Polycyclic aromatic hydrocarbons in silicone wristbands of Uruguayan children: measurement and exposure source exploration.

Polycyclic aromatic hydrocarbons (PAHs) pose health risks to children, potentially resulting in stunted growth, obesity, and cognitive deficits, but lack of reliable and noninvasive means to measure PAHs results in poor understanding of exposure patterns and sources in this vulnerable population. In this study, 24 children aged ∼7 years (9 boys and 15 girls) from Montevideo, Uruguay wore silicone wristbands for 8 days to monitor the exposure of 27 PAHs. Wristbands were extracted using a modified ethyl acetate tandem solid phase extraction clean up and then analyzed via gas chromatography with tandem mass spectrometry. This analysis has reported LODs for 27 PAHs between 0.05 and 3.91 µg L-1. Eighteen PAHs were detected in >50% of the samples with concentration medians ranging 1.2-16.3 ng g-1 of wristband. Low molecular weight PAHs (2-3 rings) such as naphthalene and its alkyl derivatives were highly correlated (0.7-0.9) in the wristbands, suggesting exposure from related sources. Exposure source exploration focused on secondhand tobacco smoke, potentially through caregivers who reported on smoking habits in an associated survey. A principal components analysis (PCA) was conducted to examine patterns in PAH compounds detected in the wristbands; subsequently, the resulting components were compared according to current smoking among caregivers. The PCA analysis revealed a grouping of participants based on higher exposure of 1-methyl naphthalene, pyrene, fluoranthene, 1-methylphenanthrene, dibenzothiophene and 2-phenyl naphthalene. The derived components did relate with parental smoking, suggesting that some participants experienced exposure to a common source of certain PAHs outside of parental smoking. This is the first study to assess PAH exposure in young children from South America. Using wristbands, our study indicates exposure to multiple, potentially harmful chemicals. Wristbands could provide a comprehensive picture of PAH exposure in children, complementing other non-invasive biomonitoring approaches.

Temperature stability of urinary F2-isoprostane and 8-hydroxy-2'-deoxyguanosine.

Background: Clinical and epidemiological studies employ long-term temperature storage but the effect of temperature on the stability of oxidative stress (OS) markers is unknown. We investigated the effects of storage at -20 °C and -80 °C over 4-9 months on F2-isoprostanes (F2-IsoP) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in urine of children, a population group among whom the measurement of these markers is still limited. Methods: Paired spot urine samples from 87 children aged 8.9-16.9 years (52.9% boys) were analyzed. Samples were preserved with 0.005% (w/v) butylated hydroxytoluene, portioned and stored within 2.5 h (median) of collection. Samples were analyzed in duplicate or triplicate using commercial ELISA kits and their correlations were evaluated. Results: F2-IsoP and 8-OHdG showed high correlations (Spearman rho of 0.90 and 0.97, respectively; P < 0.0001) with storage at -20 °C and -80 °C. There was a strong agreement among categories of values for F2-IsoP (Kappa = 0.76 ± 0.08, agreement = 83.9%, P < 0.0001) and 8-OHdG: (Kappa = 0.83 ± 0.08, agreement = 88.4%, P < 0.0001). The correlation between the temperatures for F2-IsoP concentrations was also high when stored for <4 (0.93), 4 (0.93), and 5 months (0.88), all P < 0.0001. For 8-OHdG, Spearman correlations at <8, 8, and 9 months of storage at -20 °C and -80 °C were 0.95, 0.98, and 0.96 (all P < 0.0001), respectively. Conclusions: Urine storage with BHT for up to nine months at a temperature of -20 °C to -80 °C yields highly comparable concentrations of F2-IsoP and 8-OHdG.

Dietary Predictors of Urinary Biomarkers of Pyrethroids in the General Population - A Scoping Review.

