Prenatal exposure to the organophosphate pesticide chlorpyrifos and childhood tremor
Highlights
- •Prenatal chlorpyrifos exposure is associated with tremor in middle childhood, which may be a sign of the insecticide's effects on nervous system function.
- •Tremor could have adverse effects on daily motor tasks such as handwriting and writing-based school performance.
- •This report adds to the body of evidence suggesting that prenatal exposure to chlorpyrifos, at current standard usage levels, is associated with a range of persistent and inter-related developmental problems.
Abstract
Background
The organophosphate insecticide chlorpyrifos (CPF), widely used for agricultural purposes, has been linked to neurodevelopmental deficits. Possible motor effects at low to moderate levels of exposure have not been evaluated.
Methods
Prenatal exposure to CPF was measured in umbilical cord blood in a sample of 263 inner-city minority children, who were followed prospectively. At approximately 11 years of age (mean age 10.9 ± 0.85 years, range = 9.0–13.9), during a neuropsychological assessment, children were asked to draw Archimedes spirals. These were rated by a senior neurologist specializing in movement disorders who was blind to CPF exposure level.
Results
Compared to all other children, those with prenatal CPF exposure in the upper quartile range (n = 43) were more likely to exhibit mild or mild to moderate tremor (≥1) in either arm (p = 0.03), both arms (p = 0.02), the dominant arm (p = 0.01), and the non-dominant arm (p = 0.055). Logistic regression analyses showed significant CPF effects on tremor in both arms, either arm, the dominant arm (p-values <0.05), and the non-dominant arm (p = 0.06), after adjustment for sex, age at testing, ethnicity, and medication.
Conclusion
Prenatal CPF exposure is associated with tremor in middle childhood, which may be a sign of the insecticide's effects on nervous system function.
Introduction
Chlorpyrifos (CPF) (0,0-diethyl-0-3,5,6-trichloro-2-pyridyl phosphorothioate) is a broad-spectrum, chlorinated organophosphate (OP) insecticide. Prior to regulatory action by the Environmental Protection Agency in 2001, which banned residential use, CPF applications were particularly heavy in urban areas, where the exposed populations included pregnant women (Whyatt et al., 2003, Berkowitz et al., 2003). In a sample of pregnant women in New York City (Perera et al., 2002), detectable levels of CPF were found in 99.7% of personal air samples, 100% of indoor air samples, and 64–70% of blood samples collected from umbilical cord plasma at delivery (Whyatt et al., 2003). Chlorpyrifos is currently used for agricultural purposes across the United States, with the heaviest applications in California, and is one of the most widely used insecticides in the world (Solomon et al., 2014, Grube et al., 2011).
In animal studies, CPF exposure leads to disruption of neuronal development, neurotransmitter systems (Slotkin, 2004; Aldridge et al., 2005; Slotkin and Seidler, 2005), and synaptic formation in different brain regions (Qiao et al., 2004). These neurodevelopmental effects are associated at a later point with functional impairments in learning, short-term working memory, and long-term reference memory (Levin et al., 2002).
In humans, OPs have been detected in amniotic fluid (Bradman et al., 2003) and are known to cross the placenta, reaching the fetus during a period of rapid brain development (Richardson, 1995; Whyatt et al., 2005). Using urinary metabolites as the biomarker of exposure, several studies have reported that prenatal maternal OP exposure was associated with abnormal neonatal reflexes (Engel et al., 2007, Young et al., 2005), mental deficits and pervasive development disorder at 2 years of age (Eskenazi et al., 2007), and attention problems at 31⁄2–5 years of age (Marks et al., 2010). With a different biomarker of exposure (the parent compound of CPF), sampled in umbilical cord plasma, higher levels of prenatal CPF (greater than 6.17 pg/g) were associated with reduced birth weight and birth length (Whyatt et al., 2005), 3.5- to 6-point adjusted mean decrements on the 3-year Bayley Scales of Infant Development, a 2-fold increased risk of mental delay (<80 points) and a 5-fold increased risk of motor delay (<80 points) on the 3-year Bayley Scales of Infant Development (Rauh et al., 2006), and increased number of problems related to attention, attention deficit hyperactivity disorder, and pervasive developmental disorder as measured by the Child Behavior Checklist at 2–3 years (Rauh et al., 2006). Persistent effects of prenatal OP pesticide exposures on cognitive outcomes have been reported through 7 years of age in both rural (Bouchard et al., 2011) and urban populations (Rauh et al., 2011, Engel et al., 2011). CPF effects on brain structural development has been demonstrated by magnetic resonance imaging (MRI) in a sample of urban children ages 5.9–11.2 years of age, including cortical thinning and regionally specific cortical deformations (Rauh et al., 2012).
