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.

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.

Setting course for a translational pharmacology and a predictive toxicology based on the numerical probability of clinical relevance.

For a significant share of the chemicals, current bioassays mispredicted the outcomes in the reference methods they simulate. For any drug or chemical, and depending on the regulatory or corporate situation, three different approaches calculate the numerical probability by which agreement (or discrepancy) can be statistically expected between (1) the result of a predictive bioassay, and (2) the outcome on its reference method. If such concordance is expected with enough confidence based on a sufficient percentage probability, then specific results from that bioassay can be considered as correctly predictive. The statistical approaches analyzed in this article assist in valuable tasks, including (1) a better translation of the clinical relevance (or insignificance) of specific preclinical findings; (2) waiving unnecessary animal testing (or any other unpredictive testing; e.g., a given in vitro bioassay), and (3) in advancing only the most promising candidates in the pharmaceutical, pesticide, or chemical development process.

Concurrent urinary organophosphate metabolites and acetylcholinesterase activity in Ecuadorian adolescents.

BACKGROUND: Organophosphates are insecticides that inhibit the enzymatic activity of acetylcholinesterase (AChE). Because of this, AChE is considered a physiological marker of organophosphate exposure in agricultural settings. However, limited research exists on the associations between urinary organophosphate metabolites and AChE activity in children. METHODS: This study included 526 participants from 2 exams (April and July-October 2016) of ages 12-17 years living in agricultural communities in Ecuador. AChE activity was measured at both examinations, and organophosphate metabolites, including para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPy), and malathion dicarboxylic acid (MDA) were measured in urine collected in July-October. We used generalized estimating equation generalized linear model (GEEGLM), adjusting for hemoglobin, creatinine, and other demographic and anthropometric covariates, to estimate associations of urinary metabolite concentrations with AChE activity (July-October) and AChE% change between April and July-October. RESULTS: The mean (SD) of AChE and AChE% change (April vs July-October) were 3.67 U/mL (0.54) and -2.5% (15.4%), respectively. AChE activity was inversely associated with PNP concentration, whereas AChE% change was inversely associated with PNP and MDA. There was evidence of a threshold: difference was only significant above the 80th percentile of PNP concentration (AChE difference per SD increase of metabolite = -0.12 U/mL [95%CI: 0.20, -0.04]). Likewise, associations with AChE% change were significant only above the 80th percentile of TCPy (AChE % change per SD increase of metabolite = -1.38% [95%CI: 2.43%, -0.32%]) and PNP -2.47% [95%CI: 4.45%, -0.50%]). PNP concentration at ≥80th percentile was associated with elevated ORs for low AChE activity of 2.9 (95% CI: 1.5, 5.7) and for AChE inhibition of ≤ -10% of 3.7 (95% CI: 1.4, 9.8). CONCLUSIONS: Urinary organophosphate metabolites, including PNP, TCPy and MDA, particularly at concentrations above the 80th percentile, were associated with lower AChE activity among adolescents. These findings bring attention to the value of using multiple constructs of pesticide exposure in epidemiologic studies.

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.

Applying Bayesian forecasting to predictive toxicology: The probability of innate carcinogenicity to humans of colorants synthesized from benzidine.

The preclinical identification of health hazards relies on the performance (the historic concordance to the respective gold standard) of regulatorily recommended bioassays. However, any testing with less than 100% sensitivity (or 100% specificity) can deliver false results (outcomes discordant to the respective gold standard). Conversely, the predictive values approach (a.k.a. Bayesian forecasting) weighs (1) the performance of the predictive bioassay (battery, or framework) with (2) the prevalence of -positivity to the respective gold standard- in the most representative category to which the test substance can be allocated. Thus, the predictive values approach (PVA) provides the numeric probability for the toxicity to humans of chemicals that, circumstantially, are evaluable only through nonclinical data. Consequently, the PVA improves the predictivity of nonclinical toxicology, and increases the impact of hazard identifications entirely based on preclinical data. This article aimed to introduce the PVA through a worked example. Due to their toxicological homogeneity and public health relevance, the superfamily of colorants synthesized from benzidine (BZ) or some mutagenic congeners was selected (colorings hereafter mentioned as BZ-related-colorants). Through the PVA, the numeric probability of innate carcinogenicity to humans of 259 BZ-related-colorants was either estimated from rodent carcinogenesis bioassays (RCBs) or predicted from methods alternative to the RCB. A discussion was provided on (1) some limitations and implications of the PVA, and (2) the probable significance of the predictive values figured here for 259 BZ-related-colorings.

