial and toxic for neurobehavioral outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pediatric lead (Pb) exposure impacts cognitive function and behavior and co-exposure to manganese (Mn) may enhance neurotoxicity. Objectives: To assess cognitive and behavioral function in adolescents with environmental exposure to Pb and Mn. Methods: In this cross sectional study, cognitive function and behavior were examined in healthy adolescents with environmental exposure to metals. The Wechsler Intelligence Scale for Children (WISC) and the Conners-Wells’ Adolescent Self-Report Scale Long Form (CASS:L) were used to assess cognitive and behavioral function, respectively. ALAD polymorphisms rs1800435 and rs1139488 were measured as potential modifiers. Results: We examined 299 adolescents (49.2% females) aged 11–14 years. Blood lead (BPb) averaged 1.71μg/dL (median 1.5, range 0.44–10.2), mean Blood Manganese (BMn) was 11.1μg/dL (median 10.9, range 4.00–24.1). Average total IQ was 106.3 (verbal IQ=102, performance IQ=109.3). According to a multiple regression model considering the effect of other covariates, a reduction of about 2.4 IQ points resulted from a two-fold increase of BPb. The Benchmark Level of BPb associated with a loss of 1 IQ-point (BML01) was 0.19μg/dL, with a lower 95% confidence limit (BMLL01) of 0.11μg/dL. A very weak correlation resulted between BPb and the ADHD-like behavior (Kendall''s tau rank correlation=0.074, p=0.07). No influence of ALAD genotype was observed on any outcome. Manganese was not associated with cognitive and behavioral outcomes, nor was there any interaction with lead. Conclusions: These findings demonstrate that very low level of lead exposure has a significant negative impact on cognitive function in adolescent children. Being an essential micro-nutrient, manganese may not cause cognitive effects at these low exposure levels. [Copyright &y& Elsevier]

Abstract: Background and objective: Increased prevalence of Parkinsonism was observed in Valcamonica, Italy, a region impacted by ferroalloy plants emissions containing manganese and other metals for a century until 2001. The aim of this study was to assess neurobehavioral functions in adolescents from the impacted region and the reference area of Garda Lake. Methods: Adolescents age 11–14 years were recruited through the school system for neuro-behavioral testing. Metals including manganese, lead, iron, zinc, copper were measured in airborne particulate matter collected with 24-h personal samplers, and in soil, tap water, blood, urine and hair. Independent variables included parental education and socio-economic status, children''s body mass index, number of siblings, parity order, smoking and drinking habits. Results: A total of 311 subjects (49.2% females), residing in either the exposed (n =154) or the reference (n =157) area participated. Average airborne and soil manganese were respectively 49.5ng/m3 (median 31.4, range 1.24–517) and 958ppm (median 897, range 465–1729) in the impacted area, and 27.4ng/m3 (median 24.7, range 5.3–85.9) ng/m3 and 427ppm (median 409 range 160–734) in the reference area. Regression models showed significant impairment of motor coordination (Luria-Nebraska test, p =0.0005), hand dexterity (Aiming Pursuit test, p =0.0115) and odor identification (Sniffin’ task, p =0.003) associated with soil manganese. Tremor intensity was positively associated with blood (p =0.005) and hair (p =0.01) manganese. Conclusion: Historical environmental exposure to manganese from ferroalloy emission reflected by the concentration in soil and the biomarkers was associated with sub-clinical deficits in olfactory and motor function among adolescents. [Copyright &y& Elsevier]

Background: Metal exposures can adversely impact olfactory function. Few studies have examined this association in children. Further, metal exposure occurs as a mixture, yet previous studies of metal-associated olfactory dysfunction only examined individual metals. Preventing olfactory dysfunctions can improve quality of life and prevent neurodegenerative diseases with long-term health implications., Objective: We aimed to test the association between exposure to a mixture of 12 metals measured in environmental sources and olfactory function among children and adolescents residing in the industrialized province of Brescia, Italy., Methods: We enrolled 130 children between 6 and 13 years old (51.5% females) and used the "Sniffin' Sticks" test to measure olfactory performance in identifying smells. We used a portable X-ray fluorescence instrument to determine concentrations of metals (arsenic (As), calcium, cadmium (Cd), chromium, copper, iron, manganese, lead (Pb), antimony, titanium, vanadium and zinc) in outdoor and indoor deposited dust and soil samples collected from