Evidence that low to moderate prenatal exposures to CPF and/or OP chemicals, in general, may disrupt motor processes is limited to the reports of detrimental effects on neonatal reflexes (Engel et al., 2007, Young et al., 2005) and psychomotor development on the Bayley Scales of Infant development at 3 years of age (Rauh et al., 2006). To date, there are no studies evaluating the longer-term consequences of prenatal exposure to CPF on motor development or movement disturbance.
Tremor is a condition that is highly prevalent in human populations, particularly among the elderly (Louis et al., 1998, Louis et al., 2000, Lieberman et al., 1994). Among adults, tremor is associated with exposure to several environmental chemicals, including lead (Louis et al., 2003, Dogu et al., 2007), pesticides (Louis et al., 2006, Jiménez-Jiménez et al., 2007) and harmane, a beta-carboline alkaloid found in coffee, tobacco smoke, and animal protein (Louis et al., 2002). Less attention has been devoted to the prevalence, clinical features and correlates of tremor among children. A recent report showed that mild tremor is common in children (33.1% of an urban sample with mean age of 11 years), and covaries significantly with several demographic and clinical factors as well as usage of certain medications (Louis et al., 2015).
The present study was undertaken to identify the longer-term motoric consequences of prenatal exposure to CPF in a sample of New York City children at approximately 11–14 years of age, as part of a larger prospective cohort study. Since CPF has been linked to motor problems at high levels of acute exposure, we hypothesized that prenatal CPF exposure would be associated with increased tremor in this sample of children.
Section snippets
Participants and recruitment
The subjects for this report are participants in an ongoing prospective cohort study of inner-city mothers and their newborn infants (Perera et al., 2002). The cohort study was initiated in 1997 to evaluate the effects of prenatal exposures to ambient pollutants on neurocognitive development in a cohort of mothers and newborns from low-income communities in New York City. Non-smoking women (classified by self-report and validated by blood cotinine levels less than 15 ng/ml), aged 18–35 years,
Descriptive statistics
There were 271 children with all available data (Table 1). Age was inversely, but not significantly, associated with the spiral score in both the dominant (Spearman's r = −0.09, p = 0.13) and the non-dominant arm (Spearman's r = −0.04, p = 0.55), such that higher age corresponded weakly with less tremor. Ethnicity was only weakly associated with tremor, such that Dominican children had higher tremor scores than African American children on all four measures. This difference approached significance for
Discussion
The present findings show that children with high prenatal exposure to chlorpyrifos were significantly more likely to show mild or mild to moderate tremor in one or both arms when assessed between the ages of 9 and 13.9 years of age. The proportion with mild or mild to moderate tremor among the high exposure group ranged from 16.3% to 39.5%, depending on the arm, as compared to 6.1–22.8% in the low exposure group. To our knowledge, this is the first report of tremor resulting from early life
Conflict of interest
The authors declare that there are no conflicts of interest.
Disclosure
The authors declare that there are no conflicts of interest and no competing financial interests.
Transparency document
.
Acknowledgements
Dr. Rauh has received research support for this work from the National Institutes of Health: NIEHS #R01 ES015579 (principal investigator), NIDA #R01 DA027100 (principal investigator), and #R01 ES015282 (co-investigator). Dr. Rauh has also received support for this work from the National Institutes of Environmental Health and the U.S. Environmental Protection Agency (US EPA) Children's Environmental Health Center grant (co-investigator) NIEHS/EPA #P01 ES09600/#R82702701, NIEHS/EPA #P01
References (47)
- D.B. Barr et al.
