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Background: Pyrethroid insecticides are used both residentially and agriculturally and their toxicity targets the nervous system of insects. They might also interfere with development and function of the human brain. A few epidemiological studies suggest that exposure to pyrethroids may be associated with neurobehavioral problems in children but there is little data on potential associations with cognitive outcomes. Furthermore, many studies showed that the neurotoxic effects of several pesticides are modified by sex, hence, considerations of potential sex-differences are important to investigate., Objective: To study the cross-sectional association between urinary levels of pyrethroid metabolites and neurodevelopment, including neurobehavioral and cognitive outcomes, in preschool-age children, and to examine whether sex might modify these associations., Methods: We used data from a follow-up examination of the Maternal-Infant Research on Environmental Chemicals (MIREC), the MIREC Child Development study (MIREC-CD Plus) on children at age 3-4 years living in 6 Canadian cities. For each participant, we collected a urine sample for measurements of pyrethroids metabolites (cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA, 4-F-3-PBA). We assessed neurodevelopment with the Wechsler Primary and Preschool Scale of Intelligence-III (WPPSI-III) and two scales of the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). Parents reported children's behavior using the Behavior Assessment System for Children-2 (BASC-2) and the Social Responsiveness Scale-2 (SRS-2). We examined associations between children's urinary pyrethroid metabolite concentrations and neurodevelopmental scores with multiple linear regression models, adjusting for confounders, in boys and girls separately., Results: The study included 179 children (mean age: 3.2 y, range 2.8-4.0). The detection frequencies were high for most pyrethroid metabolites (83-100%), but lower for 4-F-3-PBA (36%). Higher concentrations of cis-DBCA were significantly associated with lower verbal, performance and full-scale IQ scores in boys (e.g., for a 2-fold increase in cis-DBCA, β = -2.0; 95% CI: -3.4, -0.6 for full-scale IQ). In girls, the only metabolite associated with cognitive scores was 3-PBA, which was associated with lower verbal IQ scores (β = -1.3, 95% CI: -2.6, -0.1). For neurobehavioral outcomes in boys, there were associations between poorer BASC-2 Adaptive Skills scores with higher concentrations of cis-DCCA (β = -1.6, 95% CI: -2.3, -0.9), trans-DCCA (β = -1.5, 95% CI: -2.2, -0.8), 3-PBA (β = -1.7, 95% CI: -2.5, -0.9), and sum of pyrethroid metabolites (β = -1.8, 95% CI: -2.6, -0.9). In girls, we observed a significant association between higher concentration of cis-DCCA and better BASC-2 Adaptive Skills score (β = 1.0; 95% CI, 0.2, 1.8), but not with other urinary pyrethroids metabolites. Scores on the SRS-2 and BRIEF-P were not associated with pyrethroid metabolites., Conclusion: There were associations between some pyrethroid pesticide metabolites and indicators of neurodevelopmental disorder, especially among boys. These associations are in agreement with previous studies and could suggest that exposure to pyrethroid pesticides represents a risk of potential toxicity for the cognitive development of children, and a risk for behavioral development. However, the cross-sectional nature of this study limits causal inferences., 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 B.V. All rights reserved.)

