POLICY FORUM

Organophosphate exposures during

pregnancy and child neurodevelopment:
Recommendations for essential policy
reforms
Irva Hertz-Picciotto ID1*, Jennifer B. Sass2, Stephanie Engel3, Deborah H. Bennett1,
Asa Bradman4, Brenda Eskenazi4, Bruce Lanphear5, Robin Whyatt6

1 Environmental Health Sciences Center and Department of Public Health Sciences, School of Medicine,
a1111111111 University of California Davis, Davis, California, United States of America, 2 Natural Resources Defense
a1111111111 Council, and George Washington University, Washington, DC, United States of America, 3 Department of
a1111111111 Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States of America,
a1111111111 4 School of Public Health, University of California Berkeley, Berkeley, California, United States of America,
a1111111111 5 BC Children’s Hospital, Faculty of Health Sciences, Simon Fraser University, Vancouver, BC, Canada,
6 Mailman School of Public Health and Children’s Center for Environmental Health at Columbia University,
New York, New York, United States of America

* ihp@ucdavis.edu

OPEN ACCESS
Summary points
Citation: Hertz-Picciotto I, Sass JB, Engel S,
Bennett DH, Bradman A, Eskenazi B, et al. (2018)
Organophosphate exposures during pregnancy • Widespread use of organophosphate (OP) pesticides to control insects has resulted in
and child neurodevelopment: Recommendations
ubiquitous human exposures.
for essential policy reforms. PLoS Med 15(10):
e1002671. https://doi.org/10.1371/journal. • High exposures to OP pesticides are responsible for poisonings and deaths, particularly
pmed.1002671
in developing countries.
Published: October 24, 2018
• Compelling evidence indicates that prenatal exposure at low levels is putting children at
Copyright: © 2018 Hertz-Picciotto et al. This is an risk for cognitive and behavioral deficits and for neurodevelopmental disorders.
open access article distributed under the terms of
the Creative Commons Attribution License, which To protect children worldwide, we recommend the following:
permits unrestricted use, distribution, and
reproduction in any medium, provided the original • Governments phase out chlorpyrifos and other OP pesticides, monitor watersheds and
author and source are credited. other sources of human exposures, promote use of integrated pest management (IPM)
through incentives and training in agroecology, and implement mandatory surveillance
Funding: This work was supported by Project
TENDR, which has received grants from John of pesticide-related illness.
Merck Fund (https://www.jmfund.org/), Ceres
• Health professions implement curricula on the hazards from OP pesticides in nursing
Trust Fund (https://cerestrust.org/), Passport
Foundation, and the National Institute of
and medical schools and in continuing medical education courses and educate their
Environmental Health Sciences (R13ES026504). patients and the public about these hazards.
As co-Executive Director of Project TENDR, IHP
• Agricultural entities accelerate the development of nontoxic approaches to pest control
received grants from Ceres Trust Fund for work by
Project TENDR to increase awareness of the through IPM and ensure the safety of workers through training and provision of protec-
scientific evidence regarding pesticides and tive equipment when toxic chemicals are to be used.
neurodevelopment and to develop policy
recommendations for reduction of such exposures.
BL, JBS, and SE received support from Project
TENDR provided by the John Merck Fund to attend
Project TENDR meetings where this manuscript
was discussed. The funders had no role in study

PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002671 October 24, 2018 1 / 15

