Sex and adrenal hormones in association with insecticide biomarkers among adolescents living in ecuadorian agricultural communities.

BACKGROUND: Organophosphate, pyrethroid, and neonicotinoid insecticides have resulted in adrenal and gonadal hormone disruption in animal and in vitro studies; limited epidemiologic evidence exists in humans. We assessed relationships of urinary insecticide metabolite concentrations with adrenal and gonadal hormones in adolescents living in Ecuadorean agricultural communities. METHODS: In 2016, we examined 522 Ecuadorian adolescents (11-17y, 50.7% female, 22% Indigenous; ESPINA study). We measured urinary insecticide metabolites, blood acetylcholinesterase activity (AChE), and salivary testosterone, dehydroepiandrosterone (DHEA), 17ß-estradiol, and cortisol. We used general linear models to assess linear (ß = % hormone difference per 50% increase of metabolite concentration) and curvilinear relationships (ß2 = hormone difference per unit increase in squared ln-metabolite) between ln-metabolite or AChE and ln-hormone concentrations, stratified by sex, adjusting for anthropometric, demographic, and awakening response variables. Bayesian Kernel Machine Regression was used to assess non-linear associations and interactions. RESULTS: The organophosphate metabolite malathion dicarboxylic acid (MDA) had positive associations with testosterone (ßboys = 5.88% [1.21%, 10.78%], ßgirls = 4.10% [-0.02%, 8.39%]), and cortisol (ßboys = 6.06 [-0.23%, 12.75%]. Para-nitrophenol (organophosphate) had negatively-trending curvilinear associations, with testosterone (ß2boys = -0.17 (-0.33, -0.003), p = 0.04) and DHEA (ß2boys = -0.49 (-0.80, -0.19), p = 0.001) in boys. The neonicotinoid summary score (ßboys = 5.60% [0.14%, 11.36%]) and the neonicotinoid acetamiprid-N-desmethyl (ßboys = 3.90% [1.28%, 6.58%]) were positively associated with 17ß-estradiol, measured in boys only. No associations between the pyrethroid 3-phenoxybenzoic acid and hormones were observed. In girls, bivariate response associations identified interactions of MDA, Para-nitrophenol, and 3,5,6-trichloro-2-pyridinol (organophosphates) with testosterone and DHEA concentrations. In boys, we observed an interaction of MDA and Para-nitrophenol with DHEA. No associations were identified for AChE. CONCLUSIONS: We observed evidence of endocrine disruption for specific organophosphate and neonicotinoid metabolite exposures in adolescents. Urinary organophosphate metabolites were associated with testosterone and DHEA concentrations, with stronger associations in boys than girls. Urinary neonicotinoids were positively associated with 17ß-estradiol. Longitudinal repeat-measures analyses would be beneficial for causal inference.

Triangulation of epidemiological evidence and risk of bias evaluation: A proposed framework and applied example using formaldehyde exposure and risk of myeloid leukemias.

Evidence triangulation may help identify the impact of study design elements on study findings and to tease out biased results when evaluating potential causal relationships; however, methods for triangulating epidemiologic evidence are evolving and have not been standardized. Building upon key principles of epidemiologic evidence triangulation and risk of bias assessment, and responding to the National Academies of Sciences, Engineering, and Medicine (NASEM) call for applied triangulation examples, the objective of this manuscript is to propose a triangulation framework and to apply it as an illustrative example to epidemiologic studies examining the possible relationship between occupational formaldehyde exposure and risk of myeloid leukemias (ML) including acute (AML) and chronic (CML) types. A nine-component triangulation framework for epidemiological evidence was developed incorporating study quality and ROB guidance from various federal health agencies (i.e., US EPA TSCA and NTP OHAT). Several components of the triangulation framework also drew from widely used epidemiological analytic tools such as stratified meta-analysis and sensitivity analysis. Regarding the applied example, fourteen studies were identified and assessed using the following primary study quality domains to explore potential key sources of bias: 1) study design and analysis; 2) study participation; 3) exposure assessment; 4) outcome assessment; and 5) potential confounding. Across studies, methodological limitations possibly contributing to biased results were observed within most domains. Interestingly, results from one study - often providing the largest and least-precise relative risk estimates, likely reflecting study biases, deviated from most primary study findings indicating no such associations. Triangulation of epidemiological evidence appears to be helpful in exploring inconsistent results for the identification of study results possibly reflecting various biases. Nonetheless, triangulation methodologies require additional development and application to real-world examples to enhance objectivity and reproducibility.