Background: Manganese (Mn) is an element found in the environment and certain geographic areas have elevated concentrations in soil and water du to natural conditions or anthropic activities. A growing body of data suggests that exposure to manganese in drinking water could be neurotoxic., Objective: Firstly, we aimed to examine the association between exposure to manganese from drinking water and cognition in children consuming well water. Secondly, we also aimed to examine the relation between cognition and manganese concentrations in children's hair, nail, and saliva., Methods: A total 259 children from 189 households consuming well water were included in the present study (ages 5.9 to 13.7 years). We assessed children's cognition with the WISC-IV, and we used five indicators of manganese exposure: concentration in tap water, intake from the consumption of water divided by child's weight, manganese concentration in children's hair, toe nail, and saliva. We used General Estimating Equation analysis to assess the relation between manganese exposure indicators and IQ scores, adjusting for potential confounders, and taking into account family clusters., Results: Drinking water manganese concentrations were generally low, with 48% of children consuming water <5μg/L, 25% >50μg/L, and 4% >400μg/L. Results differed by sex. In girls, higher manganese concentration in water, hair, and toe nail were associated with poorer Performance IQ scores but this was significant only for toe nail (for a 10-fold increase in manganese, β: -5.65, 95% CIs: -10.97, -0.32). Opposite associations were observed in boys, i.e., better Performance IQ scores with higher manganese concentration hair, toe nail, and water, the latter being significant (β: 2.66, 95% CIs: 0.44, 4.89). Verbal IQ scores did not seem to be associated with manganese exposure indicators., Conclusions: Drinking water manganese levels were considerably lower than in previous studies reporting neurotoxic effects. There was no clear indication of an association between exposure to manganese and cognitive development in this sample of school-age children although the data suggest there might be sex-specific associations. Given the low levels of exposure and sex-specific associations, a larger sample size would have been required to increase the statistical power and better characterize the relations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Manganese is commonly found in water but potential neurotoxic effects from exposure through drinking water are poorly understood. We previously reported a cross-sectional study showing that drinking water Mn concentration was associated with lower IQ in children aged 6 to 13 years., Objective: For this follow-up study, we aimed to re-assess the relation between exposure to Mn from drinking water and IQ at adolescence. In addition, we aimed to examine whether changes in drinking water Mn concentration was associated with changes in IQ scores., Methods: From the 380 children enrolled in the baseline study, 287 participated to this follow-up study conducted in average 4.4 years after. Mn concentration was measured in home tap water and children's hair. The relationships between these Mn exposure indicators and IQ scores (Weschsler Abbreviated Scale of Intelligence) at follow-up were assessed with linear regression analysis, adjusting for potential confounders. Intra-individual differences in IQ scores between the two examinations were compared for children whose Mn concentration in water remained stable between examinations, increased or decreased., Results: The mean age at follow-up was 13.7 years (range, 10.5 to 18.0 years). Geometric mean of Mn concentration in water at follow-up was 14.5μg/L. Higher Mn concentration in water measured at follow-up was associated with lower Performance IQ in girls (β for a 10-fold increase=-2.8, 95% confidence intervals [CI] -4.8 to -0.8) and higher Performance IQ in boys (β=3.9, 95% CI 1.4 to 6.4). IQ scores were not significantly associated with Mn concentration in hair, although similar trends as for concentration in water were observed. For children whose Mn concentration in water increased between baseline and follow-up, Performance IQ scores decreased significantly (intra-individual difference, -2.4 points)., Conclusion: Higher levels of Mn in drinking water were associated with lower Performance IQ in girls, whereas the opposite was observed in boys. These findings suggest long-term exposure to Mn through drinking water is associated differently with cognition in boys and girls., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We evaluated hair, toenails, and saliva (whole and supernatant) as biomarkers of exposure to manganese (Mn) in 274 school age children (6-13 years) consuming well water in southeastern New Brunswick, Canada. Mn concentrations in tap water ranged from <0.03 to 1046μgL -1 (geometric mean 5.96μgL -1 ). The geometric mean of Mn intake