Harvey Checkoway’s research while affiliated with University of California, San Diego and other places

Introduction Occupational exposure to respirable crystalline silica (RCS) has been associated with both silicosis and lung cancer, but no systematic review (SR) specifically focused on exposure-response relationships has been published for these diseases. Methods We conducted this SR in compliance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. PubMed searches, supplemented with Web of Science and Google Scholar searches, identified 1,007 potentially relevant articles. After applying selection criteria and removing duplicates, 65 publications were reviewed and evaluated, 20 of which presented at least semi-quantitative exposure-response results for lung cancer (n = 12) and/or silicosis (n = 10). Results Cumulative RCS exposure was most commonly reported. Increasing silicosis risk with increasing cumulative RCS exposure was reported in all studies, with exposure thresholds indicated, but at different cumulative exposures. For most studies defining silicosis as International Labor Organization (ILO) score ≥ 1/0, substantially increased risks were clear at or above 1 mg-/m³-yr. For lung cancer, exposure-response estimates were mixed with 4 studies reporting no statistically significantly increased relative risk of lung cancer at any cumulative RCS exposure. Three studies reported statistically significant increased risks but only for high cumulative RCS exposures. Residual confounding by smoking was not explicitly discussed in most studies. One case–control study presented an exposure-response analysis for silica and lung cancer limited to never-smokers with substantial silica exposure; risk was increased only among those in the highest RCS exposure category. Studies with more detailed smoking information generally reported risks close to background levels except at the highest cumulative RCS exposure categories. Conclusion Silicosis risk clearly and consistently was increased above cumulative exposure thresholds of roughly 1 mg/m³-years across most studies. However, for lung cancer, results were heterogeneous with potential residual confounding by smoking complicating interpretation. Results suggest that lung cancer risk may not be increased at cumulative RCS exposures below the reported exposure thresholds for silicosis risk.

Introduction: Pesticide drift, known as off-target movement of pesticides, is a source of pesticide exposure in agricultural communities like Pedro Moncayo (PM), Ecuador. As pesticide exposure is associated with negative health outcomes, characterizing potential exposure by drift is crucial for developing public health interventions. Yet no contemporary agriculture maps exist for PM. Methods: Sentinel-2 T17NQA and T17NRA tiles from January 2021 to October 2022 were used, vegetation fraction (V) time series were created, and Uniform Manifold Approximation and Projection (UMAP) was applied to V time series (V-UMAP). Temporal endmembers (tEMs) of V-UMAP images unmixed the time series. Accuracy was calculated using 2001 ground truth points. 500 adults in PM were evaluated in 2022. Mass-spectrometry measured urinary concentrations of organophosphate, pyrethroid, and herbicide biomarkers. Home distance to the nearest agricultural field (home-field distance) and surface area of agriculture for buffers around the home (home-ag SAbuffer size) were calculated. Generalized estimating equations (GEE) and logistic regression, assessed associations between home-field distance and home-ag SA with metabolite concentration, overall and stratified by sex. Results: Four tEMs were used to create an agricultural map that had 72.6% accuracy and 75.3% precision. Pesticide drift analysis showed that a 1% increase in home-ag SA50m was associated with 103.7% higher 2,4-dichlorophenoxyacetic acid (2,4-D) concentration and strengthen in males (β=288.9% 95% Confidence Interval: [44.5%, 946.8%]). Negative associations were observed for para-nitrophenol (PNP) with home-ag SA50m (-31.0% [-53.0%, -1.4%]) and 3,5,6-Trichloro-2-pyridinol (TCPY) concentration with home-ag SA150m (-0.13% [-0.25, -0.01]) in women. Having 0.001 km2 higher home-ag SA50m had a 33% higher risk of having detectable malathion dicarboxylic acid (MDA). Conclusion: UMAP successfully identified distinct tEMs to create agricultural maps with moderate accuracy. Associations between home-field distance and home-ag SA with biomarkers suggest agricultural drift of 2,4-D and MDA, but not PNP and TCPY parent chemicals. Future studies should incorporate participant movement and crop type mapping for improved pesticide drift characterization.

Background Systemic inflammation has been associated with lower neurobehavioral performance in diverse populations, yet the evidence in adolescents remains lacking. Cytokines can alter neural network activity to induce neurocognitive changes. This work seeks to investigate the association between inflammation and neurobehavior in adolescents living in a rural region of Ecuador. Methods We examined 535 adolescents in rural communities of Ecuador (ESPINA study), 508 of which had neurobehavioral assessments (NEPSY-II) and circulating plasma levels of inflammatory markers (CRP, IL-6, TNF-⍺, sICAM-1, sVCAM-1, SAA, and sCD14). Associations between inflammatory biomarker concentrations and neurobehavioral scores were examined using adjusted bivariate semi-parametric models with generalized estimating equations. A partial least squares regression approach was used to create composite variables from multiple inflammation biomarkers and model their association with cognitive outcomes. Results Higher sCD14 and TNF-α concentrations were significantly associated with lower social perception scores, by −0.465 units (95% CI: −0.80, −0.13) and −0.418 units (−0.72, −0.12) for every 50% increase in inflammatory marker concentration, respectively. Similarly, every 50% increase in the inflammation summary score was associated with a significantly lower Social Perception score by −0.112 units (−0.19, −0.03). A greater inflammatory composite variable from seven markers was associated with lower scores in language (β = −0.11, p = 0.043), visuospatial processing (β = −0.15, p = 0.086), and social perception (β = −0.22, p = 0.005) domains. Conclusions Higher levels of inflammation were associated with lower neurobehavioral performance in adolescents, especially with social perception. In addition, using a robust analytic method to examine an association between a composite inflammatory variable integrating seven markers led to additional findings, including the domains of language and visuospatial processing. A longitudinal follow-up of such investigations could unveil potential changes in inflammation-neurobehavior performance links through developmental stages and intervention opportunities.