Urinary Glyphosate, 2,4-D and DEET Biomarkers in Relation to Neurobehavioral Performance in Ecuadorian Adolescents in the ESPINA Cohort.

BACKGROUND: Herbicides are the most used class of pesticides worldwide, and insect repellents are widely used globally. Yet, there is a dearth of studies characterizing the associations between these chemical groups and human neurobehavior. Experimental studies suggest that glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) herbicides can affect neurobehavior and the cholinergic and glutamatergic pathways in the brain. We aim to assess whether herbicides and insect repellents are associated with neurobehavioral performance in adolescents. METHODS: We assessed 519 participants (11-17 years of age) living in agricultural communities in Ecuador. We quantified urinary concentrations of glyphosate, 2,4-D, and two N,N-diethyl-meta-toluamide (DEET) insect repellent metabolites [3-(diethylcarbamoyl)benzoic acid (DCBA) and 3-(ethylcarbamoyl)benzoic acid (ECBA)] using isotope-dilution mass spectrometry. We assessed neurobehavioral performance using 9 subtests across 5 domains (attention/inhibitory control, memory/learning, language, visuospatial processing, and social perception). We characterized the associations using generalized estimating equations and multiple imputation for metabolites below detection limits. Models were adjusted for demographic and anthropometric characteristics, urinary creatinine, and sexual maturation. Mediation by salivary cortisol, dehydroepiandrosterone, 17ß-estradiol, and testosterone was assessed using structural equation modeling. RESULTS: The mean of each neurobehavioral domain score was between 7.0 and 8.7 [standard deviation (SD) range: 2.0-2.3]. Glyphosate was detected in 98.3% of participants, 2,4-D in 66.2%, DCBA in 63.3%, and ECBA in 33.4%. 2,4-D was negatively associated with all neurobehavioral domains, but statistically significant associations were observed with attention/inhibition [score difference per 50% higher metabolite concentration (ß)=-0.19 95% confidence interval (CI): -0.31, -0.07], language [ß=-0.12 (95% CI: -0.23, -0.01)], and memory/learning [ß=-0.11 (95% CI: -0.22, 0.01)]. Glyphosate had a statistically significant negative association only with social perception [ß=-0.08 (95% CI: -0.14, -0.01)]. DEET metabolites were not associated with neurobehavioral performance. Mediation by gender and adrenal hormones was not observed. CONCLUSION: This study describes worse neurobehavioral performance associated with herbicide exposures in adolescents, particularly with 2,4-D. Replication of these findings among other pediatric and adult populations is needed. https://doi.org/10.1289/EHP11383.

The prevalence of sleep-disordered breathing and associated risk factors in patients with decompensated congestive heart failure in Mozambique.

STUDY OBJECTIVES: Sleep-disordered breathing (SDB) is common in patients with congestive heart failure and has important implications regarding symptoms and prognosis. However, the burden of SDB on those with heart failure has not been well characterized in developing countries, including Mozambique in sub-Saharan Africa. Diagnosing SDB in individuals with congestive heart failure is important because treatment of SDB may improve outcomes. METHODS: Between September 2014 and April 2017, patients hospitalized in a specialized cardiology unit in Maputo, Mozambique with decompensated congestive heart failure were recruited using convenience sampling. We determined the prevalence of SDB and associated risk factors. RESULTS: A total of 165 patients were recruited, of which 145 had evaluable sleep study data. The overall prevalence of SDB in patients with decompensated congestive heart failure was 72%, and of these 46% had Cheyne-Stokes respirations. Male sex, higher body mass index, and lower left ventricular ejection fraction were all associated with a higher likelihood of SDB and more severe SDB. Cheyne-Stokes respirations were associated with male sex, lower ejection fraction, and larger left atrial size. CONCLUSIONS: We conclude that in sub-Saharan Africa SDB is common in decompensated congestive heart failure and strongly predicted by demographic and echocardiographic parameters. This study highlights the need for the development of diagnostic tools and management strategies for patients with severe heart failure in resource-limited settings. CITATION: Lo S, Mbanze I, Orr JE, et al. The prevalence of sleep-disordered breathing and associated risk factors in patients with decompensated congestive heart failure in Mozambique. J Clin Sleep Med. 2023;19(6):1103-1110.