BACKGROUND: Pyrethroid pesticides are ubiquitous environmental contaminants, contributing to chronic and potentially harmful exposure among the general population. Although studies have measured pesticide residues on agricultural products, the link between food intake and concentrations of pyrethroid biomarkers in urine remains unclear. OBJECTIVE: This scoping review aims to analyze peer-reviewed publications investigating dietary predictors of pyrethroid exposure through urinary biomarkers. We assess existing evidence, identify research gaps, and highlight current limitations. METHODS: We conducted a comprehensive search using PubMed and Google Scholar. Eligible studies examined associations between diets, food items or dietary components, and measured urinary pyrethroid biomarkers. No geographical restriction was applied to our search. Results were summarized in themes referring to study characteristics, relevant outcomes, biomarker measurement, dietary assessment and statistical analyses. RESULTS: We identified 20 relevant articles. Most studies presented evidence on associations between the consumption of organic diets or food items and reduced concentrations of 3-phenobenzoic acid metabolites in urine. There was less evidence for diet affecting other pyrethroid-specific biomarkers. Dietary assessment methodologies and recall periods varied, as did the number and timing of urine collections. Many studies did not control for potential alternative pyrethroid sources, exposure to other pesticides, or demographic and socioeconomic characteristics. CONCLUSION: Researchers should consider standardized dietary assessment, chemical analyses of foods consumed, adequate recall time, and food preparation methods. Consistency in biomarker measurement, including urine collection time and corrections for specific gravity or creatinine, is needed. Ensuring the validity of such studies also requires larger samples and appropriate control for confounders.

Pyrethroid and Chlorpyrifos Pesticide Exposure, General Intellectual Abilities, and Executive Functions of School Children from Montevideo, Uruguay.

Children's developing brains are susceptible to pesticides. Less is known about the effect of exposure to chlorpyrifos and pyrethroids on executive functions (EF). We measured urinary 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of chlorpyrifos, and urinary 3-phenoxybenzoic acid (3-PBA), a general, nonspecific metabolite of pyrethroids in first-grade children from Montevideo, Uruguay (n = 241, age 80.6 ± 6.4 months, 58.1% boys). EFs were assessed with the Intra-dimensional/Extra-dimensional shift (IED), Spatial Span (SSP), and Stockings of Cambridge (SOC) tests from the Cambridge Neuropsychological Test Automated (CANTAB) Battery. General intellectual ability (GIA) was assessed using the Woodcock-Muñoz Cognitive battery. Median (range) urinary TCPy and 3-PBA levels were 16.7 (1.9, 356.9) ng/mg of creatinine and 3.3 (0.3, 110.6) ng/mg of creatinine, respectively. In multivariable generalized linear models, urinary TCPy was inversely associated with postdimensional errors on the IED task ß [95% CI]: -0.11 [-0.17, -0.06]. Urinary 3-PBA was inversely associated with the total number of trials -0.07 [-0.10, -0.04], and the total number of errors -0.12 [-0.18, -0.07] on the IED task. When TCPy and 3-PBA were modeled together, the associations did not differ from single-metabolite models. We found no evidence of effect modification by blood lead level (BLL). Pesticide exposure may affect EF performance in urban children.

Reducing the complexity of high-dimensional environmental data: An analytical framework using LASSO with considerations of confounding for statistical inference.

PURPOSE: Frameworks for selecting exposures in high-dimensional environmental datasets, while considering confounding, are lacking. We present a two-step approach for exposure selection with subsequent confounder adjustment for statistical inference. METHODS: We measured cognitive ability in 338 children using the Woodcock-Muñoz General Intellectual Ability (GIA) score, and potential associated features across several environmental domains. Initially, 111 variables theoretically associated with GIA score were introduced into a Least Absolute Shrinkage and Selection Operator (LASSO) in a 50% feature selection subsample. Effect estimates for selected features were subsequently modeled in linear regressions in a 50% inference (hold out) subsample, first adjusting for sex and age and later for covariates selected via directed acyclic graphs (DAGs). All models were adjusted for clustering by school. RESULTS: Of the 15 LASSO selected variables, eleven were not associated with GIA score following our inference modeling approach. Four variables were associated with GIA scores, including: serum ferritin adjusted for inflammation (inversely), mother's IQ (positively), father's education (positively), and hours per day the child works on homework (positively). Serum ferritin was not in the expected direction. CONCLUSIONS: Our two-step approach moves high-dimensional feature selection a step further by incorporating DAG-based confounder adjustment for statistical inference.

