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Bibliography Tag: neurodevelopmental toxicity

Zuanazzi et al., 2020

Zuanazzi, N. R., Ghisi, N. C., & Oliveira, E. C.; “Analysis of global trends and gaps for studies about 2,4-D herbicide toxicity: A scientometric review;” Chemosphere, 2020, 241, 125016; DOI: 10.1016/j.chemosphere.2019.125016.


2,4-dichlorophenoxyacetic acid (2,4-D) is a herbicide that is used worldwide in agricultural and urban activities to control pests, reaching natural environments directly or indirectly. The research on 2,4-D toxicology and mutagenicity has advanced rapidly, and for this reason, this review summarizes the available data in Web of Science (WoS) to provide insights into the specific characteristics of 2,4-D toxicity and mutagenicity. Contrary to traditional reviews, this study uses a new method to quantitatively visualize and summarize information about the development of this field. Among all countries, the USA was the most active contributor with the largest publication and centrality, followed by Canada and China. The WoS categories ‘Toxicology’ and ‘Biochemical and Molecular Biology’ were the areas of greatest influence. 2,4-D research was strongly related to the keywords glyphosate, atrazine, water and gene expression. The studies trended to be focused on occupational risk, neurotoxicity, resistance or tolerance to herbicides, and to non-target species (especially aquatic ones) and molecular imprinting. In general, the authors have worked collaboratively, with concentrated efforts, allowing important advances in this field. Future research on 2,4-D toxicology and mutagenicity should probably focus on molecular biology, especially gene expression, assessment of exposure in human or other vertebrate bioindicators, and pesticide degradation studies. In summary, this scientometric analysis allowed us to make inferences about global trends in 2,4-D toxicology and mutagenicity, in order to identify tendencies and gaps and thus contribute to future research efforts.


Parron et al, 2011

Parron, T., Requena, M., Hernandez, A. F., & Alarcon, R.; “Association between environmental exposure to pesticides and neurodegenerative diseases;” Toxicology and Applied Pharmacology, 2011, 256(3), 379-385; DOI: 10.1016/j.taap.2011.05.006.


Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer’s disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. FULL TEXT

Ross et al., 2013

Ross, S. M., McManus, I. C., Harrison, V., & Mason, O.; “Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review;” Critical Reviews in Toxicology, 2013, 43(1), 21-44; DOI: 10.3109/10408444.2012.738645.


Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes. The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning. Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis. This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported). Data were assimilated from more than 1600 participants. The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed. FULL TEXT

Smith et al., 2020

Smith, Dylan B., Arce, Andres N., Ramos Rodrigues, Ana, Bischoff, Philipp H., Burris, Daisy, Ahmed, Farah, & Gill, Richard J.; “Insecticide exposure during brood or early-adult development reduces brain growth and impairs adult learning in bumblebees;” Proceedings of the Royal Society B: Biological Sciences, 2020, 287(1922); DOI: 10.1098/rspb.2019.2442.


For social bees, an understudied step in evaluating pesticide risk is how contaminated food entering colonies affects residing offspring development and maturation. For instance, neurotoxic insecticide compounds in food could affect central nervous system development predisposing individuals to become poorer task performers later-in-life. Studying bumblebee colonies provisioned with neonicotinoid spiked nectar substitute, we measured brain volume and learning behaviour of 3 or 12-day old adults that had experienced in-hive exposure during brood and/or early-stage adult development. Micro-computed tomography scanning and segmentation of multiple brain neuropils showed exposure during either of the developmental stages caused reduced mushroom body calycal growth relative to unexposed workers. Associated with this was a lower probability of responding to a sucrose reward and lower learning performance in an olfactory conditioning test. While calycal volume of control workers positively correlated with learning score, this relationship was absent for exposed workers indicating neuropil functional impairment. Comparison of 3- and 12-day adults exposed during brood development showed a similar degree of reduced calycal volume and impaired behaviour highlighting lasting and irrecoverable effects from exposure despite no adult exposure. Our findings help explain how the onset of pesticide exposure to whole colonies can lead to lag-effects on growth and resultant dysfunction. FULL TEXT

Ait-Bali et al., 2020

Ait-Bali, Y., Ba-M’hamed, S., Gambarotta, G., Sassoe-Pognetto, M., Giustetto, M., & Bennis, M.; “Pre- and postnatal exposure to glyphosate-based herbicide causes behavioral and cognitive impairments in adult mice: evidence of cortical ad hippocampal dysfunction;” Archives of Toxicology, 2020; DOI: 10.1007/s00204-020-02677-7.