participants' households. We used an extension of weighted quantile sum (WQS) regression to test the association between exposure to metal mixtures in multiple environmental media and olfactory function adjusting for age, sex, socio-economic status, intelligence quotient and parents' smoking status., Results: A higher multi-source mixture was significantly associated with a reduced Sniffin' Sticks identification score (β = -0.228; 95% CI -0.433, -0.020). Indoor dust concentrations of Pb, Cd and As provided the strongest contributions to this association (13.8%, 13.3% and 10.1%, respectively). The metal mixture in indoor dust contributed more (for 8 metals out of 12) to the association between metals and olfactory function compared to soil or outdoor dust., Impact Statement: Among a mixture of 12 metals measured in three different environmental sources (soil, outdoor and indoor dust), we identified Pb, Cd and As measured in indoor dust as the main contributors to reduced olfactory function in children and adolescents residing in an industrialized area. Exposure to indoor pollution can be effectively reduced through individual and public health interventions allowing to prevent the deterioration of olfactory functions. Moreover, the identification of the factors that can deteriorate olfactory functions can be a helpful instrument to improve quality of life and prevent neurodegenerative diseases as long-term health implications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Externalizing disorders, such as attention-deficit/hyperactivity disorder (ADHD), account for the majority of the child/adolescent referrals to mental health services and increase risk for later-life psychopathology. Although the expression of externalizing disorders is more common among males, few studies have addressed how sex modifies associations between metal exposure and adolescent externalizing symptoms. This study aimed to examine sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood. Among 150 adolescents and young adults (55% female, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study in Brescia, Italy, we measured five metals (manganese (Mn), lead (Pb), copper (Cu), chromium (Cr), nickel (Ni)) in four biological matrices (blood, urine, hair, and saliva). Externalizing symptoms were assessed using the Achenbach System of Empirically Based Assessment (ASEBA) Youth Self-Report (YSR) or Adult Self Report (ASR). Using generalized weighted quantile sum (WQS) regression, we investigated the moderating effect of sex (i.e., assigned at birth) on associations between the joint effect of exposure to the metal mixture and externalizing symptoms, adjusting for age and socioeconomic status. We observed that metal mixture exposure was differentially associated with aggressive behavior in males compared to females (β = -0.058, 95% CI [-0.126, -0.009]). In males, exposure was significantly associated with more externalizing problems, and aggressive and intrusive behaviors, driven by Pb, Cu and Cr. In females, exposure was not significantly associated with any externalizing symptoms. These findings suggest that the effect of metal exposure on externalizing symptoms differs in magnitude between the sexes, with males being more vulnerable to increased externalizing symptoms following metal exposure. Furthermore, our findings support the hypothesis that sex-specific vulnerabilities to mixed metal exposure during adolescence/young adulthood may play a role in sex disparities observed in mental health disorders, particularly those characterized by externalizing symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Biomarker concentrations of metals are associated with neurodevelopment, and these associations may be modified by nutritional status (e.g., iron deficiency). No prior study on associations of metal mixtures with neurodevelopment has assessed effect modification by iron status., Objectives: We aimed to quantify associations of an industry-relevant metal mixture with verbal learning and memory among adolescents, and to investigate the modifying role of iron status on those associations., Methods: We used cross-sectional data from 383 Italian adolescents (10-14 years) living in proximity to ferroalloy industry. Verbal learning and memory was assessed using the California Verbal Learning Test for Children (CVLT-C), and metals were quantified in hair (manganese, copper, chromium) or blood (lead) using inductively coupled plasma mass spectrometry. Serum ferritin, a proxy for iron status, was measured using immunoassays. Covariate-adjusted associations of the metal mixture with CVLT subtests were estimated using Bayesian Kernel Machine Regression, and modification of the mixture associations by ferritin was examined., Results: Compared to the 50th