**PETITION TO REVOKE ALL TOLERANCES AND CANCEL ALL REGISTRATIONS FOR THE
PESTICIDE CHLORPYRIFOS**

**Filed 12 September 2007**

The Natural Resources Defense Council (NRDC) and Pesticide Action
Network North America (PANNA) petition the U.S. Environmental Protection
Agency (EPA) to revoke all tolerances and cancel all registrations for
the pesticide chlorpyrifos. This petition is filed pursuant to 21 U.S.C.
§ 346a(d).

# Introduction

Chlorpyrifos is one of the most widely used insecticides in the United
States. It is used on various food and feed crops, on golf courses, as a
non-structural wood treatment, and as an adult mosquitocide.
Agriculturally, approximately 10 millions pounds are applied annually,
with use on corn comprising the largest market (using approximately 5.5
million pounds ai). [^1]

Chlorpyrifos belongs to a class of pesticides called organophosphates,
which EPA has grouped together based on their common mechanism of
toxicity. The devastating effects of this class of pesticides,
originally designed as wartime nerve agents including sarin gas, are
attributed to their inactivation of an enzyme called cholinesterase.[^2]
This enzyme is responsible for the timely deactivation of the nerve
signaling protein acetylcholine.

Acetylcholine is a messenger of the nervous system, a
"neurotransmitter," which carries the signal from a nerve cell to its
target. Important targets of acetylcholine include muscles, sweat
glands, the digestive system, and even heart and brain cells. In
particular, acetylcholine signals activity of the "rest and digest"
portions of the nervous system (the parasympathetic system) that
stimulates digestion, slows the heart rate, and helps the body to
conserve energy. The organophosphate pesticides, including chlorpyrifos,
block the ability of cholinesterase to deactivate acetylcholine after
its message is delivered. The resulting accumulation of acetylcholine
causes over-activation of all its targets. Clinical symptoms of
organophosphate poisoning can include: eye pupil contraction, increased
salivation, nausea, dizziness, confusion, convulsions, involuntary
urination and defecation, and, in extreme cases, death by suffocation
resulting from loss of respiratory muscle control.

The state of the science identifying many various adverse health effects
associated with dietary exposure to chlorpyrifos supports a ban on
chlorpyrifos and revocation of all food tolerances. This petition
summarizes the overwhelming scientific evidence that chlorpyrifos is too
dangerous to be re-registered for food uses.

# Legal Standard 

EPA regulates pesticides under two statutes, the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. § 346a and the Federal Fungicide,
Insecticide, and Rodenticide Act (FIFRA), 7 U.S.C. § 136 *et seq.* The
Food Quality Protection Act of 1996 ("FQPA") significantly amended both
the FFDCA and FIFRA by mandating that health-based and child-protective
standards drive decisions about acceptable levels of pesticide residues
in food and the environment. FIFRA requires that pesticides must be
registered to be sold in the United States.[^3] EPA may not register a
pesticide unless the chemical will perform its intended function without
causing any "unreasonable adverse effects on the environment."[^4]

The FFDCA, as amended by the FQPA, authorizes EPA to set tolerances
(maximum allowable levels) for pesticide residues in food or to grant
exemptions from the requirement to have a tolerance.[^5] EPA may
"establish or leave in effect a tolerance for a pesticide chemical
residue in or on a food only if the Administrator determines that the
tolerance is safe."[^6] The term "safe" means that "there is a
reasonable certainty that no harm will result from aggregate exposure"
to the pesticide, "including all anticipated dietary exposures and all
other exposures for which there is reliable information."[^7] A
pesticide may not be used on a particular food unless there is a
tolerance or exemption for that food.[^8] The Food and Drug
Administration and the U.S. Department of Agriculture are charged with
enforcing these regulations by randomly sampling fruits and vegetables
for exceedances of tolerances or use of unregistered pesticides or
banned pesticides.

The FFDCA explicitly requires that EPA, in establishing a tolerance,
must assess the risk that a pesticide poses to infants and children in
particular.[^9] Before EPA can establish a tolerance, the Agency shall
"ensure that there is a reasonable certainty that no harm will result to
infants and children from aggregate exposure" to the pesticide, and
shall "publish a specific determination regarding the safety of the
pesticide chemical residue for infants and children."[^10] In ensuring
that the statutory safety standard is met, EPA must consider available
information concerning "the special susceptibility of infants and
children," including "neurological differences between infants and
children and adults, and effects of *in utero* exposure to pesticide
chemicals."[^11] EPA must also base its tolerance decision on available
information about "food consumption patterns unique to infants and
children" and the "cumulative effects on infants and children of
\[pesticides\] that have a common mechanism of toxicity."[^12] EPA
acknowledges that, when setting new tolerances under the standard, it
"must now focus explicitly on exposures and risks to children and
infants."[^13]