Background Adolescents living in agricultural areas are at higher risk of secondary pesticide exposure; however, there is limited evidence to confirm exposure by pesticide drift for greenhouse floriculture, like rose production. Methods 525 adolescents (12-17, 49% male) living in Pedro Moncayo, Ecuador were assessed in 2016. Urinary concentrations of creatinine and pesticide biomarkers (organophosphates, neonicotinoids, and pyrethroids) were measured using mass-spectrometry. Home distance to the nearest greenhouse and surface area of greenhouses within various buffer sizes around the home were calculated. Linear regression assessed whether home distance and surface area of greenhouses was associated with creatinine-adjusted metabolite concentration, adjusting for demographic, socioeconomic, and anthropometric variables. Geospatially weighted regression (GWR) was conducted, adjusting for similar covariates. Getis-ord Gi* identified hot and cold spots using a 1994m distance band. Results The associations between residential distance to greenhouses and urinary pesticide metabolites differed by metabolite type. The adjusted mean concentrations of OHIM (neonicotinoid) were greater (p-difference=0.02) among participants living within 200m (1.08 ug/g of creatinine) vs >200m (0.64 ug/g); however, the opposite was observed for 3,5,6-Trichloro-2-pyridinol (TCPy, organophosphate; 0-200m: 3.63 ug/g vs >200m: 4.30 ug/g, p-diff= 0.05). In linear models, greater distances were negatively associated with para-nitrophenol (PNP, organophosphate; percent difference per 50% greater distance [95% CI]: -2.5% [-4.9%, -0.1%]) and somewhat with 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy, organophosphate; -4.0% [-8.3%, 0.4%]), among participants living within 200m of greenhouses. Concurring with the adjusted means analyses, opposite (positive) associations were observed for TCPy (2.1% [95%CI: 0.3%, 3.9%]). Organophosphate and pyrethroid hotspots were found in parishes with greater greenhouse density, whereas neonicotinoid hot spots were in parishes with the lowest greenhouse density. Conclusion We observed negative associations between residential distance to greenhouses with OHIM, PNP and to some extent IMPy, suggesting that imidacloprid, parathion and diazinon is drifting from floricultural greenhouses and reaching children living within 200m. Positive TCPy associations suggest greenhouses weren’t the chlorpyrifos source during this study period, which implies that non-floricultural open-air agriculture (e.g. corn, potatoes, strawberries, grains) may be a source. Further research incorporating diverse geospatial constructs of pesticide sources, pesticide use reports (if available), participant location tracking, and repeated metabolite measurements is recommended.

There is growing evidence that per- and polyfluoroalkyl substances (PFAS) may alter serum lipid concentrations; however, this topic is understudied in adolescents and Latin American populations. We aimed to characterize these associations among adolescents in Ecuador's main floricultural region. This cross-sectional study included 97 adolescents ages 11-17 years from Pedro Moncayo County, Ecuador. Generalized estimating equation models were applied to estimate the associations of serum perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) concentrations with serum lipids. Models were adjusted for age, gender, height, body mass index (BMI), acetylcholinesterase (AChE) activity, and hemoglobin concentrations. We observed statistically significant sex-specific associations of all PFAS with triglycerides. Significant inverse relationships between PFAS and triglycerides were observed in females (% lipid difference per 50% increase in: PFOS= -15.0% [95%CI: -24.72, -4.06], PFNA= -25.49% [-36.93, -12.00], and PFOA= -16.55% [-28.16, -3.07]) but not in males. No associations were observed between total cholesterol, high-density lipoprotein (HDL), or low-density lipoprotein (LDL) cholesterol and any PFAS. PFOS, PFOA, and PFNA were inversely associated with triglycerides in adolescent females but not males. Further characterization of sex-specific associations of PFAS and blood lipids in adolescents is warranted.