percentile of the metal mixture, the 90th percentile was associated with a 0.12 standard deviation [SD] (95% CI = -0.27, 0.50), 0.16 SD (95% CI = -0.11, 0.44), and 0.11 SD (95% CI = -0.20, 0.43) increase in the number of words recalled for trial 5, long delay free, and long delay cued recall, respectively. For an increase from its 25th to 75th percentiles, copper was beneficially associated the recall trials when other metals were fixed at their 50th percentiles (for example, trial 5 recall: β = 0.31, 95% CI = 0.14, 0.48). The association between copper and trial 5 recall was stronger at the 75th percentile of ferritin, compared to the 25th or 50th percentiles., Conclusions: In this metal mixture, copper was beneficially associated with neurodevelopment, which was more apparent at higher ferritin concentrations. These findings suggest that metal associations with neurodevelopment may depend on iron status, which has important public health implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Understanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition., Objective: We sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers., Methods: Deciduous teeth were collected from 195 participants (ages 10-14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation - birth), early postnatal (birth - 1.5 years) and childhood (∼1.5 - 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models., Results: Adjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: β = 0.20 (95 % CI: 0.02, 0.38)] and Block design [β = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [β = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [β = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure., Conclusion: Our results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Every day humans are exposed to mixtures of chemicals, such as lead (Pb) and manganese (Mn). An underappreciated aspect of studying the health effects of mixtures is the role that the exposure biomarker media (blood, hair, etc.) may play in estimating the effects of the mixture. Different biomarker media represent different aspects of each chemical's toxicokinetics, thus no single medium can fully capture the toxicokinetic profile for all the chemicals in a mixture. A potential solution to this problem is to combine exposure data across different media to derive integrated estimates of each chemical's internal concentration. This concept, formalized as a multi-media biomarker (MMB) has proven effective for estimating the health impacts of Pb exposure, but may also be useful to estimate mixture effects, such as the joint effects of metals like Pb and Mn, while factoring in how the association changes based upon the biomarker media. Levels of Pb and Mn were quantified in five media: blood, hair, nails, urine, and saliva in the Public Health Impact of Metals Exposure (PHIME) project, a study of Italian adolescents aged 10-14 years. MMBs were derived for both metals using weighted quantile sum (WQS) regression across the five media. Age-adjusted Wechsler Intelligence Scale for Children (WISC) IQ scores, measured at the same time as the exposure measures, were the primary outcome and models were adjusted for sex and socioeconomic status. The levels Pb and Mn were relatively low, with median blood Pb of 1.27 (IQR: 0.84) μg/dL and median blood Mn of 1.09 (IQR: 0.45) μg/dL. Quartile increases in a Pb-Mn combination predicted decreased Full Scale IQ of 1.9 points (95% CI: 0.3, 3.5) when Pb and Mn exposure levels were estimated using MMBs, while individual regressions for each metal were not associated with Full Scale IQ. Additionally, a quartile increase in the WQS index of Pb and Mn, measured using MMBs, were associated with reductions in Verbal IQ by 2.8 points (1.0, 4.5). Weights that determine the contributions of the metals to the joint effect highlighted that the contribution of the Pb-Mn was 72-28% for Full Scale IQ and 42-58% for Verbal IQ. We found that the joint effects of Pb and Mn are strongly affected by the medium used to measure exposure and that the joint effects of the Pb and Mn MMBs on cognition were the stronger than any individual biomarker. Thus, increase power and accuracy for measuring mixture effects compared to individual biomarkers. As the number of chemicals in mixtures increases, appropriate biomarker selection will become increasingly important and MMBs are a natural way to reduce bias in such analyses., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Exposure assessment traditionally relies on biomarkers that measure chemical concentrations in individual biological media (i.e., blood, urine, etc.). However, chemicals distribute unevenly among different biological media; thus, each medium provides incomplete information about body burden. We propose that