Associations of a Metal Mixture Measured in Multiple Biomarkers with IQ: Evidence from Italian Adolescents Living near Ferroalloy Industry.

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, 0.08µg/g; hair Cu, 9.6µg/g; hair Cr, 0.05µg/g; and blood Pb, 1.3µg/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, 5.4µg/g), higher concentrations (90th percentiles) of the mixture of Mn, Pb, and Cr (0.3µg/g, 2.6µg/dL, and 0.1µg/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. https://doi.org/10.1289/EHP6803.

Proactive interception and care of Frailty and Multimorbidity in older persons: the experience of the European Innovation Partnership on Active and Healthy Ageing and the response of Parma Local Health Trust and Lab through European Projects.

According to the 2018 European Union Ageing Report, the demographic profile of the European population is projected to be older. Aging cannot be considered a homogeneous process, and only in certain cases is "successful", with maintained functional ability, which is determined by intrinsic capacity, the environment, and their interaction. When intrinsic capacity is lost, elders with chronic diseases develop frailty, a condition with high-risk of disability. Old-age dependency-ratio is projected to increase from 29.6% to 51.2% in the EU in 2070: thus, the need of new approaches targeting the prevention of disability. Numerous studies are conducted in the European Innovation Partnership on Active and Healthy Ageing and addressing identification, treatment, coordination and integration of care in frail older subjects. SUNFRAIL is aimed at developing a model, good practices and tools to improve the identification, prevention and care of frailty and management of multimorbidity. SPRINTT is testing the effectiveness of a multi-component treatment able to treat frailty and sarcopenia. VIGOUR, a project aimed at strengthening integrated-care in different contexts of European Countries, verifies enablers and obstacles encountered in the real world by these good practices. Through the creation of Parma-Lab and Frailty-Team in the Academic-Hospital of Parma combined with the contribution of Parma Health-Trust in the "Community Health-Centers", the Projects were translated into Health Services Arena. This response bridging European Studies and clinical practice, aims to early detecting and caring 75-year older citizens with frailty and multimorbidity, living in the community, not institutionalized and at risk of hospitalization and mobility ADL-disability.

Association between personal exposure to ambient metals and respiratory disease in Italian adolescents: a cross-sectional study.

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 <10 µm in diameter (PM10) was collected for 24 h in filters using personal sampling. Mn, nickel (Ni), zinc (Zn), chromium (Cr) and iron (Fe) were measured in filters using x-ray fluorescence. Data on respiratory health was collected through questionnaire. Data for 280 adolescents were analyzed using a modified Poisson regression, and risk ratios were calculated for an interquartile (IQR) range increase in each pollutant. RESULTS: In adjusted models including PM10 as a co-pollutant, we found significant associations between concentrations of Mn (RR: 1.09, 95% CI [1.00, 1.18] per 42 ng/m(3) increase), Ni (RR: 1.11, 95% CI [1.03, 1.21] per 4 ng/m(3) increase) and Cr (RR: 1.08, 95% CI [1.06, 1.11] per 9 ng/m(3) increase) and parental report of asthma. We also found significant associations between increased Mn and Ni and increased risk of asthma medication use in the past 12 months (RR: 1.13, 95% CI [1.04, 1.29] and (RR: 1.13, 95 % CI [1.01, 1.27] respectively). CONCLUSIONS: Our findings suggest that exposure to ambient Mn, Ni and Cr may be associated with adverse respiratory outcomes.

Effects of Manganese Exposure on Olfactory Functions in Teenagers: A Pilot Study.

Long-term exposure to environmental manganese (Mn) affects not only attention and neuromotor functions but also olfactory functions of a pre-adolescent local population who have spent their whole life span in contaminated areas. In order to investigate the effect of such exposure at the level of the central nervous system we set up a pilot fMRI experiment pointing at differences of brain activities between a non-exposed population (nine subjects) and an exposed one (three subjects). We also measured the volume of the olfactory bulb as well as the identification of standard olfactory stimuli. Our results suggest that young subjects exposed to Mn exhibit a reduction of BOLD signal, subjective odor sensitivity and olfactory bulb volume. Moreover a region of interest SPM analysis showed a specifically reduced response of the limbic system in relation to Mn exposure, suggesting an alteration of the brain network dealing with emotional responses.

Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese.

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.

Hair as a biomarker of environmental manganese exposure.

The absence of well-validated biomarkers of manganese (Mn) exposure in children remains a major obstacle for studies of Mn toxicity. We developed a hair cleaning methodology to establish the utility of hair as an exposure biomarker for Mn and other metals (Pb, Cr, Cu), using ICPMS, scanning electron microscopy, and laser ablation ICPMS to evaluate cleaning efficacy. Exogenous metal contamination on hair that was untreated or intentionally contaminated with dust or Mn-contaminated water was effectively removed using a cleaning method of 0.5%Triton X-100 sonication plus 1 N nitric acid sonication. This cleaning method was then used on hair samples from children (n = 121) in an ongoing study of environmental Mn exposure and related health effects. Mean hair Mn levels were 0.121 µg/g (median = 0.073 µg/g, range = 0.011-0.736 µg/g), which are ∼4 to 70-fold lower than levels reported in other pediatric Mn studies. Hair Mn levels were also significantly higher in children living in the vicinity of active, but not historic, ferroalloy plant emissions compared to controls (P < 0.001). These data show that hair can be effectively cleaned of exogenous metal contamination, and they substantiate the use of hair Mn levels as a biomarker of environmental Mn exposure in children.