A multi-analyte method for the quantification of contemporary pesticides in human serum and plasma using high resolution mass spectrometry
J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci.
(2002) - K. Dam et al.
Neonatal chlorpyrifos exposure alters synaptic development and neuronal activity in cholinergic and catecholaminergic pathways
Dev. Brain Res.
(1999) - M.A. Furlong et al.
Prenatal exposure to organophosphate pesticides and reciprocal social behavior in childhood
Environ. Int.
(2014) - E.D. Levin et al.
Prenatal chlorpyrifos exposure in rats causes persistent behavioral alternations
Neurotoxicol. Teratol.
(2002) - E.D. Louis et al.
Organochlorine pesticide exposure in essential tremor: a case–control study using biological and occupational exposure assessments
Neurotoxicology
(2006) - E.D. Louis et al.
Tremor in a population-based cohort of children in New York City
Pediatr. Neurol.
(2015) - D. Qiao et al.
Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood
Dev. Brain Res.
(2004) - T.A. Slotkin
Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates
Toxicol. Appl. Pharmacol.
(2004) - T.A. Slotkin et al.
The alterations in CNS serotonergic mechanisms caused by neonatal chlorpyrifos exposure are permanent
Dev. Brain Res.
(2005) - T.A. Slotkin et al.
Functional alterations in CNS catecholamine systems in adolescence and adulthood after neonatal chlorpyrifos exposure
Dev. Brain Res.
(2002)
Biomarkers in assessing residential insecticide exposures during pregnancy and effects on fetal growth
Toxicol. Appl. Pharmacol.
(2005)
Association between in utero organophosphate exposure and abnormal reflexes in neonates
Neurotoxicology
(2005)
In utero exposure to nicotine and chlorpyrifos, alone and in combination produced persistent sensorimotor deficits and Purkinje neuronal loss in the cerebellum of adult offspring rats
J. Toxicol. Environ. Health
(2006)
Pesticide urinary metabolite levels of children in eastern North Carolina farmworker households
Environ. Health Perspect.
(2007)
Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure
Environ. Health Perspect.
(2005)
Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort
Environ. Health Perspect.
(2003)
Prenatal exposure to organophosphate pesticides and IQ in 7-year-old children
Environ. Health Perspect.
(2011)
Measurement of pesticides and other toxicants in amnionic fluid as a potential biomarker of prenatal exposure: a validation study
Environ. Health Perspect.
(2003)
Pesticides and their metabolites in the homes and urine of farmworker children living in the Salinas Valley, CA
J. Expo. Sci. Environ. Epidemiol.
(2007)
Consensus statement of the movement disorder society on tremor. Ad hoc Scientific Committee
Mov. Disord.
(1998)
Elevated blood lead concentrations in essential tremor: a case–control study in Mersin, Turkey
Environ. Health Perspect.
(2007)
Prenatal organophosphate metabolite and organochlorine levels and performance on the Brazelton Neonatal Behavioral Assessment Scale in a multiethnic pregnancy cohort
Am. J. Epidemiol.
(2007)
Prenatal exposure to organophosphates, paraoxonase 1, and cognitive development in childhood
Environ. Health Perspect.
(2011)
Cited by (81)
Disruption in thyroid signaling pathway: A mechanism for the effect of endocrine-disrupting chemicals on child neurodevelopment
2018, Frontiers in EndocrinologyHuman health implications of organic food and organic agriculture: A comprehensive review
2017, Environmental Health: A Global Access Science SourceChemical Pesticides and Human Health: The Urgent Need for a New Concept in Agriculture
2016, Frontiers in Public HealthResearch Review: Environmental exposures, neurodevelopment, and child mental health – new paradigms for the study of brain and behavioral effects
2016, Journal of Child Psychology and Psychiatry and Allied Disciplines
Copyright © 2015 Published by Elsevier Inc.