machine learning and statistical approaches can create integrated exposure estimates from multiple biomarker matrices that better represent the overall body burden, which we term multi-media biomarkers (MMBs). We measured lead (Pb) in blood, urine, hair and nails from 251 Italian adolescents aged 11-14 years from the Public Health Impact of Metals Exposure (PHIME) cohort. We derived aggregated MMBs from the four biomarkers and then tested their association with Wechsler Intelligence Scale for Children (WISC) IQ scores. We used three approaches to derive the Pb MMB: one supervised learning technique, weighted quantile sum regression (WQS), and two unsupervised learning techniques, independent component analysis (ICA) and non-negative matrix factorization (NMF). Overall, the Pb MMB derived using WQS was most consistently associated with IQ scores and was the only method to be statistically significant for Verbal IQ, Performance IQ and Total IQ. A one standard deviation increase in the WQS MMB was associated with lower Verbal IQ (β [95% CI] = -2.2 points [-3.7, -0.6]), Performance IQ (-1.9 points [-3.5, -0.4]) and Total IQ (-2.1 points [-3.8, -0.5]). Blood Pb was negatively associated with only Verbal IQ, with a one standard deviation increase in blood Pb being associated with a -1.7 point (95% CI: [-3.3, -0.1]) decrease in Verbal IQ. Increases of one standard deviation in the ICA MMB were associated with lower Verbal IQ (-1.7 points [-3.3, -0.1]) and lower Total IQ (-1.7 points [-3.3, -0.1]). Similarly, an increase of one standard deviation in the NMF MMB was associated with lower Verbal IQ (-1.8 points [-3.4, -0.2]) and lower Total IQ (-1.8 points [-3.4, -0.2]). Weights highlighting the contributions of each medium to the MMB revealed that blood Pb was the largest contributor to most MMBs, although the weights varied from more than 80% for the ICA and NMF MMBs to between 30% and 54% for the WQS-derived MMBs. Our results suggest that MMBs better reflect the total body burden of a chemical that may be acting on target organs than individual biomarkers. Estimating MMBs improved our ability to estimate the full impact of Pb on IQ. Compared with individual Pb biomarkers, including blood, a Pb MMB derived using WQS was more strongly associated with IQ scores. MMBs may increase statistical power when the choice of exposure medium is unclear or when the sample size is small. Future work will need to validate these methods in other cohorts and for other chemicals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Maturational processes in the developing brain are disrupted by exposure to environmental toxicants, setting the stage for deviant developmental trajectories. Manganese (Mn) is an essential nutrient that is neurotoxic at high levels of exposure, particularly affecting the basal ganglia and prefrontal cortex. Both the intensity and timing of exposure matter; deciduous teeth can be used to retrospectively and objectively determine early-life windows of vulnerability. The aim of this pilot study was to examine associations between prenatal, early postnatal and childhood dentine Mn concentrations and intrinsic functional connectivity (iFC) of adolescents' brains. 14 adolescents (12-18 years; 6 girls) from northern Italian regions with either current, historic or no Mn contamination, completed a 10-minute resting state functional Magnetic Resonance Imaging (MRI) scan in an 1.5T MRI scanner. We estimated prenatal, early postnatal and childhood Mn concentrations in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. We performed seed-based correlation analyses, focusing on six subcortical seeds (left and right caudate, putamen, pallidum) and one cortical seed (bilateral middle frontal gyrus) from Harvard-Oxford atlases. We examined linear and quadratic correlations between log-transformed Mn concentrations and seed-based iFC (Bonferroni-corrected p<0.0023), controlling for either socio-economic status, sex or age. Dentine Mn concentrations (Mn:Calcium ratio) were highest during the prenatal period (median = 0.48) and significantly declined during the early postnatal (median = 0.14) and childhood periods (median = 0.006). Postnatal Mn concentrations were associated with: 1) increased iFC between the middle frontal gyrus and medial prefrontal cortex; 2) decreased iFC between the right putamen and pre- and postcentral gyrus. Together, these findings suggest that early postnatal Mn concentrations are associated with increased iFC within cognitive control brain areas, but decreased iFC between motor areas in adolescents. Future studies should replicate these findings in larger samples, and link brain connectivity measures to cognitive and motor outcomes., Competing Interests: The authors have declared that no competing interests exist.