The numerical probability of carcinogenicity to humans of some antimicrobials: Nitro-monoaromatics (including 5-nitrofurans and 5-nitroimidazoles), quinoxaline-1,4-dioxides (including carbadox), and chloramphenicol.

Many substances are already tested in the long-term rodent bioassay (RCB). Nonetheless, statements such as the following are common in the regulatory literature: "the significance of the carcinogenicity findings in rodents relative to the therapeutic use of drugs in humans is unknown." (U.S. FDA prescribing information for nitrofurantoin). In the absence of epidemiological data, chemicals carcinogenic in RCBs are typically classified as either possibly or probably carcinogenic to humans, particularly without the -numerical probability for the carcinogenicity to humans- (PPV) of the classified substance. Through the biostatistics-based and regulatorily pertinent -predictive values approach- (PVA), the present study investigated the PPV of several antimicrobials relevant to human or veterinary medicine. A combination of structure-activity relationship, mutagenicity, and tumor-related histopathology was used to resolve reliable and pertinent PPVs. For 62 specific antimicrobials (e.g., carbadox), a 97.9% (or more) probability of carcinogenicity to humans was estimated. For nitrofurantoin, a 99.9% probability of carcinogenicity to humans was reckoned. Therefore, a risk-benefit evaluation on the in-force authorization of nitrofurantoin for uncomplicated human urinary infections is needed. A discussion was provided on the involved mechanisms of carcinogenic action and some regulatory implications of the findings. Neither this study nor the PVA aimed to encourage indiscriminate animal testing but the contrary, to reduce unnecessary or redundant in vivo testing by powering the predictivity of nonclinical toxicology.

The 2-year rodent bioassay in drug and chemical carcinogenicity testing: Performance, utility, and configuration for cancer hazard identification.

For several intended uses of chemicals, the 2-year rodent bioassay (RCB) has been the benchmark method to screen the carcinogenicity to humans of substances, according to the hazard identification sphere. Despite the ongoing controversy around this traditional testing, the RCB is in force and being used by stakeholders. After assembling the RCB's ability to forecast the carcinogenicity to humans of substances, the current review aimed to provide a discussion on the RCB's (1) sensitivity and specificity; (2) utility; (3) configuration, and (4) provisional role in the regulatory policy. In general, RCBs conducted at maximum tolerated doses (MTDs) exhibited a functional ability to (1) not missing the great majority of human carcinogens, and to (2) not responding to the large majority of human non-carcinogens. There is citable evidence supporting the use of MTDs to render RCBs as sensitive as possible, particularly provided the ethically-justified small samples used in RCBs. The literature shows that rodent-specific mechanisms of chemical carcinogenesis contribute significant unspecificity to RCBs. Nonetheless, the paradox between a functional sensitivity and a significant unspecificity can be predictively resolved through the application of Bayesian forecasting. In terms of performance to forecast the carcinogenicity to humans of either genotoxic or non-genotoxic substances, 2-species-RCBs added no value over the rat-RCB. Nevertheless, there is preliminary evidence cautioning that 15% of the rodent carcinogens probably carcinogenic to humans could be missed if mouse-RCBs are indiscriminately discontinued. More than thirteen RCB-related issues relevant to regulatory pharmacology and toxicology were discussed and summarized in this review.

The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators.