design, data collection and analysis, decision to Introduction
publish, or preparation of the manuscript.
Organophosphate (OP) compounds were originally developed as human nerve gas agents dur-
Competing interests: I have read the journal’s
ing the 1930s–1940s, and some were later adapted as insecticides at lower doses [1]. High
policy and the authors of this manuscript have the
following competing interests: IHP received NIH
exposure to OP compounds leads to acute poisoning from the irreversible inhibition of the
grants to study pesticides in relation to child enzyme acetylcholinesterase (AChE), resulting in cholinergic syndrome (including narrowed
neurodevelopment and mental health pupils, excessive salivation, bronchoconstriction, mental confusion, convulsions or tremors,
(R01ES015359, P01ES011269, UG3-OD023365, and in some cases, death). Additionally, delayed polyneuropathy has been described in associa-
P30ES023513, EPA R829388, R833292) and tion with high exposures [1].
grants from Ceres Trust Fund for work by Project
In the United States, many OP pesticides—including malathion, dichlorvos, azinphos-
TENDR to increase awareness of the scientific
evidence regarding pesticides and methyl, and chlorpyrifos—were licensed for insecticidal use before requirements to evaluate
neurodevelopment and to develop policy human toxicity or ecologic effects were established [2]. Because OP pesticides rapidly degrade
recommendations for reduction of such exposures. in the environment, they were considered safer than persistent organochlorine insecticides
JBS is employed by NRDC, an environmental non- like DDT, aldrin, and dieldrin, but over 40 OP pesticides, including the most commonly used
governmental organization. JBS, on behalf of
ones, are now considered by the US Environmental Protection Agency (EPA) [3] and/or the
NRDC, is providing scientific support for a lawsuit
challenging USEPA approval of chlorpyrifos and
WHO Food and Agriculture Organization [4] to be moderately or highly hazardous to human
other organophosphate pesticides. JBS, on behalf health.
of NRDC, has expressed public positions on the The most comprehensive global database on recent pesticide use includes information
scientific evidence of harm to human health and reported by 71 countries in five regions [5]. Annual use during 2010–2015 of OP pesticides in
the environment from chlorpyrifos and other agriculture averages 1,145 tonnes (i.e., metric tons) for 13 African countries, 4,342 tonnes for
pesticides. NRDC and JBS have no direct or
11 Caribbean and Central American countries, 10,013 tonnes for 24 European countries,
indirect financial or fiduciary interest in the
manufacture or sale of any pesticide or chemical or 13,404 tonnes for 6 South American countries, and 29,554 tonnes for 17 Asian countries, with
methodology that is the subject of this manuscript. India dominating use. We additionally obtained data from the US [6] and have mapped total
SE received grant funding related to environmental annual agricultural OP use by country (Fig 1) and total annual agricultural use by country per
exposures and child neurodevelopment (UNC 1,000 square km (S1 Fig). Widespread use of OP pesticides in agriculture—as well as in homes,
Chapel Hill Gillings Innovation Lab; NIH grants
parks, schools, and hospitals and on golf courses, right-of-ways, and other public spaces—has
R01ES021777, P01ES09584; and EPA R8208270).
DHB was supported by NIH grants to study
led to ubiquitous human exposure.
pesticides in relation to child development and OP pesticides present a range of health hazards. Here we review the scientific evidence of
health (P01ES011269, UG3-OD023365, P30- OP impacts on child neurodevelopment. In addition, we discuss inadequacies in current OP
ES023513, EPA R833292). BE was supported by pesticide regulations and present recommendations for urgently needed policy change.
NIH grants to study pesticides and child
neurodevelopment (R01ES026994,
UG3OD023356, R24ES028529, R01ES020360; Neurodevelopmental effects of OP pesticides
CIHR 241846, R01ES023067, R56ES023591). RW
Systematic reviews and multiple epidemiologic studies in the US and other countries, span-
received funding from NIH for studies of
environment including pyrethroid exposure and
ning diverse populations in both urban and agricultural settings, have linked OP exposures
child development (R01ES021482, P01ES09600, during fetal development with poorer cognitive, behavioral, and social development in chil-
EPA RD83214101). IHP and AB provided expert dren [7–11]. Generally, levels of exposure in these studies are too low to induce measurable
testimony (unpaid) to the California Senate depression of cholinesterase in adults. In one review, adverse effects of OP pesticide exposure
Committee on Environmental Quality regarding on neurodevelopment were seen in all but one of the 27 studies evaluated; the strongest associ-
commercial agricultural pesticide applications near
ations occurred following prenatal exposures [9]. Outcomes associated with OP pesticide
schools; IHP provided expert consultation (unpaid)
to the State of California Governor’s staff on use of exposure to the fetus include abnormal primitive reflexes in newborns; mental and motor
chlorpyrifos in agriculture. IHP submitted delays among preschoolers; and decreases in working and visual memory, processing speed,
information to the US EPA regarding regulation of verbal comprehension, perceptual reasoning, and IQ among elementary school–age children.
chlorpyrifos in agriculture (unpaid). IHP is Co- Prenatal exposures also elevated risks for symptoms or diagnoses of attention-deficit/hyperac-
Director of Project TENDR (unpaid), an
tivity disorder (ADHD) and autism spectrum disorder (ASD).
organization seeking to reduce the incidence of
child neurodevelopment disorders by eliminating
Consistent with the wide range of outcomes reported in human studies, the toxicity of
or lowering exposures that increase risks. IHP early-life OP pesticides on neurodevelopmental end points has been confirmed in experimen-
serves on the Science Advisory Board to the tal animal studies. Parallel with epidemiologic findings, effects on cognition, motor activity,
California Breast Cancer Prevention Program and social behaviors were repeatedly demonstrated in rodents dosed in early life with concen-
(unpaid). BE served as a member, National trations of OPs eliciting little to no inhibition of AChE in the brain [10,12]. The timing of

PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002671 October 24, 2018 2 / 15