Evaluating how occupational exposure to organophosphates and pyrethroids impacts ADHD severity in Egyptian male adolescents.

BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by deficits in attention and hyperactivity/impulsivity that cause impairments to daily living. An area of long-standing concern is understanding links between environmental toxicants, including pesticides, and the development or worsening of ADHD. OBJECTIVES: The present study evaluated associations between occupational pesticide exposure, specifically organophosphate (OP) pesticides, chlorpyrifos (CPF) and the pyrethroids (PYR) alpha-cypermethrin (αCM) and lambda-cyhalothrin (λCH), and symptoms of ADHD in a longitudinal study among Egyptian adolescent males. METHODS: Participants (N = 226, mean age = 17) were Egyptian adolescent males who either applied pesticides or were non-applicators. Urinary trichloro-2-pyridinol (TCPy) was measured as a specific metabolite biomarker of exposure to chlorpyrifos. Urinary 3-phenoxybenzoic acid (3-PBA) was measured as a general metabolite biomarker of exposure to pyrethroids, while urinary cis-3-(2,2- dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA) was measured as a specific biomarker of exposure to αCM and lambda cyhalothric acid (λCH acid) measured as a specific biomarker of exposure to λCH. Ordinal logistic regression models controlling for age were used to determine the likelihood of ADHD development (measured via parent-reported ADHD symptoms) as the level of biomarkers of pesticide exposure increased. RESULTS: Cis-DCCA was the only biomarker associated with higher likelihood ADHD symptoms (> 0.60 vs. 0-0.17 µg/g creatinine; OR = 2.82, 95% CI: 1.29-6.14). All participants reported clinical levels of ADHD symptoms when compared to national norms used in the United States. TCPy, trans-DCCA and λCH acid were not associated with risk of ADHD symptoms after controlling for levels of cis-DCCA. No other metabolites were associated with the number of ADHD symptoms. There were no interaction effects found for exposure to both OPs and Pyrethroids. DISCUSSION: The results suggest that exposure to the pyrethroid αCM is associated with more ADHD symptoms. Methodological and cultural considerations in need of further study are discussed.

Therapeutic efficacy of the humanized JAA-F11 anti-Thomsen-Friedenreich antibody constructs H2aL2a and H3L3 in human breast and lung cancer xenograft models.

The Thomsen-Friedenreich antigen (TF-Ag-α) is found on ~85% of human carcinomas but is cryptic on normal tissue. The humanized highly specific hJAA-F11-H2aL2a and -H3L3 antibodies target TF-Ag-α without binding to TF-Ag-beta (found on surface glycolipids of some normal cells). The relative affinity of H3L3 is 17 times that of H2aL2a, which would seem to favor superior efficacy, however, increased affinity can result in less tumor penetration. To assess the potential therapeutic efficacy of these antibodies, four human cancer- mouse xenograft models were treated with H2aL2a and H3L3. The tumor xenograft models used were human non-small cell lung cancer, H520, and small cell lung cancer, HTB171 in nude mice and human triple negative breast cancer, MDA-MB-231 and HCC1806 in SCID mice. H2aL2a significantly decreased tumor growth in both breast and both lung cancer models. H2aL2a showed statistically equal or better efficacy than H3L3 and has superior production capabilities. These results suggest that H2aL2a may be superior as a naked antibody, as an antibody drug conjugate or as a radiolabeled antibody, however the higher affinity of H3L3 may lead to better efficacy in bi-specific therapies in which the binding is decreased due to the presence of only one TF-Ag-α binding site.

Acute and Cumulative Effects of Repeated Exposure to Chlorpyrifos on the Liver and Kidney Function among Egyptian Adolescents.