Background Systemic inflammation has been associated with lower neurobehavioral performance in diverse populations, yet the evidence in adolescents remains lacking. Cytokines can alter neural network activity to induce neurocognitive changes. This work seeks to investigate the association between inflammation and neurobehavior in adolescents living in a rural region of Ecuador. Methods We examined 535 adolescents in rural communities of Ecuador (ESPINA study), 508 of which had neurobehavioral assessments (NEPSY-II) and circulating plasma levels of inflammatory markers (CRP, IL-6, TNF-alpha, sICAM-1, sVCAM-1, SAA, and sCD14). Associations between inflammatory biomarker concentrations and neurobehavioral scores were examined using adjusted bivariate semi-parametric models with generalized estimating equations. A partial least square regression approach was used to create composite variables from multiple inflammation biomarkers and model their association with cognitive outcomes. Results Higher sCD14 and TNF-alpha concentrations were significantly associated with lower social perception scores, by -0.47 units (95% CI: -0.80, -0.13) and -0.42 (-0.72, -0.12) for every 50% increase in inflammatory marker concentration, respectively. Similarly, every 50% increase in the inflammation summary score was associated with a significantly lower Social Perception score by -0.11 units (-0.19, -0.03). A unit increase in inflammatory composites of seven markers were associated with lower scores in language (-0.11 units, p=0.04), visuospatial processing (-0.15, p= 0.09), and social perception (-0.22, p=0.005) domains. Conclusions Higher levels of inflammation were associated with lower neurobehavioral performance in adolescents, especially with social perception. In addition, using a robust analytic method to examine an association between a composite inflammatory variable integrating seven markers led to additional findings, including the domains of language and visuospatial processing. A longitudinal follow-up of such investigations could unveil potential changes in inflammation-neurobehavior performance links through developmental stages and intervention opportunities.

Background: Adolescents living in agricultural areas are at higher risk of secondary pesticide exposure; however, there is limited evidence to confirm exposure by pesticide drift for greenhouse floriculture. Methods: 525 adolescents (12-17, 49% male) living in Pedro Moncayo, Ecuador were assessed in 2016. Mass spectrometry measured urinary concentrations of creatinine and insecticide pesticide biomarkers. Linear regression assessed whether home distance to the nearest greenhouse was associated with creatinine-adjusted metabolite concentration, adjusting for demographic, socioeconomic, and anthropometric variables. Getis-Ord Gi* identified hot and cold spots using a 1994m distance band. Results: The adjusted mean concentrations of OHIM (neonicotinoid) were greater (p-difference=0.02) among participants living within 200m (1.08 ug/g) vs >200m (0.64 ug/g); 3,5,6-Trichloro-2-pyridinol (TCPy, organophosphate; 0-200m: 3.63 ug/g vs >200m: 4.30 ug/g, p-difference= 0.05) showed the opposite trend. In linear models, greater distances were negatively associated with para-nitrophenol (PNP, organophosphate; %difference per 50% greater distance [95% CI]: -2.5% [-4.9%, -0.1%]) and somewhat with 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy, organophosphate; -4.0% [-8.3%, 0.4%]), among participants living within 200m of greenhouses. Positive associations were observed for TCPy (2.1% [95%CI: 0.3%, 3.9%]). Organophosphate and pyrethroid hotspots were in parishes with greater greenhouse density, whereas neonicotinoid hot spots were in parishes with the lowest greenhouse density. Conclusion: We observed negative associations between residential distance to greenhouses with OHIM, PNP and IMPy, suggesting that imidacloprid, parathion and diazinon is drifting from floricultural greenhouse. Positive TCPy associations suggest chlorpyrifos may be from non-floricultural open-air agriculture during this study period. Further research incorporating diverse geospatial constructs of pesticide sources is recommended.

Idiopathic Parkinson’s disease is determined by a combination of genetic and environmental factors. Recently, the first genome-wide association study on short-tandem repeats in Parkinson’s disease reported on eight suggestive short-tandem repeat-based risk loci (α = 5.3 × 10−6), of which four were novel, i.e. they had not been implicated in Parkinson’s disease risk by genome-wide association analyses of single-nucleotide polymorphisms before. Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinson’s disease case–control dataset (n = 4757). Furthermore, we combined the results from both studies by meta-analysis resulting in the largest Parkinson’s disease genome-wide association study of short-tandem repeats to date (n = 43 844). Lastly, we investigated whether leading short-tandem repeat risk variants exert functional effects on gene expression regulation based on methylation quantitative trait locus data in human ‘post-mortem’ brain (n = 142). None of the eight previously reported short-tandem repeats were significantly associated with Parkinson’s disease in our independent dataset after multiple testing correction (α = 6.25 × 10−3). However, we observed modest support for short-tandem repeats near CCAR2 and NCOR1 in the updated meta-analyses of all available data. While the genome-wide meta-analysis did not reveal additional study-wide significant (α = 6.3 × 10−7) short-tandem repeat signals, we identified seven novel suggestive Parkinson’s disease short-tandem repeat risk loci (α = 5.3 × 10−6). Of these, especially a short-tandem repeat near MEIOSIN showed consistent evidence for association across datasets. CCAR2, NCOR1 and one novel suggestive locus identified here (LINC01012) emerged from colocalization analyses showing evidence for a shared causal short-tandem repeat variant affecting both Parkinson’s disease risk and cis DNA methylation in brain. Larger studies, ideally using short-tandem repeats called from whole-sequencing data, are needed to more fully investigate their role in Parkinson’s disease.