Research Council of the National Academies, exposure played a critical role in the biochemical and anatomic targets affected, as well as in
Committee to Review California’s Risk Assessment the specific behavioral and developmental alterations evoked [12].
for Pesticides (unpaid); and serves currently as a
Since publication of the epidemiologic reviews, a higher likelihood of an ASD diagnosis was
member of the National Advisory Environmental
Health Sciences Council (unpaid). RW submitted observed for children born to women residing within (versus beyond) 1.5 km of OP pesticide
information to the US EPA regarding regulation of applications on agricultural fields; the strongest associations were for chlorpyrifos [13].
chlorpyrifos (unpaid). RW is a founding member/ Another recent study showed that higher OP pesticide metabolite concentrations in maternal
advisor to International Society for Children’s urine during pregnancy were associated with ASD traits identified in adolescence [14]. Other
Health and the Environment (unpaid) and serves
research teams reported residential proximity to agricultural OP use during fetal development
on the science advisory board for Women’s Voices
for the Earth (unpaid). BL has no competing
to be associated with reduction in child’s IQ at age 7 years [15] and higher umbilical cord
interests to report. blood concentrations of chlorpyrifos with mild to moderate arm tremors in children at
approximately age 11 years [16]. Risks for impaired neurodevelopment were greater among
Abbreviations: AChE, acetylcholinesterase; ADHD,
attention-deficit/hyperactivity disorder; ASD,
children of farmworkers, who experience higher exposures [17], and children with genetic sus-
autism spectrum disorder; EPA, Environmental ceptibility factors that reduce capacity to detoxify OP pesticides [7]. In the same study that
Protection Agency; FFDCA, Federal Food, Drug, and examined ASD, moderate to severe developmental delay was associated with nearby applica-
Cosmetic Act; FIFRA, Federal Insecticide, tions of carbamates, similar to OP pesticides, but not with OP pesticides [13]. Two other stud-
Fungicide, and Rodenticide Act; FQPA, Food Quality ies, both conducted in urban cohorts of higher social and economic status, found no
Protection Act; IPM, integrated pest management;
associations of OP pesticide metabolites with scores on intelligence tests [18,19]. Still, the
JMPM, Joint FAO/WHO Meeting on Pesticide
Management; lbs/yr, pounds per year; OP, weight of evidence clearly indicates that OP exposures during prenatal development are likely
organophosphate; PAN, Pesticide Action Network; detrimental to brain function.
PON1, paraoxonase 1. Accurate measurement of exposure is critical in environmental health studies. The OP pes-
Provenance: Not commissioned; externally peer ticide studies determined exposure in various ways, ranging from quantification of OP metab-
reviewed. olites in maternal urine collected during pregnancy and direct measurement of chlorpyrifos in
umbilical cord blood to quantifying nearby pesticide use by geographically linking residential
addresses with California’s database of commercial pesticide applications [20,21]. The Califor-
nia Pesticide Use Report Database, which contains specific pesticide quantity and the date and
location of each application, has been validated by two exposure assessment studies, which
showed that the amount applied within a few days to a week correlates highly with measured
ambient air concentrations in nearby locations [22,23]. In the vast majority of studies
reviewed, objective measures (both biologic markers and validated application data) were gen-
erated according to scientifically established protocols and obtained independently of the
child’s outcome.

Concerns at both high and low OP exposures

Critical to understanding the influences on early child neurodevelopment is the distinction
between acute effects after high-level exposures versus sequelae from chronic lower exposures.
As noted above, by inhibiting the enzyme AChE, high-level OPs cause acute, in some cases
fatal, effects in humans [2]. Indeed, internationally, pesticide poisonings take a heavy toll, esti-
mated at 200,000 deaths per year [24], with approximately 99% occurring in developing coun-
tries [25]. About 110,000 pesticide self-poisoning deaths occur each year globally, which
represents an average across the reporting countries of 13.7% of all suicides [26], with a wide
range from 0.9% in low- and middle-income European countries to 48.3% for low- and mid-
dle-income countries of the Western Pacific region.
Large quantities of highly hazardous OP pesticides are imported into developing countries.
For example, OP pesticides ranked fourth among 24 chemical groups of pesticides imported
into Central American countries [27], for which the two OP pesticides imported in the greatest
quantity (terbufos and methamidophos) have been targeted for phaseout by the Rotterdam
Convention, an international trade agreement on hazardous chemicals aimed at protecting
human health and the environment [4,28]. Pesticide poisoning affects agricultural workers

PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002671 October 24, 2018 3 / 15