The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays. Nonetheless, any predictive testing (eg, safety pharmacology) with less than 100% sensitivity or 100% specificity is prone to deliver false positive or negative results (namely, outcomes discordant to the clinical gold standard). It was recently suggested that the statistics-based and regulatory pertinent "predictive values approach" (PVA) might help to reach a more predictive use of preclinical testing data. To resolve the associated probability of carcinogenicity to humans, the PVA was applied to 37 pharmaceuticals bearing inadequate epidemiological evidence of carcinogenicity, but identifiable as unequivocal mutagens. According to current knowledge, a 98.9% (or more) probability of carcinogenicity to humans was reckoned for those 37 genotoxic drugs. Accordingly, these pharmaceutical drugs might be either scientifically or regulatorily regarded as "carcinogenic to humans." In the USA, European Union, or Canada as examples, the great majority of these 37 pharmaceuticals are authorized for medical use in humans. From the results of the present appraisal, the following is suggested (1) for the pharmaceuticals listed in this report, to include significant carcinogenicity warnings in their prescribing information; (2) to conduct pharmacoepidemiology studies or risk-benefit analyses (if warranted), and (3) based on the respective risk-benefit analyses, to re-evaluate the authorization of hydralazine and phenoxybenzamine as antihypertensives, oxcarbazepine as an anticonvulsant, and phenazopyridine as a urinary tract antimicrobial or analgesic. For the four latter drugs (eg, phenoxybenzamine), a 99.5% probability of carcinogenicity to humans was estimated.

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.

The 2-year rodent bioassay in drug and chemical carcinogenesis testing: Sensitivity, according to the framework of carcinogenic action.

The long-term rodent bioassay (RCB) has been the gold-standard for the pre-marketing prediction of chemical and drug carcinogenicity to humans. Nonetheless, the validity of this toxicity test has remained elusive for several decades. In the quest to uncover the performance of the RCB, its sensitivity (SEN) was charted as the first step. This appraisal was based on (a) chemicals with sufficient epidemiological evidence of carcinogenicity, and (b) other substances with limited epidemiological evidence, or remarkable classifications of carcinogenicity based on mechanistic or pharmacological data. In the present study, chemicals evaluated for their carcinogenicity to humans in IARC Monographs volumes 1-123, U.S. EPA IRIS Assessments, and U.S. NTP RoC were considered. This investigation gathered additional evidence supporting that, in hazard identification, the RCB is unwarranted for mutagenic or direct-acting genotoxicants. However, for purposes of risk assessment or management, the RCB might be justified whenever there is a lack of reliable and/or comprehensive epidemiological data. The RCB exhibited a significantly different SEN for threshold-based human carcinogens compared to non-threshold-based ones. With threshold-based chemicals, to increase the SEN of the testing from 80% (rat-RCB) to 90%, the 2-species RCB might be warranted. Nevertheless, the resolve would depend on the viewpoint, and on the future analysis of the overall performance of the RCB. In terms of SEN, and cancer hazard identification, the comparison between the RCB and alternative methods (e.g. rasH2 mouse, Tg.AC mouse) is now enabled.

Drug excipients, food additives, and cosmetic ingredients probably not carcinogenic to humans reveal a functional specificity for the 2-year rodent bioassay.

Regarding carcinogenicity testing, the long-term rodent bioassay (RCB) has been the test required by most regulatory agencies across the world. Nonetheless, due to the lack of knowledge about its specificity, it has been argued that the RCB is unspecific or even invalid. Because of the substantial limitations of epidemiology to identify chemicals probably not carcinogenic to humans (PNCH), it has been very difficult to address the specificity of the RCB. Nevertheless, because mechanistic/pharmacological data are currently recognized as a valid stream of evidence for the identification of chemical hazards, the road is now open to gain insight into the specificity of the RCB. Based on sound mechanistic/pharmacological data that support the classification of chemicals as PNCH, 100 PNCH substances were gathered in this investigation. Contrary to what was previously forecast, in this study, the RCB exhibited a functional specificity that ranged from 83% to 91%, depending on the settings of the testing (2-species vs. rats only, and the nominal maximum tolerated dose). Other contributions of this work were: (a) enabling the comparison, in terms of specificity, between the RCB and the alternative methods that could replace it (eg, Tg.AC mouse, rasH2 mouse); (b) disclosing what the specificity is for alternative methods that were developed using the RCB as the reference standard; and (c) expanding the previous narrow (only seven substances) set of chemicals identified as not likely to be carcinogenic to humans by hazard identification programs.