Furthermore, "an additional tenfold margin of safety for the pesticide
chemical residue and other sources of exposure shall be applied for
infants and children to take into account potential pre- and post-natal
toxicity and completeness of the data with respect to exposure and
toxicity to infants and children."[^14] EPA can depart from this
requirement and use a different margin of safety "*only if*, on the
basis of *reliable data*, such margin will be safe for infants and
children."[^15]

Tolerance decisions are driven by the level of pesticide residue
detected on food, which is the amount of pesticide that remains on a
commodity after a pesticide is applied at a rate that meets or exceeds
effective pest control.[^16] They are "not based primarily on health
considerations\.... Their primary purpose is to ensure compliance with
good agricultural practice."[^17] On the other hand, reference doses
(RfD), which represent the amount of pesticide residue that is safe for
consumers to eat, are set, if at all, after tolerances. Based on residue
data from food and drinking water and considering complexities, such as
cooking, if the dietary exposure exceeds the RfD, EPA informs the
registrant that the tolerance is unacceptably high. The registrant is
tasked with proposing mitigation options, such as a lower application
rate or cancellation of that use. As such, the pesticide control
framework was established to maintain pesticide residues on food not at
safe levels but at or below tolerance levels.

# Factual Background

In 2001, EPA completed the chlorpyrifos aggregate assessment, called an
Interim Reregistration Eligibility Decision (IRED), which revised, but
retained, many of the pre-existing food tolerances (allowable residue
limits on food).[^18] In its 2002 comments on the IRED (Docket ID No.
OPP-34203G), NRDC challenged the scientific limitations of the IRED,
identified evidence of harm, and highlighted that there is inadequate
evidence to establish a safe level at which infants and children will
not suffer any developmental harm due to chlorpyrifos exposure. EPA
never responded directly to NRDC's comments or other comments submitted
by other public interest advocates, including the Pesticide Action
Network North America (PANNA) and the New York Attorney General (Docket
ID No. OPP-34203G).

In 2006, EPA completed the cumulative risk assessment (CRA) for all
organophosphates (OPs), including chlorpyrifos, and reaffirmed the
chlorpyrifos IRED without change, despite new, significant published
studies that emerged during this time showing harm. Without addressing
the comments by NRDC and other public interest advocates and without
referencing much of the data that had been available since 2001, the
Agency concluded that chlorpyrifos uses would be eligible for
reregistration and that the current pesticide tolerances met the legal
safety standard.[^19] Because EPA failed to respond to any of NRDC's
comments, this petition incorporates by reference the January 14, 2002
NRDC comments and those of other public health advocates.

According to EPA, tolerances are generally reassessed under two possible
scenarios. First, an application to register a new use for a pesticide
forces EPA to review the aggregate assessment and determine whether the
new use 'fits' into the aggregate risk evaluation (i.e. the aggregate
exposure from all use scenarios is at or below the RfD); second, during
registration review, which occurs about every fifteen years, must
reconsider the aggregate risk evaluation. [^20] Tolerances are not
reassessed based on new data, new science, or new evidence of harm.
However, scientific evidence that has emerged since 2001 when the
chlorpyrifos IRED was published reinforce the earlier science showing
that exposure to chlorpyrifos causes many adverse health effects. In
fact, both the weaknesses in the studies relied on by EPA in the IRED
and the failure to incorporate evidentiary science since 2001 undermine
EPA's decision to re-register chlorpyrifos and retain its tolerances. In
this petition we summarize the pre-2001 data and identify relevant
post-2001 scientific evidence relevant to the risk assessment of
chlorpyrifos.

#  {#section .unnumbered}

# A Risk Assessment Must Account for the Full Spectrum of Toxicity

The assessment of the health effects associated with particular
pesticides includes both an aggregate assessment, which analyzes the
risk from multiple routes of exposures (food, water, residential uses)
to a single pesticide, and a cumulative assessment, which analyzes the
risk from cumulative exposure to a class of pesticides that share a
common mode of action. The Agency grouped chlorpyrifos with the other
organophosphates to conducts its cumulative risk assessment. For the
organophosphate cumulative assessment, EPA used the endpoint of plasma
and red blood cell cholinesterase inhibition in dams to determine an
acceptable maximum level of cumulative exposure to organophosphate
pesticides (identified as a 10% effect level, or benchmark dose 10,
BMD10).