 Fig 1. Average annual tonnes of OP pesticides used in agriculture, by country, 2010–2015. Darker shading indicates greater usage. Gray shading indicates that
no data were available during that time period. For countries with data available for some but not all years during 2010–2015, the available data within that period
were used. Source for US data was [6]; and for all other countries, [5]. Map created with mapchart.net. OP, organophosphate.
https://doi.org/10.1371/journal.pmed.1002671.g001

who often receive little or no instruction on the use of hazardous substances, are not provided
with personal protective equipment, and/or operate application equipment that is not properly
maintained. Additionally, overuse, misuse, and accidents have led to deaths of schoolchildren,
e.g., in India in 2013, China in 2014, and Bangladesh in 2015, from consumption of meals with
high levels of OP pesticides [4,24,29,30].
As tragic as these acute poisonings are, an OP pesticide exposure in the absence of overt
poisoning does not imply that neurologic damage has not occurred—for both children and
adults [31]). The US EPA concluded in 2016 that the existing epidemiologic literature pro-
vided “sufficient evidence that there are neurodevelopmental effects occurring at chlorpyrifos
exposure levels below that required to cause acetylcholinesterase inhibition” [11]. Such
chronic, low-level exposures are often overlooked or dismissed as benign because neither the
pregnant woman nor the fetus shows clinically visible signs or symptoms. Furthermore, the
developmental deficits do not manifest until months or years later. Indeed, the scientific con-
sensus is that AChE inhibition is uninformative with regard to neurodevelopmental effects in
children and that the toxic effects from chronic, low-level exposure occur at concentrations
too low to inhibit cholinesterase [1,9]. The evidence thus indicates that OP pesticides can inter-
fere with brain development at levels previously thought to be safe or inconsequential.
Hence, AChE inhibition cannot be used as a biomarker to identify neurodevelopmentally
harmful OP pesticide exposures. Reliance on AChE inhibition for regulatory purposes
obscures the serious threat that OP pesticides pose to early brain development and represents
an unscientific and inadequate approach to health risk assessment. In fact, other effects appear
likely to mediate the OP toxicity to neuronal systems that is foundational for childhood behav-
ioral and cognitive deficits. Toxicologic evidence implicates OP pesticides in neuroinflamma-
tion, protein-kinase C receptor signaling, insulin resistance, dopaminergic and glutamatergic

PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002671 October 24, 2018 4 / 15

 neurotransmission, and interference with DNA synthesis and nuclear transcription factor
functioning, mechanisms highly relevant for brain development [12,32–34].
Indeed, as-yet-undiscovered harm may emerge from further follow-up of those exposed in
early life. Outcomes from fetal exposures appear to be persistent, with associations observed
into mid- and late childhood. One cohort repeatedly showed deficits in memory, IQ, and
attention deficits or ADHD at ages 2, 3, 5, and 7 years, whereas another exhibited deficits in
mental development and reasoning in infancy and at ages 6–9 years (reviewed in [8]). Children
with high versus low chlorpyrifos concentrations in their umbilical cord blood had differences
in brain volume in regions responsible for attention, receptive language processing, social cog-
nition, and regulation of inhibition [35]. These neuroanatomic alterations, which potentially
constitute a pathway from pesticide exposure to the associated behavioral and cognitive defi-
cits, may be permanent.

Pesticide regulation
Pesticide regulations vary widely across the globe. As with pesticide usage, no database has
consolidated this information for all countries. Table 1 shows available data on 47 OP insecti-
cides [36] banned by one or more countries, as well as the level of health hazard and the num-
ber of countries that have banned each OP pesticide. The most comprehensive database
available on current governmental regulation of pesticides provides data covering 39 of these
47 OP insecticides, obtained from 106 countries outside the US [37]. Included in this database
are total bans, along with denials of approval, but not restrictions. Of the 106 countries, 81%
have regulated one or more of the 39 OP insecticides [37]. The 28 countries of the European
Union have taken action on the most OP pesticides (33). Additional countries that have
banned more than 10 include the US (26), Cambodia (15), China (15), Saudi Arabia (15),
Guinea (12), Korea (12), Mauritania (12), and Thailand (12). Notably, having regulations in
place does not necessarily mean that they are enforced. Furthermore, some of the most toxic
OP pesticides that are banned across dozens of countries are exported elsewhere, often to
developing countries and sometimes in large quantities, for example, to Costa Rica and Guate-
mala [27]. In Mexico, at least a dozen OP pesticides that are classified as highly hazardous by
the WHO Food and Agriculture Organization are used [38].
Within the US, the EPA regulates pesticides under two overlapping statutes—the Federal
Food, Drug, and Cosmetic Act (FFDCA) and the Federal Insecticide, Fungicide, and Rodenti-
cide Act (FIFRA). Many of the insecticides banned in the US were initially licensed prior to
1970, when required health and safety assessment was minimal and before the US EPA was
formed. As a result of legislation in the 1970s requiring increased health and safety studies, vol-
untary agreements were reached between manufacturers and the EPA to cancel or phase out
registrations for some pesticides, including 18 OP insecticides.
In 1996, the Food Quality Protection Act (FQPA) amended FIFRA and FFDCA by
requiring the EPA to include additional safety factors to protect children because of their
greater exposures and heightened susceptibility [39]. Children have larger body burdens
of pesticides because of greater intake of food, water, and air than adults, per unit of their
body weight; they explore the world through mouthing behaviors; and they frequently
crawl or play on floors where pesticides and other toxic chemicals settle. Heightened sus-
ceptibility during early years arises in part from immature detoxifying enzyme systems,
including paraoxonase 1 (PON1) [7,40,41]. Under the FQPA, the EPA must show that
there is reasonable certainty that no harm will result from aggregate exposure to the pesti-
cide, including all anticipated dietary exposures and all other exposures for which there is
reliable information.

PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002671 October 24, 2018 5 / 15

Table 1. OP insecticides, hazard levels, and number of countries banning them.
Compound1 Hazard level Number of countries (outside US) Banned OPs in US designated by X. All other OPs on list are
that have banned it2 currently registered for use in the US3
US FAO-WHO5 PAN2
EPA4
1 Acephate M M H 31
2 Azinphos-methyl H H H 39 X
��
3 Cadusafos H H 31
��
4 Chlorethoxyphos E H 29
5 Chlorfenvinphos H H H 35 X
6 Chlorpyrifos M M H 2
��
7 Chlorpyrifos-methyl S H 1
8 Chlorthiophos6,7 H �� �� ��
X
9 Coumaphos H H H 30
10 Dichlorfos M H H 32
(dichlorvos)
11 Dialifor/dialifos6,7 H �� �� ��
X
12 Diazinon M M H 30
13 Dicrotophos H H H 34
��
14 Dimethoate M H 4
15 Dioxathion6,7 H �� �� ��
X
16 Disulfoton H E H 38 X
17 Ethion M M — 30 X
18 Ethoprop M E H 8
(ethoprophos)
19 Ethyl parathion7 H �� �� ��
X
20 Fenamiphos H H H 6 X
21 Fenitrothion M M H 28
22 Fenthion M M H 30 X
23 Fonofos (fenophos)6 H ��
— 33 X
24 Isazophos6,7 �� �� �� ��
X
6 ��
25 Isofenphos H — 29 X
26 Malathion M S H 2
27 Methamidophos H H H 49 X
28 Methidathion H H H 34 X
29 Methyl parathion H E H 59 X
30 Mevinphos H E H 37 X
31 Monocrotophos H H H 60 X
32 Naled M M H 28
33 Oxydemeton-methyl M H H 30 X
34 Phorate H E H 37
35 Phosalone M M — 29 X
36 Phosmet7 M M �� ��

37 Phosphamidon H E H 49 X
38 Phostebupirim7 �� �� �� ��

39 Pirimiphos-methyl7 M M �� ��

40 Profenofos M M H 29 X
41 Propetamphos M H H 28 X
42 Sulfotepp H E H 32 X
6,7 �� �� ��
43 Sulprofos M X
(Continued )

PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002671 October 24, 2018 6 / 15

Table 1. (Continued)

Compound1 Hazard level Number of countries (outside US) Banned OPs in US designated by X. All other OPs on list are
that have banned it2 currently registered for use in the US3
US FAO-WHO5 PAN2
EPA4
44 Temephos M S H 28 X
45 Terbufos H E H 34
��
46 Tetrachlorvinphos M H 28
47 Trichlorfon M M H 32

Level of hazard: E, extreme; H, high; M, moderate; S, slight

��
, not classified;—, not H (PAN6 ranking); X, banned in the US.
1
This list of OP insecticides is taken from the US EPA Office of Pesticide Programs “Organophosphorus Cumulative Risk Assessment, 2006 Update” [36] (Table ES-1,
p. 16 “OP Pesticides Considered in the 2006 Update of the Cumulative Risk Assessment”), from which we have excluded those pesticides that are not insecticides.
2
Hazard Ranking and number of countries that banned: from PAN International Consolidated List of Banned Pesticides [37] (http://pan-international.org/pan-
international-consolidated-list-of-banned-pesticides/). Methods and sources for collection of these data are described in the Explanatory Notes: (http://pan-
international.org/wp-content/uploads/Consolidated-List-of-Bans-Explanatory-2017April.pdf). This list does not include restrictions, only bans or decisions to not
approve.
3
A "banned" pesticide in the US is defined as a pesticide for which all registered uses have been prohibited by final EPA action and includes pesticides that have been
withdrawn through voluntary agreements between industry and the US EPA. Status of OPs that are either banned or registered for use in the US provided in personal
communication from Yu-Ting Guilaran (Director, Pesticide Re-evaluation Division, Office of Pesticide Programs, US EPA) to JBS, July 12, 13, and 23, 2018.
4
Hazard ranking [3].
5
Hazard ranking [4]: The concept of and criteria for “Highly Hazardous Pesticides” was initially described in the JMPM second report in 2008,”Report of the 2nd FAO/
WHO Joint Meeting on Pesticide Management” (last accessed July 2018) (http://www.fao.org/fileadmin/templates/agphome/documents/Pests_Pesticides/Code/Report.
pdf). As scientific understanding of mechanisms for pesticide toxicity has advanced, these have been included, as described in the 2016 publication of “International
Code of Conduct on Pesticide Management Guidelines on Highly Hazardous Pesticides” (http://apps.who.int/iris/bitstream/handle/10665/205561/9789241510417_eng.
pdf;jsessionid=D3B3CCA5B28692A5F3D437B2CF7F0AA0?sequence=1). The FAO-WHO JMPM defined banned pesticides thus: “Banned pesticide means a pesticide
all uses of which have been prohibited by final regulatory action, in order to protect human health or the environment. It includes a pesticide that has been refused
approval for first-time use, or has been withdrawn by industry either from the domestic market or from further consideration in the domestic approval process, and
where there is clear evidence that such action has been taken in order to protect human health or the environment.”
6
Considered to be obsolete or no longer used as a pesticide, according to the WHO Recommended Classification of Pesticide Hazards, 2010.
7
Not included in the PAN database.
Abbreviations: EPA, Environmental Protection Agency; FAO-WHO, WHO Food and Agriculture Organization; JMPM, Joint FAO/WHO Meeting on Pesticide
Management; OP, organophosphate; PAN, Pesticide Action Network.