Environmental manganese exposure and cognitive control in a South African population.

OBJECTIVE: To characterize the association between environmental (residential air) manganese (Mn) exposure and cognitive performance, focusing on cognitive control, in a Black African population. METHODS: We administered the Go-No-Go, Digit Span, and Matrix Reasoning tests to population-based samples age ≥40 from a high Mn (smelter) exposed community, Meyerton (N = 629), and a demographically comparable low (background levels) non-exposed community, Ethembalethu, (N = 96) in Gauteng province, South Africa. We investigated the associations between community and performance on the cognitive tests, using linear regression. We adjusted a priori for age and sex, and examined the effect of adjustment for education, nonverbal IQ, smoking, and alcohol consumption. We measured airborne PM2.5-Mn to confirm community exposure differences. RESULTS: Compared to Ethembalethu residents, Meyerton residents' test scores were lower (poorer) for all tests: 0.55 (95 % confidence interval [CI] 0.08, 1.03) lower scores for Matrix Reasoning, 0.34 (95 % CI -0.07, 0.75) lower for Digit Span, and 0.15 (95 % CI 0.09, 0.21) lower for Go-No-Go (high frequency discriminability index [probability]). The latter represented the most marked difference in terms of z-scores (0.50, 95 % CI 0.30, 0.71 standard deviations lower). The mean of the z-score of each of the three tests was also lower (0.34, 95 % CI 0.18, 0.50 standard deviations lower). These associations were similar in men and women, but attenuated with adjustment for education. Differences for Matrix Reasoning and Digit Span between the two communities were observed only among those who had lived in Meyerton ≥10 years, whereas for Go-No-Go, differences were also apparent among those who had lived in Meyerton <10 years. Mean PM2.5-Mn at a long-term fixed site in Meyerton was 203 ng/m3 and 10 ng/m3 in Ethembalethu. CONCLUSION: Residence in a community near a high Mn emission source is associated with cognitive dysfunction, including aspects of cognitive control as assessed by the Go-No-Go test.

Testosterone, estradiol, DHEA and cortisol in relation to anxiety and depression scores in adolescents.

Background Adrenal and sex hormone dysregulation have been independently associated with increased depression and anxiety. Cortisol can modify production of sex hormones and hormone-mood associations. This study evaluated associations and interplay of sex and adrenal hormones with depression and anxiety. Methods We assessed 545 Ecuadorian adolescents (11-17y, 50.4% female, ESPINA) for depression and anxiety symptoms using standardized scales. Testosterone, cortisol, dehydroepiandrosterone (DHEA), and estradiol (boys only) were measured in saliva. We performed logistic regression modeling to calculate odds ratios (OR) of elevated depression or anxiety (scores ≥60) comparing participants with low (<10th percentile) and elevated hormones (≥90th percentile) to normal concentrations (10th-90th percentile). Effect modification by cortisol and testosterone was assessed. Models adjusted for demographic, anthropometric, and circadian measures. Results In all participants, elevated testosterone (OR [95%CI:]=1.78 [0.98, 3.23]) and cortisol (OR=1.69 [0.95, 2.99]) were marginally associated with elevated anxiety scores. In boys, elevated estradiol was associated with elevated depression (OR=4.75 [1.95, 11.56]) and anxiety scores (OR=2.43 [1.01, 5.84]). In linear regression, estradiol was positively associated with depression (difference/10% hormone increase (ß=0.45 [0.15, 0.75]) and anxiety scores (ß=0.42 [0.13, 0.72]). Higher cortisol levels strengthened the depression association with estradiol in boys (ß=0.54 [0.12, 0.96]), and with testosterone (ß= -0.19 [-0.35, -0.03]) and DHEA (ß= -0.12 [-0.22, -0.02]) in girls. Testosterone also modified associations. Limitations This was a cross-sectional analysis. Discussion Elevated testosterone, cortisol, and estradiol (≥90th percentile) were associated with altered mood. Cortisol and testosterone were considerable effect modifiers to the associations of most hormones with depression and anxiety.

Solvent exposed occupations and risk of Parkinson disease in Finland.