The predictivity of the -alert performance- functionality of the OECD QSAR-Toolbox (c/w further issues on the predictivity of nonclinical testing).

The OECD QSAR-Toolbox can be considered a milestone in predictive toxicology. Because of the reliability of its supporting institutions (OECD and ECHA), its broadness in terms of feeder databases, and its predictive capacity, the QSAR-Toolbox is called to have a major role in regulatory toxicology. Recently, a novel functionality was built for the QSAR-Toolbox: the alert performance (AP). This prompted us to analyze the strengths, potentialities, and limitations of this new functionality, especially in the light of a pivotal framework recently discussed in the literature for the predictive use of nonclinical screening and testing. After meticulous analysis, and through some worked examples, high predictive capacity and applicability were found for the AP in both predictive and regulatory toxicology. For a specified chemical, the AP is useful in (a) anticipating its overall results in a given nonclinical test; (b) predicting its overall results regarding a selected toxicological endpoint in humans, and (c) facilitating post- to pre-test probabilities approaches that may support regulatory authorization for waiving the conduction of selected tests in laboratory animals. Furthermore, if a QSAR-Toolbox initiative is developed in or extended to pharmacology (e.g., safety pharmacology, drug abuse potential), it could represent another milestone; one that would give rise to the field of predictive pharmacology.

The NTP Report on Carcinogens: A valuable resource for public health, a challenge for regulatory science.

The Report on Carcinogens (RoC), from the National Toxicology Program of the USA, is one of the world-leading programs for the identification and acknowledgment of substances that represent a hazard of cancer to humans. RoC covers several essential topics concerning environmental, occupational, and pharmaceutical agents that are known to be, or reasonably anticipated to be carcinogenic to humans. To promote the highest exploitation by its potential users, several RoC aspects and features were put together into one article. For doing so, a comprehensive description is provided regarding RoC history, scope, general features, listing criteria, contents, handbook, and website. Secondary and tertiary aims for this work were (a) to point out some improvement opportunities for the RoC, and (b) to discuss pending issues in regulatory science and cancer hazard assessments. In this regard, for agents classified as probably, likely, reasonably anticipated, possibly or suspected to be a human carcinogen, there is a lack of quantitative knowledge concerning the likelihood of those agents actually being carcinogenic to humans. Elucidating these probabilities is necessary, because the duration of current regulations and the arrival of new acts may depend on it. On the other hand, there is a dramatic imbalance in priorities toward carcinogens, compared with non-carcinogens, in current cancer hazard identification programs. That vision may ignore that the availability on the market of chemicals classified as probably not carcinogenic to humans can also be important for the employment, alimentation, economy, quality of life of consumers, and human health.

Associations of acetylcholinesterase activity with depression and anxiety symptoms among adolescents growing up near pesticide spray sites.

BACKGROUND: The cholinergic system has an important role in mood regulation. Cholinesterase inhibitor pesticides (e.g. organophosphates) appear to increase depression and anxiety symptoms in the few existing animal and human studies. Human studies have not described such associations using biomarkers of exposure and studies among children are needed. METHODS: We studied 529 adolescents (ages 11-17y) in agricultural communities in the Ecuadorian Andes (ESPINA study). Acetylcholinesterase (AChE) activity was measured in a finger-stick sample. Anxiety and depression symptoms were assessed using the CDI-2 and MASC-2 (greater scores reflect greater internalizing symptoms). Models adjusted for age, gender, hemoglobin, income among others. RESULTS: The median age was 14.38y and 51% were female. The mean (SD) of the following parameters were: AChE 3.7 U/mL (0.55), depression T-score 53.0 (9.4) and anxiety T-score: 57.6 (9.8). Lower AChE activity (reflecting greater cholinesterase inhibitor exposure) was associated with higher depression symptoms (difference per SD decrease of AChE [ß [95% CI:]]: 1.09 [0.02, 2.16]), was stronger among girls (ß = 1.61) than boys (ß = 0.69), and among younger (<14.38y, ß = 1.61) vs. older children (ß = 0.57). The associations were strongest among girls <14.38y (ß = 3.30 [0.54, 6.05], OR for elevated symptoms per SD decrease in AChE = 2.58 [1.26, 5.27]). No associations were observed with anxiety scores. Analyses of AChE change between 2008 and 2016 concurred with these findings. DISCUSSION: We observed associations between a biomarker of pesticide exposure and children's depression symptoms. Lower AChE activity may create risk for depression in teenagers, particularly among girls during early adolescence.