Alternately, for the individual aggregate assessment of chlorpyrifos,
EPA identified the critical endpoint as structural alterations in brain
development in exposed rodent pups at the lowest dose tested to
determine an acceptable maximum level of aggregate exposure to
chlorpyrifos (identified as the RfD).[^21] The Agency determined that
there was demonstrated evidence of neuropathology and increased
susceptibility following pre-natal exposure to chlorpyrifos.[^22] Since
the developmental neurotoxicity test (DNT) did not identify a no-effect
level, and to account for possible non-cholinergic effects in the brain,
EPA retained the FQPA factor of 10X. [^23] However, this petition
reviews scientific evidence that a 10X factor is insufficient, and, as
explained below, no safe level of early-life exposure to chlorpyrifos
can be supported.

For the organophosphate cumulative assessment, EPA used only the
endpoint of cholinesterase inhibition in female rat brain at 21-days of
exposure. The Agency argues that there was no evidence of differences
between adults and pups for this endpoint and eliminated the FQPA factor
by dropping it to 1X. However, as discussed below, the Agency's
explanation for this decision does not reflect a true representation of
the data used by EPA.

## Genetic Evidence of Vulnerable Populations

[]{.mark}

As part of the risk calculation for a particular pesticide, EPA will
often include an intra-species variability factor to account for the
variation between different people's responses to the same exposure
(both chemical and dose). The same dosage of chlorpyrifos may be very
harmful to one person and have no effect on another person. This is
because of individualized factors that include differences in
nutritional status, health or disease status, activity level, lifestyle,
exposure to other chemicals or agents, and inherent genetic differences
in the activity of the enzymes that break down toxic chemicals in the
body. Conventionally, the Agency uses a standard intra-species factor of
10X, presuming no more than a 10-fold difference in susceptibility
across a diverse human population.

Paraoxonase (PON1) is a protein (enzyme) that behaves very differently
from one individual to the next, and aids in recovering from pesticide
toxicity. PON1 detoxifies many of the organophosphates, particularly
chlorpyrifos, through catalyzing the hydrolysis of its toxic oxon
metabolite. In other words, PON1 breaks down the toxic by-products of
chlorpyrifos that are produced during its metabolism, so that they do
not build up in the body. A slow-acting genotype of PON1 is less
efficient at detoxifying the oxon and is therefore associated with
increased pesticide toxicity.[^24]

Published epidemiologic studies by Furlong and colleagues in 2003 and
2006 report that the age-related activity of PON1 may impair the ability
for perinatal and juvenile animals and humans to recover from pesticide
toxicity.[^25]^,^ [^26] In fact, the authors reported in their 2006
paper a 164-fold variation in sensitivity to chlorpyrifos between the
most sensitive newborn and the least sensitive mother.[^27] Although EPA
claims to have reviewed this study for the OP CRA , the study supports
an intraspecies factor of over 164X whereas the Agency applied only a
10X intraspecies factor to all the organophosphates.[^28] In the OP
CRA,The Agency specifically acknowledged, and subsequently disregarded,
the Furlong et al. study, instead relying on a 2002 study that used a
physiologically-based pharmacokinetic (PBPK) model for chlorpyrifos to
find that the "response was relatively insensitive to changes in oxonase
activity at low doses." [^29] Despite EPA's stated preference for human
data, and despite the availability of significant informative data
derived from unintentionally exposed people (occupational and
environmental epidemiologic studies, human biomonitoring \[internal
dose\], and human passive dosimetry \[external measurements\]), in this
case the Agency relied on the model to support its assessment. PBPK
models are only as reliable as the data used to design them; they are
therefore meant to help bridge data gaps, not override robust data.

EPA's treatment of the PON1 studies with respect to the calculation of
the intra-species uncertainty factor provides a stunning example of the
Agency turning a blind eye to relevant, robust data. Furthermore, using
an intra-species variability factor of 100X or higher -- as the results
from the Furlong study should prescribe -- would drive the tolerances
below practicable levels of detections. Practically, tolerances set
below the level of detection available for the most sensitive detection
methods makes the tolerance unenforceable. EPA should not have ignored
the result of the Furlong study and should have applied an intra-species
variability factor of at least 150X in the aggregate and cumulative
assessments; practically, the Agency should revoke all tolerances for
chlorpyrifos.