resulting from the consumption of water was 0.25 (0-34.95) μg kg -1 day -1 . Both Mn concentration in water and Mn intake were significantly correlated with Mn in hair (r=0.60 and r=0.53, respectively), Mn in toenail (r=0.29 and r=0.37 respectively) and to a lesser extent with Mn in saliva supernatant (r=0.14 and r=0.18, respectively). Mn in whole saliva did not correlate with Mn in water or Mn intake. Both Mn in hair and Mn in toenail allowed to discriminate the most exposed group from the least exposed group, based on Mn in water and Mn intake from water. In this group of children with low level Mn exposure, Mn concentrations in hair, and toenails reflected reasonably well Mn exposure from drinking water, whereas Mn content in saliva correlated less strongly., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Manganese (Mn) can have neurotoxic effects upon overexposure. We previously reported poorer cognitive and motor development in children exposed to Mn through drinking water, suggesting possible neurotoxic effects from Mn in water. Hyperintensity in the globus pallidus (GP) on T1-weighted magnetic resonance imaging (MRI) indicates excessive brain Mn accumulation. Previous studies have reported GP hyperintensity related to Mn exposure in occupationally exposed individuals. However, no study has used MRI in children exposed to Mn in drinking water and who show no sign of overt intoxication., Objective: To examine MRI signal intensity in the GP in children exposed to contrasted levels of Mn in drinking water., Methods: We enrolled 13 children exposed to low Mn concentration in water and 10 children (ages 9-15 years) with high concentration (median of 1 and 145μg/L, respectively). We calculated three MRI T1 indexes: (i) standard pallidal index (PI) using frontal white matter as reference; (ii) PI using pericranial muscles as reference; and (iii) T1 relaxation time. Each MRI index was compared between exposure groups, and with respect to the estimated Mn intake from water consumption., Results: The standard PI did not differ between Mn-exposure groups. However, children in the group with high water-Mn concentration had significantly lower pericranial muscles PI than those with lower exposure and, accordingly, higher T1 relaxation time. Mn intake from water consumption was not correlated with the standard PI, but was significantly related to the pericranial muscles PI and T1 relaxation time. Motor performance was significantly lower in the high-exposure group., Conclusion: We observed lower signal intensity in the GP of children with higher exposure to Mn from drinking water. This result stands in contrast to previous MRI reports showing GP hyperintensity with greater Mn exposure. Differences in exposure pathways are discussed as a potential explanation for this discrepancy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The appropriate exposure metrics for characterizing manganese (Mn) exposure associated with neurobehavioral effects have not been established. Blood levels of Mn (B-Mn) provide a potentially important intermediate marker of Mn airborne exposures. Using data from a study of a population of silicon- and ferro-manganese alloy production workers employed between 1973 and 1991, B-Mn levels were modeled in relation to prior Mn exposure using detailed work histories and estimated respirable Mn concentrations from air-sampling records. Despite wide variation in exposure levels estimated for individual jobs, duration of employment (exposure) was itself a strong predictor of B-Mn levels and strongest when an 80-day half-life was applied to contributions over time (t=6.95, 7.44, respectively; p<10(-5)). Partitioning exposure concentrations based on process origin into two categories: (1) "large" respirable particulate (Mn-LRP) derived mainly from mechanically generated dust, and (2) "small" respirable particulate (Mn-SRP) primarily electric furnace condensation fume, revealed that B-Mn levels largely track the small, fume exposures. With a half-life of 65 days applied in a model with cumulative exposure terms for both Mn-LRP (t=-0.16, p=0.87) and Mn-SRP (t=6.45, p<10(-5)), the contribution of the large-size fraction contribution was negligible. Constructing metrics based on the square root of SRP exposure concentrations produced a better model fit (t=7.87 vs. 7.44, R(2)=0.2333 vs. 0.2157). In a model containing both duration (t=0.79, p=0.43) and (square root) fume (t=2.47, p=0.01) metrics, the duration term was a weak contributor. Furnace-derived, small respirable Mn particulate appears to be the primary contributor to B-Mn levels, with a dose-rate dependence in a population chronically exposed to Mn, with air-concentrations declining in recent years. These observations may reflect the presence of homeostatic control of Mn levels in the blood and other body tissues and be useful in assessing Mn exposures for evaluating neurotoxic effects., (Published by Elsevier B.V.)