BACKGROUND: There is a paucity of research that tracks changes in liver and kidney function among pesticide applicators. The aim of the current study was to investigate the role of repeated seasonal exposure to the organophosphorus pesticide, chlorpyrifos, on serum measures of liver and kidney function. METHODS: Pesticide exposure was assessed by measuring the urinary concentrations of 3,5,6-trichloro-2 pyridinol (TCPy), a specific biomarker for chlorpyrifos. Chlorpyrifos exposure and 8 serum markers of liver and kidney function were measured at 15 timepoints over 3 years prior to, during, and following the end of seasonal pesticide application among adolescent applicators and non-applicators from 4 field stations in Menoufia, Egypt. RESULTS: Urinary TCPy levels showed increases during the application cycles and recovery at the end of each application season. Altered serum markers of liver and kidney function were associated with chlorpyrifos exposure, with some markers recovering 3 months after the end of exposure each year, while other measures demonstrated progressive increase up to 300% the baseline levels at the end of 3 years. CONCLUSION: The study demonstrated that frequent assessment of liver and kidney function is a sound practice to evaluate cellular injury following chronic repeated occupational and environmental exposure to chlorpyrifos.

Evaluation of occupational pesticide exposure on Egyptian male adolescent cognitive and motor functioning.

BACKGROUND: Chronic low-level exposure to organophosphorus pesticides is associated with adverse health effects, including a decline in neurological functioning and long-term impairment. These negative effects may be more detrimental in children and adolescents due to their critical stage in development. Little work has investigated the effects of chronic exposure to pesticides, specifically chlorpyrifos (CPF) during the adolescent period. OBJECTIVES: To examine effects of CPF exposure over a year-long period within a group of male adolescents in Egypt (N = 242, mean age = 17.36), including both pesticide applicators and non-applicators. METHODS: Associations between average CPF exposure (measured via urinary metabolite levels of 3,5,6-trichloro-2-pyridinol [TCPy]) and neurobehavioral functioning were examined in a 1-year longitudinal study. Given previous literature, higher levels of TCPy were expected to be associated with worse neurobehavioral functioning. RESULTS: Using mixed effects linear regression, average TCPy exposure predicted deficits in more complex neurobehavioral tasks (Benton visual retention, digit span reverse, match to sample, serial digit learning, and alternating tapping) with estimates of effects ranging from -0.049 to 0.031. Age (effects ranging from 0.033 to 0.090) and field station (effects ranging from -1.266 to -0.278) were significantly predictive of neurobehavioral functioning over time. An interaction effect was found for field station and TCPy across several neurobehavioral domains. DISCUSSION: Results show that occupational exposure to pesticides may have particularly deleterious effects on complex neurobehavioral domains. Additionally, differences across field stations and the age at which individuals are exposed may be important factors to investigate in future research.

Effect of exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) on mitochondrial DNA (mtDNA) copy number in rats.

Mitochondria are intracellular organelles responsible for biological oxidation and energy production. These organelles are susceptible to damage from oxidative stress and compensate for damage by increasing the number of copies of their own genome, mitochondrial DNA (mtDNA). Cancer and environmental exposure to some pollutants have also been associated with altered mtDNA copy number. Since exposures to polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been shown to increase oxidative stress, we hypothesize that mtDNA copy number will be altered with exposure to these compounds. mtDNA copy number was measured in DNA from archived frozen liver and lung specimens from the National Toxicology Program (NTP) study of female Harlan Sprague Dawley rats exposed to TCDD (3, 10, or 100 ng/kg/day), dioxin-like (DL) PCB 126 (10, 100, or 1000 ng/kg/day), non-DL PCB 153 (10, 100, or 1000 µg/kg/day), and PCB 126 + PCB 153 (10 ng/kg/day + 10 µg/kg/day, 100 ng/kg/day + 100 µg/kg/day, or 1000 ng/kg/day + 1000 µg/kg/day, respectively) for 13 and 52 weeks. An increase in mtDNA copy number was observed in the liver and lung of rats exposed to TCDD and the lung of rats exposed to the mixture of PCB 126 and PCB 153. A statistically significant positive dose-dependent trend was also observed in the lung of rats exposed to PCB 126 and a mixture of PCB 153 and PCB 126, although in neither case was the control copy number significantly exceeded at any dose level. These exposures produced a range of pathological responses in these organs in the two-year NTP studies. Conversely, there was a significant decrease or no change in mtDNA copy number in the liver and lung of rats exposed to non-DL PCB 153. This is consistent with a general lack of PCB 153 mediated liver or lung injury in the NTP study, with the exception of liver hypertrophy. Together, the results suggest that an increase in mtDNA copy number may serve as a sensitive, early biomarker of mitochondrial injury and oxidative stress that contributes to the development of the toxicity of dioxin-like compounds.