Home proximity to flower plantations and higher systolic blood pressure among children.

BACKGROUND: Pesticide drift from agricultural plantations increases the chemical exposure potential of people living nearby. Some studies have described positive associations between pesticide exposures and blood pressure (BP) in adults, whereas limited evidence in children suggests negative associations. This study characterized the association between home proximity to plantations and BP among children living in a flower-growing county in Ecuador. METHODS: We included 310 4-9-year-old children living in Pedro Moncayo County, Ecuador as part of The ESPINA study. We calculated age, gender and height-specific BP z-scores. Geographic coordinates of homes and flower plantations were collected using GPS receivers and satellite imagery. Exposure-outcome associations were analyzed using linear regression. RESULTS: The mean home distance to the nearest flower plantation was 449 m (SD: 347) and the median plantation area within 150 m of participants' homes was 989 m2 (25th-75Th percentile: 492-3164) among those with non-zero values. Children living closer to plantations had lower AChE activity. Systolic BP z-score increased with greater residential proximity to plantations (0.24 SD per 1000 m [95% CI: 0.01, 0.47]) and with greater areas of flower plantations within 150 m of homes (0.03 SD per 1000 m2 [0.00, 0.06]), after adjusting for socio-economic, anthropometric and other factors. Further adjustment for acetylcholinesterase and hemoglobin strengthened these associations. CONCLUSIONS: Proximity of homes to flower plantations and greater plantation areas within 150 m from homes were associated with higher systolic BP, independent of cholinesterase activity. This suggests that non-cholinesterase inhibitor pesticide drift from agricultural plantations may be sufficient to induce physiologic changes on children living nearby.

Agroecology and Health: Lessons from Indigenous Populations.

PURPOSE OF REVIEW: The article aims to systematize and disseminate the main contributions of indigenous ancestral wisdom in the agroecological production of food, especially in Latin America. For this purpose, it is necessary to ask whether such knowledge can be accepted by academia research groups and international forums as a valid alternative that could contribute to overcome the world's nutritional problems. RECENT FINDINGS: Although no new findings are being made, the validity of ancestral knowledge and agroecology is recognized by scientific research, and by international forums organized by agencies of the United Nations. These recommend that governments should implement them in their policies of development, and in the allocation of funds to support these initiatives. Agroecology and ancestral knowledge are being adopted by a growing number of organizations, indigenous peoples and social groups in various parts of the world, as development alternatives that respond to local needs and worldviews. Its productive potential is progressively being recognized at an international level as a model that contributes to improve the condition of people regarding nutritional food.

Immunization campaigns and political agendas: retrospective from Ecuador and El Salvador.

Since the mid-1980s international donors have promoted vertical, campaign-based strategies to help improve immunization coverage in poor countries. National immunization days (NIDs) are currently in vogue and are prominent in the worldwide polio eradication efforts. In spite of their widespread use, campaigns that include NIDs have not been well evaluated for their effects on coverage, reduction in vaccine-preventable diseases, or effects on the health system. An assessment of the results of two such campaigns implemented in Ecuador and El Salvador shows limited impact on short-term coverage and questionable effects on long-term coverage and disease incidence. Although NIDs may have substantial short-term political benefits, the vertical approach can undermine provision of routine services by ministries of health and may be counterproductive in the long-term.