INTRODUCTION: Epidemiologic and toxicology studies suggest that exposure to various solvents, especially chlorinated hydrocarbon solvents, might increase Parkinson disease (PD) risk. METHODS: In a population-based case-control study in Finland, we examined whether occupations with potential for solvent exposures were associated with PD. We identified newly diagnosed cases age 45-84 from a nationwide medication reimbursement register in 1995-2014. From the population register, we randomly selected non-PD controls matched on sex, along with birth and diagnosis years (age). We included 11,757 cases and 23,236 controls with an occupation in the 1990 census, corresponding to age 40-60. We focused on 28 occupations with ≥ 5% probability of solvent exposure according to the Finnish Job Exposure Matrix. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression modeling, adjusting for age, sex, socioeconomic status, and smoking probability. RESULTS: Similar proportions of cases (5.5%) and controls (5.6%) had an occupation with potential exposure to any solvents. However, all occupations with a point estimate above one, and all significantly or marginally significantly associated with PD (electronic/telecommunications worker [OR = 1.63, 95% CI 1.05-2.50], laboratory assistant [OR = 1.40, 95% CI 0.98-1.99], and machine/engine mechanic [OR = 1.23, 95% CI 0.99-1.52]) entailed potential for exposure to chlorinated hydrocarbon solvents, specifically. Secondary analyses indicated exposure to polycyclic aromatic hydrocarbons and some metals might contribute to the association for mechanics. CONCLUSION: PD risk might be slightly increased in occupations with potential exposure to chlorinated hydrocarbon solvents. Confirmation is required in additional studies that adjust for other occupational exposures and smoking.

Depression and anxiety in a manganese-exposed community.

OBJECTIVE: To characterize the association between residential environmental manganese (Mn) exposure and depression and anxiety, given prior associations among occupationally-exposed workers. METHODS: We administered the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) to 697 study participants in their preferred languages. These participants represented a population-based sample of residents aged ≥40 from two predominantly Black African communities in Gauteng province, South Africa: 605 in Meyerton, adjacent to a large Mn smelter, and 92 in Ethembalethu, a comparable non-exposed community. We investigated the associations between community (Meyerton vs. Ethembalethu) and severity of depression and anxiety, using linear regression, adjusting for age and sex. To document community-level differences in Mn exposure, we measured airborne PM2.5-Mn. RESULTS: Meyerton residents had BDI scores 5.63 points (95 % CI 3.07, 8.20) higher than Ethembalethu residents, with all questions contributing to this significant difference. STAI-state scores were marginally higher in Meyerton than Ethembalethu residents [2.12 (95 % CI -0.17, 4.41)], whereas STAI-trait scores were more similar between the communities [1.26 (95 % CI -0.82, 3.35)]. Mean PM2.5-Mn concentration was 203 ng/m3 at a long-term fixed site in Meyerton and 10 ng/m3 in Ethembalethu. CONCLUSION: Residence near Mn emission sources may be associated with greater depression symptomatology, and possibly current, but not lifetime, anxiety.

Principal Component Analysis of Striatal and Extrastriatal D2 Dopamine Receptor Positron Emission Tomography in Manganese-Exposed Workers.

The relationships between the neurotoxicant manganese (Mn), dopaminergic pathology, and parkinsonism remain unclear. Therefore, we used [11C](N-methyl)benperidol (NMB) positron emission tomography to investigate the associations between Mn exposure, striatal and extrastriatal D2 dopamine receptors (D2R), and motor function in 54 workers with a range of Mn exposure. Cumulative Mn exposure was estimated from work histories, and all workers were examined by a movement specialist and completed a Grooved Pegboard test (GPT). NMB D2R nondisplaceable binding potentials (BPND) were calculated for brain regions of interest. We identified 2 principal components (PCs) in a PC analysis which explained 66.8% of the regional NMB BPND variance (PC1 = 55.4%; PC2 = 11.4%). PC1 was positively correlated with NMB binding in all regions and inversely correlated with age. PC2 was driven by NMB binding in 7 brain regions (all p < .05), positively in the substantia nigra, thalamus, amygdala, and medial orbital frontal gyrus and negatively in the nucleus accumbens, anterior putamen, and caudate. PC2 was associated with both Mn exposure status and exposure duration (years). In addition, PC2 was associated with higher Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) scores and slower GPT performance. We conclude Mn exposure is associated with both striatal and extrastriatal D2R binding. Multifocal alterations in D2R expression are also associated with motor dysfunction as measured by both the GPT and UPDRS3, demonstrating a link between Mn exposure, striatal and extrastriatal D2R expression, and clinical neurotoxicity.

Severity of parkinsonism associated with environmental manganese exposure.