The progression of manganism with chronic exposure to airborne manganese (Mn) is not well understood. Here, we further investigate the findings on exposure and neurobehavioral outcomes of workers from a silico- and ferromanganese production plant and non-exposed workers from the same community in 1990 and 2004, using a variety of exposure metrics that distinguish particle size and origin within the range of respirable airborne exposures. Mn exposure matrices for large respirable particulate (Mn-LRP, dust) and small respirable particulate (Mn-SRP, fume), based on process origins, were used together with detailed work histories since 1973 (plant opening), to construct exposure metrics including burdens and cumulative burdens with various clearance half-lives. For three out of eight 1990 neurobehavioral tests analyzed with linear regression models, duration of Mn exposure was the best predictor: Luria-Nebraska Neuropsychological Battery - Motor Scale, Trail-Making B and Finger Tapping. The Luria-Nebraska Motor Scale had the strongest association (t ∼ 5.0, p < 10(-6)). For outcomes on three other tests, the duration and Mn-SRP metrics were comparable: Trail Making Test A, Cancellation H and Stroop Color-Word Test (color/word subtest). Delayed Word Recall was best predicted by Mn-SRP (based on square root or truncated air-concentrations). The Word score on the Stroop Color-Word Test was the only outcome for which Mn-LRP was the leading predictor (t = -2.92, p = 0.003), while performance on the WAIS-R Digit Span Test was not significantly predicted by any metric. For outcomes evaluated in both 1990 and 2004, a mixed-effect linear regression model was used to examine estimates of within-individual trends. Duration and Mn-SRP were associated with performance on the Luria-Nebraska Motor Scale, as well as with other outcomes that appeared to have both reversible and progressive features, including Trail Making A and B, Cancellation H and Delayed Word Recall. With the mixed-effect model, Digit Span exhibited a significant irreversible association with exposure duration (t = -2.34, p = 0.021) and Mn-SRP (square root; t = -2.38, p = 0.019) metrics. The strong prediction using duration of exposure is consistent with effective homeostatic regulation of tissue-level Mn in the observed exposure range of respirable Mn (< 0.2mg/m(3))., (Copyright © 2014. Published by Elsevier B.V.)

The association between pesticide exposure and neurobehavioral and neurodevelopmental effects is an area of increasing concern. This symposium brought together participants to explore the neurotoxic effects of pesticides across the lifespan. Endpoints examined included neurobehavioral, affective and neurodevelopmental outcomes among occupational (both adolescent and adult workers) and non-occupational populations (children). The symposium discussion highlighted many challenges for researchers concerned with the prevention of neurotoxic illness due to pesticides and generated a number of directions for further research and policy interventions for the protection of human health, highlighting the importance of examining potential long-term effects across the lifespan arising from early adolescent, childhood or prenatal exposure., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This symposium comprised five oral presentations dealing with recent findings on Mn-related cognitive and motor changes from epidemiological studies across the life span. The first contribution highlighted the usefulness of functional neuroimaging of the central nervous system (CNS) to evaluate cognitive as well as motor deficits in Mn-exposed welders. The second dealt with results of two prospective studies in Mn-exposed workers or welders showing that after decrease of Mn exposure the outcome of reversibility in adverse CNS effects may differ for motor and cognitive function and, in addition the issue of plasma Mn as a reliable biomarker for Mn exposure in welders has been addressed. The third presentation showed a brief overview of the results of an ongoing study assessing the relationship between environmental airborne Mn exposure and neurological or neuropsychological effects in adult Ohio residents living near a Mn point source. The fourth paper focused on the association between blood Mn and neurodevelopment in early childhood which seems to be sensitive to both low and high Mn concentrations. The fifth contribution gave an overview of six studies indicating a negative impact of excess environmental Mn exposure from air and drinking water on children's cognitive performance, with special attention to hair Mn as a potential biomarker of exposure. These studies highlight a series of questions about Mn neurotoxicity with respect to cognitive processes, forms and routes of exposure, adequate biomarkers of exposure, gender differences, susceptibility and exposure limits with regard to age., (Copyright © 2012 Elsevier Inc. All rights reserved.)