https://doi.org/10.1371/journal.pmed.1002671.t001

After passage of the FQPA, OP pesticide use across all market sectors declined by over 70%,
from 70 million pounds per year (lbs/yr) in 2000 to about 20 million lbs/yr in 2012 (the most
recent available data) [6]. By 2002, most nonagricultural uses were phased out by agreements
between the EPA and the pesticide manufacturers, based on results of EPA risk assessments
for chlorpyrifos and diazinon showing unacceptably high risks to residents, particularly chil-
dren, from residential pest control [42,43]. The volume of OP pesticides used on foods com-
monly consumed by children, such as fruits, decreased by 57% between 1994 and 2004, from
28 to 12 million pounds (12,701 to 5,443 metric tonnes) of active ingredient applied annually
[44]. This action resulted in dramatic reductions in blood and urine concentrations of OPs
among the US population [45]. However, agricultural OP pesticide use continues to contribute
to exposures for farmworkers, their families [15], and residents in homes, children in schools,
and other bystanders near farmlands [23], as well as to food and drinking water contamination
that affects a broader population.
In 2016, the EPA concluded that exposure to chlorpyrifos—the most commonly used OP
insecticide in the US—from either food or drinking water alone could lead to unacceptably

PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002671 October 24, 2018 7 / 15

 high population exposures and determined that some reproductive-aged women, infants, and
children consumed levels of chlorpyrifos substantially above the acceptable level for these vul-
nerable life stages [11]. The EPA also identified numerous scenarios that could result in unsafe
exposures for agricultural workers and bystanders. For these reasons, as required by law, the
EPA proposed to revoke all standards (called tolerances) that permit residues of chlorpyrifos
on food. Revocation of these tolerances would essentially ban this OP on food crops [11].
However, in March 2017, despite overwhelming evidence of harm and contrary to the EPA’s
own risk assessments, the Trump administration EPA announced that “the science addressing
neurodevelopmental effects remains unresolved, and that further evaluation of the science . . .
[therefore] is warranted to achieve greater certainty as to whether the potential exists for
adverse neurodevelopmental effects to occur from current human exposures to chlorpyrifos,”
concluding that the EPA would not cancel any uses of chlorpyrifos [46]. This action would
delay potential regulatory action until October 2022. However, on August 9, 2018, the US
Court of Appeals for the Ninth Circuit ordered the EPA to finalize the ban on chlorpyrifos
within 60 days, including a ban on all US sales and a prohibition of food contaminated by the
insecticide from reaching the US market. The court based its decision on the EPA’s 2016 find-
ings that the pesticide fails to meet federal safety standards and is particularly harmful to
infants and children. In September 2018, the EPA filed a petition for a rehearing of the chlor-
pyrifos case.