Glyphosate-based herbicides (GBH) are the most widely used pesticides worldwide. Despite considerable progress in describing the neurotoxic potential of GBH, the harmful effects on brain cytoarchitecture and behavior are still unclear. Here, we addressed the developmental impact of GBH by exposing female mice to 250 or 500 mg/kg doses of GBH during both pregnancy and lactation and then examined the downstream effects at the behavioral, neurochemical and molecular levels. We show that pre- and neonatal exposure to GBH impairs fertility and reproduction parameters as well as maternal behavior of exposed mothers. In offspring, GBH was responsible for a global delay in innate reflexes and a deficit in motor development. At the adult age, exposed animals showed a decrease of locomotor activity, sociability, learning and short- and long-term memory associated with alterations of cholinergic and dopaminergic systems. Furthermore, GBH-activated microglia and astrocytes, sign of neuroinflammation event in the medial prefrontal cortex and hippocampus. At the molecular level, a down-regulation of brain-derived neurotrophic factor (BDNF) expression and an up-regulation of tyrosine-related kinase receptor (TrkB), NR1 subunit of NMDA receptor as well as tumor necrosis factor alpha (TNFalpha) were found in the brain of GBH-exposed mice. The present work demonstrates that GBH induces numerous behavioral and cognitive abnormalities closely associated with significant histological, neurochemical and molecular impairments. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during developmental periods of central nervous system. FULL TEXT

Perro and Adams, 2017

Perro, Michelle and Adams, Vincanne, “What’s Making Our Children Sick? How Industrial Food Is Causing an Epidemic of Chronic Illness, and What Parents (and Doctors) Can Do About It,” Chelsea Green Publishing, 2017.


With chronic disorders among American children reaching epidemic levels, hundreds of thousands of parents are desperately seeking solutions to their children’s declining health, often with little medical guidance from the experts. What’s Making Our Children Sick? convincingly explains how agrochemical industrial production and genetic modification of foods is a culprit in this epidemic. Is it the only culprit? No. Most chronic health disorders have multiple causes and require careful disentanglement and complex treatments. But what if toxicants in our foods are a major culprit, one that, if corrected, could lead to tangible results and increased health? Using patient accounts of their clinical experiences and new medical insights about pathogenesis of chronic pediatric disorders—taking us into gut dysfunction and the microbiome, as well as the politics of food science—this book connects the dots to explain our kids’ ailing health.

What’s Making Our Children Sick? explores the frightening links between our efforts to create higher-yield, cost-efficient foods and an explosion of childhood morbidity, but it also offers hope and a path to effecting change. The predicament we now face is simple. Agroindustrial “innovation” in a previous era hoped to prevent the ecosystem disaster of DDT predicted in Rachel Carson’s seminal book in 1962, Silent Spring. However, this industrial agriculture movement has created a worse disaster: a toxic environment and, consequently, a toxic food supply. Pesticide use is at an all-time high, despite the fact that biotechnologies aimed to reduce the need for them in the first place. Today these chemicals find their way into our livestock and food crop industries and ultimately onto our plates. Many of these pesticides are the modern day equivalent of DDT. However, scant research exists on the chemical soup of poisons that our children consume on a daily basis. As our food supply environment reels under the pressures of industrialization via agrochemicals, our kids have become the walking evidence of this failed experiment. What’s Making Our Children Sick? exposes our current predicament and offers insight on the medical responses that are available, both to heal our kids and to reverse the compromised health of our food supply.

Oya et al., 2016

Oya, N., Ito, Y., Hioki, K., Asai, Y., Aoi, A., Sugiura, Y., Ueyama, J., Oguri, T., Kato, S., Ebara, T., & Kamijima, M.; “Quantitative analysis of organophosphate insecticide metabolites in urine extracted from disposable diapers of toddlers in Japan;” International Journal of Hygiene and Environmental Health, 2017, 220(2 Pt A), 209-216; DOI: 10.1016/j.ijheh.2016.10.009.