Evidence suggests that environmental exposures and socioeconomic factors may interact to produce metabolic changes in children. We assessed the influence of residential location and socioeconomic status (SES) on pediatric body mass index (BMI) Z-score and fasting blood glucose (FBG) concentration. Participants included 214 children aged 6-11 years who live near a large industrial complex in Taranto, Italy. Participants were grouped into residential zones based on the distance between their home address and the complex periphery (Zone 1: 0.000-4.999 km, Zone 2: 5.000-9.999 km, Zone 3: 10.000-15.000 km). BMI Z-scores were calculated via World Health Organization (WHO) pediatric reference curves. FBG was obtained via venous blood sampling. Closer residential location to the industrial complex on the order of 5.000 km was significantly associated with worsened metabolic outcomes, particularly in female children. Zone 1 participants had higher BMI-adjusted FBG than Zone 2 and 3 participants ( p < 0.05 versus Zone 2; p < 0.01 versus Zone 3). SES did not significantly influence BMI-adjusted FBG. Moreover, BMI Z-scores indicated high rates of overweight (22.0%) and obesity (22.9%) in the cohort. BMI Z-score was not significantly associated with SES or residential zone but was negatively associated with maternal education level ( p < 0.05). These results offer new evidence that residing near industrial activity may predict adverse effects on child metabolic health.

Background: 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., Methods: 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)., Results: 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., Conclusion: 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Comparisons between animal and human neurotoxicology studies are a foundation of risk assessment, but are hindered by differences in measured behaviors. The radial arm maze (RAM), a rodent visuospatial learning and memory task, has a computerized version for use in children, which may help improve comparisons between animal and human studies., Objective: To describe the characteristics and correlates of the virtual radial arm maze (VRAM) in 255 children age 10-15 years from Italy., Methods: We administered the VRAM using a laptop computer and measured children's performance using the latency, distance, and working/reference memory errors during eight trials. Using generalized linear mixed models, we described VRAM performance in relation to demographic factors, child activities, and several standard neuropsychologic tests (Italian translations), including the Conners Parent Rating Scales-Short Version (CPRS), California Verbal Learning Test (CVLT), Wechsler Intelligence Scales for Children, finger tapping speed, reaction time, and motor skills., Results: Children's VRAM performance tended to improve between trials 1 and 6 and then plateaued between trials 6 and 8. Males finished the task 14 s faster (95% confidence interval [CI]: -20, -9) than females. Children who played 2+h of video games per day finished 16 s faster (CI: -26, -6) and with 34% (CI: 5, 54%) fewer working memory errors than children who reported not playing video games. Higher IQ and better CVLT scores were associated with better VRAM performance. Higher cognitive/inattention CPRS scores were associated with more working (11%; CI: 1, 22) and reference memory errors (7%; CI: 1, 12)., Conclusions: Consistent with animal studies, VRAM performance improved over the course of test trials and males performed better than females. Better VRAM performance was related to higher IQ, fewer inattentive behaviors, and better verbal memory. The VRAM may help to improve the integration and comparison between animal and epidemiological studies of environmental neurotoxicants., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Studies have reported associations between manganese (Mn) exposures and Mn levels in blood and urine, though the suitability of these biological measures as biomarkers of exposure is not well known., Methods: We evaluated whether whole blood, plasma, and urine Mn levels reflect exposures in occupationally exposed humans., Results: In active ferroalloy workers, blood Mn was associated with total air Mn levels in subjects currently exposed to low (median = 0.42 microg/m(3), P = 0.009) and moderate (median = 4.2 microg/m(3), P = 0.007) air Mn levels, but not in workers exposed to the highest Mn levels (median = 292 microg/m(3), P = 0.31). In bridge welders blood Mn (P < 0.01), but not plasma or urine Mn was significantly associated with their cumulative respiratory exposure index. In welders, approximately 6% (range approximately 3-9%) of whole blood Mn was contained in the plasma fraction, though there was no association between whole blood and plasma Mn levels (Pearson's R = 0.258, P = 0.12). In contrast, in fresh whole blood samples spiked with Mn ex vivo approximately 80% or more of added Mn partitioned in the plasma, while only approximately 20% or less partitioned in the cellular fraction., Conclusions: These data suggest a complex and limited relationship between exposure and blood Mn levels that may depend upon exposure attributes and the latency of blood sampling relative to exposure; plasma and urine Mn appear to be of little utility as exposure biomarkers. This underscores the need to fully characterize and validate these or other biomarkers for use in constructing appropriate exposure metrics and determining exposure-effect relationships., ((c) 2007 Wiley-Liss, Inc.)