Recommendations
In 2014, the American Academy of Pediatrics called for pediatricians and governments to rec-
ognize and reduce pesticide exposures through education, pesticide labeling, public health sur-
veillance, and regulatory action [47]. In 2016, an independent group of scientists and health
professionals published the Project TENDR Consensus Statement as a national call to action to
significantly reduce exposures to chemicals—including OP pesticides—that have been identi-
fied as putting children in the US, and likely throughout the world, at increased risk of neuro-
developmental disorders [48]. Project TENDR concluded that the evidence of significant risks
to children’s neurodevelopment from OP pesticide exposure warrants strong regulatory
action. In 2017, a United Nations report on the Right to Food called for changes to agricultural
practices to ensure food that is safe, free from pesticides, and qualitatively adequate [24]. To
achieve the goal of reducing exposures to OP insecticides, we therefore propose an action plan
for governments, public health and medical institutions or organizations, and agricultural
entities. Our recommendations are detailed in Box 1. These steps would markedly reduce pre-
natal and childhood exposures to OP pesticides.
Exemplary actions at various governmental levels have been taken. At the multinational
level the EU chose to not approve close to 200 pesticides, of which over 20 are OPs, and multi-
ple individual countries have instituted bans on OPs such as dichlorvos, methamidophos, and
methyl parathion [37]. In the US, California has taken steps to limit agricultural use of pesti-
cides near schools and childcare facilities when children are present [50], and Hawaii recently
banned the distribution, sale, transport, and use of any pesticide containing chlorpyrifos as an
active ingredient [51].
In reducing OP pesticide usage, toxic effects from substitute or replacement chemicals
require scrutiny. Pyrethroid pesticides have replaced OPs as the main class of insecticides in
residential pest control products, but recent rodent laboratory studies and epidemiologic stud-
ies suggest that prenatal pyrethroid pesticide exposures may also increase the risk of adverse
neurodevelopment and behaviors and negative emotions [13,52–54]. Neonicotinoid pesticides
are now the fastest-growing class of insecticides used on crops in the US [55]; they are

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 Box 1. Recommendations to move towards elimination of human
exposures to OP pesticides
We recommend the following actions by governments:
• National and state or provincial governments, globally: phase out use of all OPs in
agriculture;
• National and state or provincial governments, globally: ban nonagricultural use of all
OPs, including household products;
• US EPA: revoke all food tolerances for chlorpyrifos, as the agency previously
proposed;
• US EPA and state governments: phase out the use of all other OPs in agriculture;
• US EPA: ban nonagricultural pest control uses of the few remaining OPs;
• In the interim, national, state, and local agencies: take steps to reduce human exposure
(e.g., require advance notification to nearby residents and schools before applications
of OP pesticides; implement restrictions on application methods such as aerial spray-
ing and air blast to reduce drift exposures and to protect water and sensitive sites such
as homes and schools);
• National, state, and local agencies: conduct regular monitoring of watersheds to ensure
OPs do not continue to pollute lakes, rivers, and streams, including those that are
sources of drinking water, and implement targeted monitoring of drinking water;
• National and state agencies: establish an effective comprehensive pesticide use and ill-
ness reporting program either nationally or through coordinated statewide programs.
We recommend that medical schools, public health programs, and healthcare
associations
• organize continuing medical education courses to educate healthcare providers on
both acute and chronic effects of exposures to toxic chemicals, including how to recog-
nize and treat children who received high OP exposures; how to advise pregnant
women and parents of young children on steps they can take to avoid pesticide expo-
sures from lice, flea, and tick treatments [49], lawn and garden products, and applica-
tions in nearby agricultural land, golf courses, schools, and shopping malls; and how
properly to clean potential pesticide residues from fruits and vegetables and to identify
which produce contain the highest levels;
• educate health providers on the necessary reporting of pesticide poisonings to state
surveillance;
• encourage schools of nursing and medicine to incorporate curricula on environmental
hazards that include pesticides and medical boards to include environmental health in
their examinations.
We recommend that agricultural entities
• provide enhanced training for workers, in the most appropriate languages and at rele-
vant educational levels, on the handling and application of pesticides and on the
worker protection standards. In the US, this means EPA Worker Protection Standards
training at the required frequency;

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 • educate workers on how to avoid take-home exposures to their families;
• institute environmentally friendly approaches to control pests—integrated pest man-
agement (IPM)—with a goal to eliminate or minimize toxic chemicals in our food
sources.