Telomeres as targets for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) in rats.

Telomere length (TL) can be affected by various factors, including age and oxidative stress. Changes in TL have been associated with chronic disease, including a higher risk for several types of cancer. Environmental exposure of humans to PCBs and dioxins has been associated with longer or shorter leukocyte TL. Relative telomere length (RTL) may serve as a biomarker associated with neoplastic and/or non-neoplastic responses observed with chronic exposures to TCDD and PCBs. RTL was measured in DNA isolated from archived frozen liver and lung tissues from the National Toxicology Program (NTP) studies conducted in female Harlan Sprague Dawley rats exposed for 13, 30, and 52 weeks to TCDD, dioxin-like (DL) PCB 126, non-DL PCB 153, and a mixture of PCB 126 and PCB 153. RTL was assessed by quantitative polymerase chain reaction (qPCR). Consistent with literature, decreased liver and lung RTL was seen with aging. Relative to time-matched vehicle controls, RTL was increased in both the liver and lung tissues of rats exposed to TCDD, PCB 126, PCB 153, and the mixture of PCB 126 and PCB 153, which is consistent with most epidemiological studies that found PCB exposures were associated with increased leukocyte RTL. Increased RTL was observed at doses and/or time points where little to no pathology was observed. In addition to serving as a biomarker of exposure to these compounds in rats and humans, increases in RTL may be an early indicator of neoplastic and non-neoplastic responses that occur following chronic exposure to TCDD and PCBs.

Catching flame retardants and pesticides in silicone wristbands: Evidence of exposure to current and legacy pollutants in Uruguayan children.

Children are exposed to many potentially toxic compounds in their daily lives and are vulnerable to the harmful effects. To date, very few non-invasive methods are available to quantify children's exposure to environmental chemicals. Due to their ease of implementation, silicone wristbands have emerged as passive samplers to study personal environmental exposures and have the potential to greatly increase our knowledge of chemical exposures in vulnerable population groups. Nevertheless, there is a limited number of studies monitoring children's exposures via silicone wristbands. In this study, we implemented this sampling technique in ongoing research activities in Montevideo, Uruguay which aim to monitor chemical exposures in a cohort of elementary school children. The silicone wristbands were worn by 24 children for 7 days; they were quantitatively analyzed using gas chromatography with tandem mass spectrometry for 45 chemical pollutants, including polychlorinated biphenyls (PCBs), pesticides, polybrominated diphenyl ethers (PBDEs), organophosphorus flame retardants (OPFRs), and novel halogenated flame-retardant chemicals (NHFRs). All classes of chemicals, except NHFRs, were identified in the passive samplers. The average number of analytes detected in each wristband was 13 ±3. OPFRs were consistently the most abundant class of analytes detected. Median concentrations of ΣOPFRs, ΣPBDEs, ΣPCBs, and dichlorodiphenyltrichloroethane (DDT) and its metabolites (dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD)) were 1020, 3.00, 0.52 and 3.79 ng/g wristband, respectively. Two major findings result from this research; differences in trends of two OPFRs (TCPP and TDCPP) are observed between studies in Uruguay and the United States, and the detection of DDT, a chemical banned in several countries, suggests that children's exposure profiles in these settings may differ from other parts of the world. This was the first study to examine children's exposome in South America using silicone wristbands and clearly points to a need for further studies.

Dioxin-like compound exposures and DNA methylation in the Anniston Community Health Survey Phase II.