Epidemiological studies linking insecticide exposure to childhood neurodevelopment have been gaining global attention. Despite the rapid development of the central nervous system in early childhood, studies regarding the biological monitoring of insecticide exposure in diapered children are limited. In this study, we aimed to clarify the concentrations of organophosphate (OP) insecticide metabolites in toddler urine extracted from disposable diapers in Japan.


We recruited diapered children from the Aichi regional subcohort participants of the Japan Environment and Children’s Study (JECS) at the time of their 18-month checkup. A total of 116 children wore designated disposable diapers overnight, which were then sent as refrigerated cargo. The urine was extracted from the diapers using acetone and analyzed by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) to determine the concentrations of six dialkyl phosphates (DAPs) (i.e., dimethyl phosphate [DMP], dimethyl thiophosphate [DMTP], dimethyl dithiophosphate [DMDTP], diethyl phosphate [DEP], diethyl thiophosphate [DETP], and diethyl dithiophosphate [DEDTP]). DAP absorption into the diapers was quantified to calculate the urinary DAP concentrations.


The DAP recovery using the developed method yielded between 54.2% (DEDTP) and 101.4% (DEP). Within-run precision expressed as the relative standard deviation was between 2.4% and 14.7%, and the between-run precision was between 3.1% and 8.5%. A Bland-Altman analysis confirmed the agreement between the results obtained by the developed method and by the measurements for the corresponding urine without diaper absorption. The geometric means (GM) of urinary DMP, DMTP, DMDTP, DEP, DETP, and total DAPs (SigmaDAP) were 3.6, 3.9, 0.9, 6.0, 0.6mug/L, and 137.6 nmol/L, respectively. The GM of DEDTP was not calculated due to its low detection rate.


We successfully established a method to measure the DAP concentrations in urine extracted from diapers and this is the first report of these pesticide concentrations in diapered children in Japan.


Farina et al., 2019

Farina, W. M., Balbuena, M. S., Herbert, L. T., Mengoni Gonalons, C., & Vazquez, D. E.; “Effects of the Herbicide Glyphosate on Honey Bee Sensory and Cognitive Abilities: Individual Impairments with Implications for the Hive;” Insects, 2019, 10(10); DOI: 10.3390/insects10100354.


The honeybee Apis mellifera is an important pollinator in both undisturbed and agricultural ecosystems. Its great versatility as an experimental model makes it an excellent proxy to evaluate the environmental impact of agrochemicals using current methodologies and procedures in environmental toxicology. The increase in agrochemical use, including those that do not target insects directly, can have deleterious effects if carried out indiscriminately. This seems to be the case of the herbicide glyphosate (GLY), the most widely used agrochemical worldwide. Its presence in honey has been reported in samples obtained from different environments. Hence, to understand its current and potential risks for this pollinator it has become essential to not only study the effects on honeybee colonies located in agricultural settings, but also its effects under laboratory conditions. Subtle deleterious effects can be detected using experimental approaches. GLY negatively affects associative learning processes of foragers, cognitive and sensory abilities of young hive bees and promotes delays in brood development. An integrated approach that considers behavior, physiology, and development allows not only to determine the effects of this agrochemical on this eusocial insect from an experimental perspective, but also to infer putative effects in disturbed environments where it is omnipresent. FULL TEXT

Marks et al., 2010

Marks, A. R., Harley, K., Bradman, A., Kogut, K., Barr, D. B., Johnson, C., Calderon, N., & Eskenazi, B.; “Organophosphate pesticide exposure and attention in young Mexican-American children: the CHAMACOS study;” Environmental Health Perspectives, 2010, 118(12), 1768-1774; DOI: 10.1289/ehp.1002056.



Exposure to organophosphate (OP) pesticides, well-known neurotoxicants, has been associated with neurobehavioral deficits in children.


We investigated whether OP exposure, as measured by urinary dialkyl phosphate (DAP) metabolites in pregnant women and their children, was associated with attention-related outcomes among Mexican-American children living in an agricultural region of California.