BACKGROUND: Exposure to occupational manganese (Mn) is associated with neurotoxic brain injury, manifesting primarily as parkinsonism. The association between environmental Mn exposure and parkinsonism is unclear. To characterize the association between environmental Mn exposure and parkinsonism, we performed population-based sampling of residents older than 40 in Meyerton, South Africa (N = 621) in residential settlements adjacent to a large Mn smelter and in a comparable non-exposed settlement in Ethembalethu, South Africa (N = 95) in 2016-2020. METHODS: A movement disorders specialist examined all participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3). Participants also completed an accelerometry-based kinematic test and a grooved pegboard test. We compared performance on the UPDRS3, grooved pegboard, and the accelerometry-based kinematic test between the settlements using linear regression, adjusting for covariates. We also measured airborne PM2.5-Mn in the study settlements. RESULTS: Mean PM2.5-Mn concentration at a long-term fixed site in Meyerton was 203 ng/m3 in 2016-2017 - approximately double that measured at two other neighborhoods in Meyerton. The mean Mn concentration in Ethembalethu was ~ 20 times lower than that of the long-term Meyerton site. UPDRS3 scores were 6.6 (CI 5.2, 7.9) points higher in Meyerton than Ethembalethu residents. Mean angular velocity for finger-tapping on the accelerometry-based kinematic test was slower in Meyerton than Ethembalethu residents [dominant hand 74.9 (CI 48.7, 101.2) and non-dominant hand 82.6 (CI 55.2, 110.1) degrees/second slower]. Similarly, Meyerton residents took longer to complete the grooved pegboard, especially for the non-dominant hand (6.9, CI -2.6, 16.3 s longer). CONCLUSIONS: Environmental airborne Mn exposures at levels substantially lower than current occupational exposure thresholds in the United States may be associated with clinical parkinsonism.

Associations of acetylcholinesterase inhibition between pesticide spray seasons with depression and anxiety symptoms in adolescents, and the role of sex and adrenal hormones on gender moderation.

BACKGROUND: Cholinesterase inhibitor pesticides, especially organophosphates, are endocrine disruptors and a few existing studies have linked self-reports of exposure with increased depression and anxiety. Some evidence suggests that associations may be stronger in women, but the mechanism of this gender difference is unclear. We assessed whether acetylcholinesterase (AChE) inhibition between 2 time points (reflecting greater cholinesterase inhibitor exposure) during different agricultural seasons in the year was associated with anxiety/depression symptoms. METHODS: We examined 300 adolescents (ages 11-17y, 51% female) living near agricultural settings in Ecuador (ESPINA study) twice in 2016: April and July-October. We assessed AChE activity (finger stick), estradiol, testosterone, dehydroepiandrosterone, cortisol (saliva) and anxiety and depression scales (CDI-2 and MASC-2). RESULTS: The mean (SD) depression and anxiety scores were 52.8 (9.3) and 58.1 (9.6), respectively. The median (25th, 75th percentile) AChE change (July-October vs April) was -3.94% (-10.45%, 5.13%). For every 10% decrease in AChE activity, there was a 0.96 unit (95%CI: 0.01, 1.90) increase in depression symptoms and an OR of elevated depression score of 1.67 (1.04, 2.66). These associations were stronger in girls (OR=2.72 [1.23, 6.00]) than boys (1.18 [0.59, 2.37]). Adjustment for cortisol, testosterone and dehydroepiandrosterone reduced gender differences by 18-62%. No associations were observed with anxiety. DISCUSSION: Inhibition of AChE activity at 2 points in time during different pesticide spray periods was associated with greater depression symptoms, affecting girls more than boys. Gender differences may be partly explained by endocrine disruption. These findings suggest that AChE inhibition may transiently affect the mood of adolescents.

Acetylcholinesterase activity and thyroid hormone levels in Ecuadorian adolescents living in agricultural settings where organophosphate pesticides are used.