The Anniston Community Health Survey (ACHS-I) was initially conducted from 2005 to 2007 to assess polychlorinated biphenyl (PCB) exposures in Anniston, Alabama residents. In 2014, a follow-up study (ACHS-II) was conducted to measure the same PCBs as in ACHS-I and additional compounds e.g., polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like non-ortho (cPCBs) substituted PCBs. In this epigenome-wide association study (EWAS), we examined the associations between PCDD, PCDF, and PCB exposures and DNA methylation. Whole blood DNA methylation was measured using Illumina EPIC arrays (n=292). We modeled lipid-adjusted toxic equivalencies (TEQs) for: ΣDioxins (sum of 28 PCDDs, PCDFs, cPCBs, and mPCBs), PCDDs, PCDFs, cPCBs, and mPCBs using robust multivariable linear regression adjusting for age, race, sex, smoking, bisulfite conversion batch, and estimated percentages of six blood cell types. Among all exposures we identified 10 genome-wide (Bonferroni p≤6.74E-08) and 116 FDR (p≤5.00E-02) significant associations representing 10 and 113 unique CpGs, respectively. Of the 10 genome-wide associations, seven (70%) occurred in the PCDDs and four (40%) of these associations had an absolute differential methylation ≥1.00%, based on the methylation difference between the highest and lowest exposure quartiles. Most of the associations (six, 60%) represented hypomethylation changes. Of the 10 unique CpGs, eight (80%) were in genes shown to be associated with dioxins and/or PCBs based on data from the 2019 Comparative Toxicogenomics Database. In this study, we have identified a set of CpGs in blood DNA that may be particularly susceptible to dioxin, furan, and dioxin-like PCB exposures.

Risk perception and behavior in Egyptian adolescent pesticide applicators: an intervention study.

BACKGROUND: Adolescents are engaged in agricultural work, including pesticide application, around the world. Adolescent pesticide applicators are more likely to be exposed to pesticides than their adult counterparts because of their application practice and hygiene habits surrounding pesticide use. There is a need for low-cost interventions to reduce pesticide exposure. We evaluated a theoretically-based educational intervention to change perceptions about the risk of pesticide use and hygiene habits during and after pesticide application for adolescent and young adult pesticide applicators in Egypt. METHODS: Young adult and adolescent male pesticide applicators were given a one-hour educational intervention to inform them about the risk of pesticide use and how to reduce pesticide exposure. The median age of participants was 18 years old. Changes in perceived susceptibility and effectiveness were measured with a survey pre and post-intervention (n = 119) on the same day. The same survey (n = 95) was given 8-months post-intervention to identify sustained effects. Observational checklists of pesticide application practice were also completed during application seasons before and after the intervention. RESULTS: There was an increase in the proportion of individuals who viewed pesticides as being a long-term health risk (74.7% pre-intervention to 97.9% post-intervention, McNemar test p < 0.001). This change remained significant when surveyed at the 8-month follow-up (90.5%, p < 0.001). There was also a sustained improvement regarding participants' views of proper hygiene practice surrounding pesticide application. Applicators were observed wearing goggles, shoes, and masks more frequently post-intervention. CONCLUSION: This theoretically-based intervention is an example of a low-cost solution that can improve adolescents' and young adults' practices regarding pesticide application and personal hygiene practices during and after pesticide application. The intervention can be applied in other countries with similar safety culture surrounding pesticide application.

Magnitude of behavioral deficits varies with job-related chlorpyrifos exposure levels among Egyptian pesticide workers.

Chronic occupational exposure to organophosphorus pesticides (OPs) is consistently associated with deficits on behavioral tests when compared to unexposed comparison groups. However, a dose-response relationship has yet to be established, leading some to doubt an association between occupational OP exposure and behavioral deficits. Pesticide application teams in Egypt who are primarily exposed to one OP, chlorpyrifos (CPF), were recruited into a field assessment. Trail Making A and the more challenging Trail Making B tests were administered to 54 engineers (who supervise the pesticide application process, usually from the side of the field), 59 technicians (who guide the pesticide applicators in the field), 31 applicators (who mix and apply pesticides using knapsack sprayers), and 150 controls (who did not work in the fields) at two different times during the OP application season as well as immediately after applications had ended and 1.5 months later. All participants were males since only males work on pesticide application teams in Egypt. Urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of CPF, confirmed the pattern of lower to higher CPF exposures from engineers to technicians to applicators, and these were all greater than urinary metabolite levels in controls. A consistent relationship between job title and performance speed on the behavioral task was observed: Controls had the best (fastest) performance on Trail Making A and B tests throughout the application season, and applicators had significantly slower performance than engineers on Trail Making A (p = 0.015) and B (p = 0.003). However, individual urinary TCPy, blood acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) levels did not predict individual performance. This study identifies a dose-related effect based on job title, which serves as a surrogate for chronic exposure in that differing job titles exhibit varying group exposure levels. The results establish that chronic occupational exposure to chlorpyrifos is neurotoxic and suggest that the classic biomarkers of recent CPF exposure are not predictive of chronic exposure effects.