Children were assessed at ages 3.5 years (n = 331) and 5 years (n = 323). Mothers completed the Child Behavior Checklist (CBCL). We administered the NEPSY-II visual attention subtest to children at 3.5 years and Conners’ Kiddie Continuous Performance Test (K-CPT) at 5 years. The K-CPT yielded a standardized attention deficit/hyperactivity disorder (ADHD) Confidence Index score. Psychometricians scored behavior of the 5-year-olds during testing using the Hillside Behavior Rating Scale.


Prenatal DAPs (nanomoles per liter) were nonsignificantly associated with maternal report of attention problems and ADHD at age 3.5 years but were significantly related at age 5 years [CBCL attention problems: beta = 0.7 points; 95% confidence interval (CI), 0.2-1.2; ADHD: beta = 1.3; 95% CI, 0.4-2.1]. Prenatal DAPs were associated with scores on the K-CPT ADHD Confidence Index > 70th percentile [odds ratio (OR) = 5.1; 95% CI, 1.7-15.7] and with a composite ADHD indicator of the various measures (OR = 3.5; 95% CI, 1.1-10.7). Some outcomes exhibited evidence of effect modification by sex, with associations found only among boys. There was also limited evidence of associations between child DAPs and attention.


In utero DAPs and, to a lesser extent, postnatal DAPs were associated adversely with attention as assessed by maternal report, psychometrician observation, and direct assessment. These associations were somewhat stronger at 5 years than at 3.5 years and were stronger in boys. FULL TEXT

Rodgaard et al., 2019

Rodgaard, E. M., Jensen, K., Vergnes, J. N., Soulieres, I., & Mottron, L.; “Temporal Changes in Effect Sizes of Studies Comparing Individuals With and Without Autism: A Meta-analysis;” JAMA Psychiatry, 2019; DOI: 10.1001/jamapsychiatry.2019.1956.



The definition and nature of autism have been highly debated, as exemplified by several revisions of the DSM (DSM-III, DSM-IIIR, DSM-IV, and DSM-5) criteria. There has recently been a move from a categorical view toward a spectrum-based view. These changes have been accompanied by a steady increase in the prevalence of the condition. Changes in the definition of autism that may increase heterogeneity could affect the results of autism research; specifically, a broadening of the population with autism could result in decreasing effect sizes of group comparison studies.


To examine the correlation between publication year and effect size of autism-control group comparisons across several domains of published autism neurocognitive research.


This meta-analysis investigated 11 meta-analyses obtained through a systematic search of PubMed for meta-analyses published from January 1, 1966, through January 27, 2019, using the search string autism AND (meta-analysis OR meta-analytic). The last search was conducted on January 27, 2019.


Meta-analyses were included if they tested the significance of group differences between individuals with autism and control individuals on a neurocognitive construct. Meta-analyses were only included if the tested group difference was significant and included data with a span of at least 15 years.

DATA EXTRACTION AND SYNTHESIS: Data were extracted and analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline using fixed-effects models.


Estimated slope of the correlation between publication year and effect size, controlling for differences in methods, sample size, and study quality.


The 11 meta-analyses included data from a total of 27723 individuals. Demographic data such as sex and age were not available for the entire data set. Seven different psychological and neurologic constructs were analyzed based on data from these meta-analyses. Downward temporal trends for effect size were found for all constructs (slopes: -0.067 to -0.003), with the trend being significant in 5 of 7 cases: emotion recognition (slope: -0.028 [95% CI, -0.048 to -0.007]), theory of mind (-0.045 [95% CI, -0.066 to -0.024]), planning (-0.067 [95% CI, -0.125 to -0.009]), P3b amplitude (-0.048 [95% CI, -0.093 to -0.004]), and brain size (-0.047 [95% CI, -0.077 to -0.016]). In contrast, 3 analogous constructs in schizophrenia, a condition that is also heterogeneous but with no reported increase in prevalence, did not show a similar trend.


The findings suggest that differences between individuals with autism and those without the diagnosis have decreased over time and that possible changes in the definition of autism from a narrowly defined and homogenous population toward an inclusive and heterogeneous population may reduce our capacity to build mechanistic models of the condition. FULL TEXT

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