BACKGROUND: Organophosphates are frequently applied insecticides that inhibit acetylcholinesterase (AChE) activity resulting in cholinergic overstimulation. Limited evidence suggests that organophosphates may alter thyroid hormone levels, although studies have yielded inconsistent findings. We aimed to test the associations between AChE activity, a physiological marker of organophosphate exposure, and thyroid function in adolescents. METHODS: We included information of 80 adolescent participants (ages 12-17y in 2016, 53% male) growing up in agricultural settings in Ecuador. We measured fingerstick erythrocytic AChE activity and hemoglobin concentration, and concurrent serum thyroid stimulating hormone (TSH) and free-T4 (fT4) concentrations. General linear models were used to test associations which adjusted for demographic and anthropometric variables. TSH associations were further adjusted for fT4. RESULTS: The mean (SD) AChE, TSH and fT4 levels were 3.77 U/mL (0.55), 2.82 µIU/ml (1.49) and 1.11 ng/dl (0.13), respectively. Lower AChE activity, indicating greater organophosphate exposure, was marginally associated with greater fT4 concentrations (difference per SD decrease in AChE activity (ß) = 0.03 ng/dL, [90% CI: 0.00, 0.06]) but not with TSH (ß = -0.01 µIU/ml, [-0.38, 0.36]). Gender modified the AChE-TSH association (p = 0.03). In girls, lower AChE activity was associated with higher fT4 levels (ß=0.05 ng/dL [0.01, 0.10]) and lower TSH concentrations (ß = -0.51 µIU/ml, [-1.00, -0.023]). No associations were observed in boys. DISCUSSION: These cross-sectional findings suggest that alterations in the cholinergic system from organophosphate exposures can increase fT4 levels coupled with a beyond-compensatory downregulation of TSH in female adolescents. This is the first study to characterize these associations in adolescents.

Residential proximity to greenhouse crops and pesticide exposure (via acetylcholinesterase activity) assessed from childhood through adolescence.

BACKGROUND: Off-target drift of pesticides from farms increases the risk of pesticide exposure of people living nearby. Cholinesterase inhibitors (i.e. organophosphates and carbamates) are frequently used in agriculture and inhibit acetylcholinesterase (AChE) activity. Greenhouse agriculture is an important production method, but it is unknown how far pesticide drift from greenhouses can extend and expose people living nearby. METHODS: This study included 1156 observations from 3 exams (2008, Apr, 2016 and Jul-Oct 2016) of 623 children aged 4-to-17 years living in agricultural communities in Ecuador. AChE, a physiological marker of cholinesterase inhibitor exposure, was measured in blood. Geographic positioning of greenhouses and homes were obtained using GPS receivers and satellite imagery. Distances between homes and the nearest greenhouse edge, and areas of greenhouse crops within various buffer zones around homes were calculated. Repeated-measures regression adjusted for hemoglobin and other covariates estimated change in AChE relative to distance from greenhouses. RESULTS: The pooled mean (SD) of AChE activity was 3.58 U/mL (0.60). The median (25th-75th %tile) residential distance to crops was 334 m (123, 648) and crop area within 500 m of homes (non-zero values only) was 18,482 m2 (7115, 61,841). Residential proximity to greenhouse crops was associated with lower AChE activity among children living within 275 m of crops (AChE difference per 100 m of proximity [95% CI] = -0.10 U/mL [-0.20, -0.006]). Lower AChE activity was associated with greater crop area within 500 m of homes (AChE difference per 1000 m2 [95% CI] = -0.026 U/mL [-0.040, -0.012]) and especially within 150 m (-0.037 U/mL [-0.065, -0.007]). CONCLUSIONS: Residential proximity to floricultural greenhouses, especially within 275 m, was associated with lower AChE activity among children, reflecting greater cholinesterase inhibitor exposure from pesticide drift. Analyses of residential proximity and crop areas near homes yielded complementary findings. Mitigation of off-target drift of pesticides from crops onto nearby homes is recommended.

[11C]dihydrotetrabenazine Positron Emission Tomography in Manganese-Exposed Workers.

OBJECTIVE: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2). METHODS: Basal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkinsonism were examined by mixed linear regression. RESULTS: Thalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m-yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P = 0.003). CONCLUSION: Mn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on monoaminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity.

Herpesvirus Infections and Risk of Parkinson's Disease.