Retention of polybrominated diphenyl ethers and hydroxylated metabolites in paired human serum and milk in relation to CYP2B6 genotype.

Polybrominated diphenyl ethers (PBDEs) and their hydroxylated metabolites (OH-BDEs) are endocrine disrupting compounds prevalent in human serum and breast milk. Retention of PBDEs and OH-BDEs in humans may be affected by differences in PBDE metabolism due to variants in cytochrome P450 2B6 (CYP2B6). The objectives of this study are to assess the partitioning profiles of PBDEs and OH-BDEs in forty-eight paired human serum and milk samples, and to evaluate the relationship between variants in CYP2B6 genotype and PBDE and OH-BDE accumulation in humans. Results show that the geometric mean (GM) concentrations of PBDEs are similar in serum (GM = 43.4 ng/g lipid) and milk samples (GM = 52.9 ng/g lipid), while OH-BDEs are retained primarily in serum (GM = 2.31 ng/g lipid), compared to milk (GM = 0.045 ng/g lipid). Participants with CYP2B6*6 genotype had a greater relative retention of PBDEs in serum and milk, and significant relationships (p <  0.05) were also observed for PBDE-47, 5-OH-BDE-47 and 6-OH-BDE-47 concentrations relative to CYP2B6*5 and CYP2B6*6 genotypes. These results are the first to show that CYP2B6 genotype is significantly related to the relative retention of PBDEs in humans, which may have direct implications for variability in the susceptibility of individuals to the potential adverse effects of these contaminants.

Polychlorinated biphenyl exposure and DNA methylation in the Anniston Community Health Survey.

Anniston, Alabama was home to a major polychlorinated biphenyl (PCB) production facility from 1929 until 1971. The Anniston Community Health Survey I and II (ACHS-I 2005-2007, ACHS-II 2013-2014) were conducted to explore the effects of PCB exposures. In this report we examined associations between PCB exposure and DNA methylation in whole blood using EPIC arrays (ACHS-I, n = 518; ACHS-II, n = 299). For both cohorts, 35 PCBs were measured in serum. We modelled methylation versus PCB wet-weight concentrations for: the sum of 35 PCBs, mono-ortho substituted PCBs, di-ortho substituted PCBs, tri/tetra-ortho substituted PCBs, oestrogenic PCBs, and antiestrogenic PCBs. Using robust multivariable linear regression, we adjusted for age, race, sex, smoking, total lipids, and six blood cell-type percentages. We carried out a two-stage analysis; discovery in ACHS-I followed by replication in ACHS-II. In ACHS-I, we identified 28 associations (17 unique CpGs) at p ≤ 6.70E-08 and 369 associations (286 unique CpGs) at FDR p ≤ 5.00E-02. A large proportion of the genes have been observed to interact with PCBs or dioxins in model studies. Among the 28 genome-wide significant CpG/PCB associations, 14 displayed replicated directional effects in ACHS-II; however, only one in ACHS-II was statistically significant at p ≤ 1.70E-04. While we identified many novel CpGs significantly associated with PCB exposures in ACHS-I, the differential methylation was modest and the effect was attenuated seven years later in ACHS-II, suggesting a lack of persistence of the associations between PCB exposures and altered DNA methylation in blood cells.

GMDTC Chelating Agent Attenuates Cisplatin-Induced Systemic Toxicity without Affecting Antitumor Efficacy.