persistent in plants, soil, and water and highly toxic to invertebrates, including endangered
aquatic species, bees, and other beneficial insects [56]. Moreover, the impacts of broad and sys-
temic pesticide use are well documented to have had significant negative ecological conse-
quences affecting terrestrial, aquatic, wetland, marine, and benthic habitats and posing risks to
ecosystem functioning and resilience.
What are the alternatives, if synthetic pesticides other than OPs are also neurotoxic?
Agriculture represents the vast majority of OP pesticide use, which includes both crop and
livestock production. Widespread implementation of IPM is needed to reduce this use. IPM is
a reduced-risk pest management strategy that emphasizes inspection, monitoring, prevention,
and pest control using the least toxic methods including (agri)cultural practices such as inter-
cropping (growing two or more crops in close proximity, which can reduce susceptibility to
disease and pests), crop rotation, and cover crops (to reduce soil erosion and improve soil
health); physical controls such as traps or bug vacuums; habitat management that encourages
beneficial insects; and biological control, such as the release of parasitic wasps to control
aphids, with pesticides used only as a last resort. When used, least-toxic pesticides are chosen
first, such as materials approved for organic farming (e.g., Bacillus thuringiensis to control Lep-
idoptera) [57].
While IPM strategies do not, in principle, forbid the use of OP and other neurotoxic pesti-
cides, these higher-risk materials serve as a last resort and should be applied in a way that pro-
tects human and environmental health. That most crops produced with OP pesticides are also
produced organically provides compelling evidence that OP pesticides are not essential [58].
Some recalcitrant pests may be difficult to manage with less toxic pesticides, which in some
instances may result in lower yields or higher production costs, reducing competitiveness.
Recent research, however, indicates that crop yields from organic and other alternative pro-
duction systems are increasing and in some cases match conventional yields [59]; these
approaches additionally would likely reduce external costs to public health and the environ-
ment [60]. To ensure that farmers are not threatened with rising costs and thinner profit mar-
gins, many agricultural trade and policy organizations recommend increased government
support for extension research and outreach needed to support transitions to less toxic materi-
als [61].
Public health, a second use of OP pesticides, represents a small fraction of their applications.
For example, OP pesticides are used for mosquito and other vector control to prevent vector-
borne diseases such as Zika virus or West Nile virus. We do not recommend abrupt changes in
pest management that would increase the risk of exposure to these viruses. We do advocate
increased funding for better understanding of the ecology and biology of these and other vec-
tors and the diseases they spread and alternative methods to control them without the use of
OP or other neurotoxic pesticides. The historical example of the Mediterranean fruit fly in Cal-
ifornia, a serious invasive agricultural pest, provides a model for application to disease vectors.
In the early 1990s, state officials used helicopters to spray malathion over residential areas

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 where over 2 million people resided [62]. Subsequent concerns [63] resulted in development
of a comprehensive sterile fruit fly release program that, combined with spot treatments often
using organically approved pesticides, has successfully controlled infestations without the need
for OP pesticide applications over wide swaths of residential areas [64,65]. Similar strategies
should also be considered for new invasive species, such as the spotted lanternfly, currently
threatening eastern US ecosystems and agriculture. Integrated vector management would
favor using least-toxic options.
Structural, indoor, and landscape pesticide applications, the third category of OP uses, can
result in high exposures. Dichlorvos, an OP already banned in many countries, is still permit-
ted indoors by the US government for flying insects. Similarly, malathion is still sold for land-
scape and garden use. Given risks of adverse health effects due to chronic, low-level exposures
and reported acute poisoning of consumers in the US [66], we recommend that all remaining
structural, indoor, and landscape use of OPs be phased out immediately, especially in environ-
ments where children are present. Basic IPM principles should be applied in these environ-
ments, including pest exclusion (i.e., screens) and traps.
To preserve health and sustainability, both indoor and outdoor pest management must ulti-
mately rely on nontoxic or less toxic alternatives; simultaneously, agriculture needs stronger
support to move towards a systems approach that minimizes use of neurotoxic pesticides
while providing healthy food and economic sustainability for farmers. The Report on the
Right to Food by the Special Rapporteur to the UN General Assembly articulates a similar phi-
losophy: in order to successfully reduce or eliminate use of hazardous pesticides, the interna-
tional community’s efforts will need to address the ecologic, social, and economic factors
currently embedded in agricultural policies. At the national level, this will require challenging
agrochemical-dependent farming to restructure and seek the safest feasible alternatives [24].
We join the American Academy of Pediatrics and the UN in recommending close surveillance
of pesticide poisonings, incentives for nonchemical approaches to pest control, monitoring of
water and food sources of pesticides, and enforcement of the public’s right to know through
full disclosure, labeling, and further communications for pesticide formulations and for resi-
dues in food, water, and elsewhere. Finally, we believe it is an ethical and social responsibility
for civil society, for the medical profession, and for the agricultural industry to disseminate
widely to the general public what is known about the sources of pesticide exposures and their
adverse impacts on health and to develop training programs in agroecology in order to achieve
a paradigm shift in food production.

Supporting information
S1 Fig. Average annual tonnes of OP pesticides used in agriculture per 1,000 square km, by
country, 2010–2015. Darker shading indicates greater usage per 1,000 square km. Gray shad-
ing indicates that no data were available during that time period. For countries with data avail-
able for some but not all years during 2010–2015, the available data within that period were
used. Source for US data was [6]; and for all other countries, [5]. Map created with mapchart.
net. OP, organophosphate.
(TIF)
S1 Text. Spanish translation of full article.
(DOCX)
S2 Text. Chinese translation of full article.
(DOCX)

PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002671 October 24, 2018 11 / 15

 S3 Text. French translation of summary bullet points.
(DOCX)
S4 Text. Italian translation of summary bullet points.
(DOCX)

Acknowledgments
We are grateful for the support from Maureen Swanson.

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