INTRODUCTION: Herpesviruses might play a role in the pathogenesis of neurodegenerative disorders. We sought to examine a possible association between alpha herpesvirus infections and Parkinson's disease. METHODS: We conducted a population-based case-control study of incident Parkinson's disease in 2009 Medicare beneficiaries age 66-90 years (89,790 cases, 118,095 randomly selected comparable controls). We classified beneficiaries with any diagnosis code for "herpes simplex" and/or "herpes zoster" in the previous 5 years as having had the respective alpha herpesviruses. In beneficiaries with Part D prescription coverage, we also identified those prescribed anti-herpetic medications. We calculated odds ratios (OR) and 95% CI between alpha herpesvirus diagnosis/treatment and Parkinson's disease with logistic regression, with adjustment for age, sex, race/ethnicity, smoking, and use of medical care. RESULTS: Parkinson's disease risk was inversely associated with herpes simplex (OR 0.79, 95% CI 0.74-0.84), herpes zoster (OR 0.88, 95% CI 0.85-0.91), and anti-herpetic medications (OR 0.87, 95% CI 0.80-0.96). CONCLUSION: Herpesvirus infection or treatment might reduce risk of Parkinson's disease, but future studies will be required to explore whether this inverse association is causal.

Occupation and Parkinson disease in the Women's Health Initiative Observational Study.

INTRODUCTION: There is a lack of consistent study findings on associations between workplace exposures and the risk of Parkinson disease (PD) and a paucity of such data on women. We assessed PD risk among occupational groups to derive insights about potential occupation-specific exposures in a large cohort of women. METHODS: The Women's Health Initiative Observational Study (WHI-OS) is a prospective cohort that enrolled 91 627 postmenopausal women, 50 to 79 years of age, from 01 October 1993 through 31 December 1998, at 40 clinical centers across the United States, with average follow-up interval of 11 years. These women reported up to three paid jobs, held the longest since age 18; these jobs were coded and duration of employment calculated. We defined a case by self-report of doctor-diagnosed PD (at baseline or follow-up), death attributed to PD, or taking medication consistent with PD. RESULTS: Among 2590 PD cases, we found evidence of excess risk among "counselors, social workers, and other community and social service specialists," and there was a suggestion of increased in risk among postsecondary teachers, and "building and grounds cleaning and maintenance" workers. There was also evidence of a deficit in risk among women who worked in sales. Results according to ever-employed and job duration were similar, except for evidence of excess risk among "health technologists and technicians" with more than 20 years of employment. Longer duration of life on a farm was associated with higher risk. CONCLUSION: Our findings paint a largely reassuring picture of occupational risks for PD among US women.

MRI Signal Intensity and Parkinsonism in Manganese-Exposed Workers.

OBJECTIVE: T1-weighted brain magnetic resonance imaging (MRI) of the basal ganglia provides a noninvasive measure of manganese (Mn) exposure, and may also represent a biomarker for clinical neurotoxicity. METHODS: We acquired T1-weighted MRI scans in 27 Mn-exposed welders, 12 other Mn-exposed workers, and 29 nonexposed participants. T1-weighted intensity indices were calculated for four basal ganglia regions. Cumulative Mn exposure was estimated from work history data. Participants were examined using the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3). RESULTS: We observed a positive dose-response association between cumulative Mn exposure and the pallidal index (PI) (ß = 2.33; 95% confidence interval [CI], 0.93 to 3.74). There was a positive relationship between the PI and UPDRS3 (ß = 0.15; 95% CI, 0.03 to 0.27). CONCLUSION: The T1-weighted pallidal signal is associated with occupational Mn exposure and severity of parkinsonism.

Considerations for refining the risk assessment process for formaldehyde: Results from an interdisciplinary workshop.

Anticipating the need to evaluate and integrate scientific evidence to inform new risk assessments or to update existing risk assessments, the Formaldehyde Panel of the American Chemistry Council (ACC), in collaboration with the University of North Carolina, convened a workshop: "Understanding Potential Human Health Cancer Risk - From Data Integration to Risk Evaluation" in October 2017. Twenty-four (24) invited-experts participated with expertise in epidemiology, toxicology, science integration and risk evaluation. Including members of the organizing committee, there were 29 participants. The meeting included eleven presentations encompassing an introduction and three sessions: (1) "integrating the formaldehyde science on nasal/nasopharyngeal carcinogenicity and potential for causality"; (2) "integrating the formaldehyde science on lymphohematopoietic cancer and potential for causality; and, (3) "formaldehyde research-data suitable for risk assessment". Here we describe key points from the presentations on epidemiology, toxicology and mechanistic studies that should inform decisions about the potential carcinogenicity of formaldehyde in humans and the discussions about approaches for structuring an integrated, comprehensive risk assessment for formaldehyde. We also note challenges expected when attempting to reconcile divergent results observed from research conducted within and across different scientific disciplines - especially toxicology and epidemiology - and in integrating diverse, multi-disciplinary mechanistic evidence.