Cisplatin is a platinum-based chemotherapeutic drug widely used in the treatment of various cancers such as testicular, ovarian, lung, bladder, and cervical cancers. However, its use and the dosage range applied have been limited by severe side effects (e.g., nephrotoxicity and ototoxicity) and by the development of resistance to cisplatin in patients during treatment. Metal chelators have shown promising potential in overcoming these problems often associated with platinum drugs. Previously, a new chelating agent, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)-4(methylthio)butanoate (GMDTC), was developed. In this study, we examined the effect of GMDTC in modifying cisplatin-induced toxicities following in vitro and in vivo exposures. GMDTC treatment dramatically reduced cisplatin-induced apoptosis and cytotoxicity in HK2 cells by decreasing the amount of intracellular platinum. In the 4T1 breast cancer mouse model, GMDTC reduced cisplatin-induced nephrotoxicity by reducing cisplatin deposition in the kidney. GMDTC attenuated cisplatin-induced elevations in blood urea nitrogen and plasma creatinine, ameliorated renal tubular dilation and vacuolation, and prevented necrosis of glomeruli and renal tubular cells. GMDTC also inhibited cisplatin-induced ototoxicity as shown by improved hearing loss which was assessed using the auditory brainstem response test. Furthermore, GMDTC attenuated cisplatin-induced hematotoxicity and hepatotoxicity. Importantly, co-treatment of cisplatin with GMDTC did not affect cisplatin antitumor efficacy. Tumor growth, size, and metastasis were all comparable between the cisplatin only and cisplatin-GMDTC co-treatment groups. In conclusion, the current study suggests that GMDTC reduces cisplatin-induced systemic toxicity by preventing the accumulation and assisting in the removal of intracellular cisplatin, without compromising cisplatin therapeutic activity. These results support the development of GMDTC as a chemotherapy protector and rescue agent to overcome the toxicity of and resistance to platinum-based antineoplastic drugs.

Occupational pesticide exposure and symptoms of attention deficit hyperactivity disorder in adolescent pesticide applicators in Egypt.

BACKGROUND: Exposure to environmental chemicals, including organophosphorus pesticides, is associated with behavioral disorders such as attention deficit hyperactivity disorder (ADHD). However, the impact of occupational pesticide exposure on ADHD development in adolescents has not been examined. OBJECTIVE: We examined the association between exposure to chlorpyrifos and ADHD symptoms among adolescents in Egypt. METHODS: Adolescent pesticide applicators and non-applicators, 12-21 years old, participated in a 10-month longitudinal study examining health effects from pesticide exposure. Repeated urine and blood samples were collected at various time points during the 10-months to assess biomarkers of chlorpyrifos exposure (urinary trichloro-2-pyridinol or TCPy) and effect (blood acetyl cholinesterase activity and butyryl cholinesterase activity). Parents from a subset of the cohort (N = 64) completed the Short Form of Conners' Parent Rating Scale - Revised. Poisson regressions were used to examine the associations between the number of ADHD symptoms and occupation and biomarkers. RESULTS: Pesticide applicators had significantly more symptoms of ADHD than participants in the non-applicator group. Urinary TCPy levels were associated with increased symptoms, demonstrating a dose-response effect. Applicators with ADHD reported applying pesticides for more hours during the application season and had greater cumulative TCPy levels than participants without ADHD. One fourth of all applicators met the criteria for an ADHD diagnosis (having 6 or more reported symptoms). CONCLUSIONS: This study provides preliminary evidence of an association between occupational exposure to chlorpyrifos and ADHD symptoms among adolescent pesticide applicators in spite of its limited small sample size. There is a critical need to investigate the susceptibility of children and adolescents to repeated occupational and environmental exposures to pesticides because the developing brain may be uniquely sensitive to the neurotoxic effects of these agents.

Preclinical Analysis of JAA-F11, a Specific Anti-Thomsen-Friedenreich Antibody via Immunohistochemistry and In Vivo Imaging.

The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG3 (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA-F11 was recently carried out as explained in a companion paper "Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA-F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse-human xenograft lung cancer model with humanized 124I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need.