## Long-Lasting Effects from Early Life Exposure in Children

Many studies published since 2001 report that fetal exposure to
chlorpyrifos is more damaging than adult exposure.[^30] Columbia
University researchers published two studies from a single New York City
(NYC) cohort reporting on the effects of chlorpyrifos on birth
outcomes[^31] and child development.[^32] The authors report on a cohort
of NYC African American and Dominican women and babies enrolled over a
number of years, that capture changes in exposure levels related to the
2000-2001 ban of chlorpyrifos for residential use.  Decreases in birth
weight and length were associated with cord blood levels of
chlorpyrifos, and the follow-up of children when they reached age 3
showed that the more highly (prenatally) exposed children (chlorpyrifos
levels of \> 6.17 pg/g plasma) were significantly more likely to
experience delays in cognitive and psychomotor development as well as
attention problems, attention-deficit/hyperactivity disorder problems,
and pervasive developmental disorder problems.  The authors report that
"the proportion of delayed children in the high-exposure group was five
times greater for the Psychomotor Development Index and 2.4 times
greater for the Mental Development Index, increasing the number of
children possibly needing early intervention services." [^33] The
adverse effects on birth outcomes were no longer observed among the
children in the cohort who were born after the ban took effect (Jan
2001) and concentrations in cord blood were significantly lower,
underscoring the benefits of the ban. These data provide strong evidence
that prenatal and early-life stage exposure to chlorpyrifos is
associated with not only poor birth outcomes (lower birth weight and
length), but also long-lasting, and possibly permanent, impaired
cognitive development.

In addition to the sensitivity of early life exposures (pre- and
peri-natal) to chlorpyrifos, there are data reporting that infants born
to mothers with genetically low activity of the PON1 detoxifying enzyme
may be an especially vulnerable population. Berkowitz and colleagues
from Mount Sinai School of Medicine determined pesticide exposure in a
cohort of over 400 women in NYC by a prenatal questionnaire and
measurement of maternal blood and urinary metabolites and fetal cord
blood. The authors correlated this self-reported exposure information
with birth outcomes and found that maternal detectable chlorpyrifos
exposure and low PON1 activity correlated with a significant, albeit
small, reduction in newborns' head circumference.[^34] The authors point
to pre-established evidence that small head size is predictive of
impaired cognitive ability to support their suggestion that the infants
of mothers with low PON1 enzyme activity may be an especially vulnerable
population.

EPA failed quantitatively to incorporate these important evidentiary
data that were published since the 2001 IRED was completed, which report
a significant association between real-world chlorpyrifos exposures and
real, developmental harm resulting from pre-birth and early childhood
exposures. As noted earlier, FQPA imposes a duty on EPA to "focus
explicitly on exposures and risks to children and infants."[^35] The
failure to consider quantitatively the full spectrum of diverse impacts
of chlorpyrifos exposure to fetuses is a direct violation of EPA's
mandate.

## No Safe Level in Rodent Developmental Neurotoxicity Study 

As discussed above, a substantial body of scientific evidence
demonstrates the fetotoxic, neurotoxic, and immunotoxic properties of
chlorpyrifos and its oxon metabolite, associated with pre-natal and
early life exposures. These exposures have been shown to result in
long-lasting, possibly permanent damage to the nervous system. There is
no evidence that there is a safe or acceptable level of exposure to
chlorpyrifos during pre-birth and early life stages. In fact, EPA staff
experts concluded in the EPA human health risk assessment of
chlorpyrifos:

> "the weight of the evidence raises concern for an increase in both the
> sensitivity and susceptibility of the fetus or young animal to adverse
> biochemical, morphological, or behavioral alterations from
> chlorpyrifos treatment during brain development. With respect to
> cholinesterase inhibition, an increase in sensitivity of the young
> compared to adults was seen all along the dose response curve, even at
> relatively low doses. There is a clear differential response (2- to
> \~5-fold ) in the young compared to the adult animal after an acute
> treatment to a relatively low dose of chlorpyrifos. There is also
> increased sensitivity found after repeated dosing (up to 9-fold), but
> at the LD10 \[lethal dose that results in a 10% death rate\] and MTD
> \[maximum tolerated dose\]. It is important to point out that *an
> uncertainty remains concerning the magnitude of the differential
> response*, given that newborn animals (less than PND 7) have not been
> characterized for sensitivity. *Results of multiple studies have
> consistently shown that the developing brain is susceptible to
> chlorpyrifos treatment*. Effects on the developing CNS that are
> indicative of the unique susceptibility to the young animal include
> changes in macromolecular synthesis, altered cell signaling and
> muscarinic receptor down regulation, as well as morphological
> alterations in brain development. An uncertainty remains regarding the
> NOAELs for the susceptibility effects. The effects observed raise a
> high degree of concern that the fetus or young animal is particularly
> susceptible to adverse outcome if exposed to chlorpyrifos."[^36]

The assessment of EPA scientific experts points to substantial
scientific evidence that early life exposures to chlorpyrifos are
extensively more harmful than adult exposures, and that the magnitude of
the differential response is uncertain. This assessment from EPA staff
scientists strongly supports the use of the default 10X FQPA factor.

## Endocrine Disrupting Effects

Thyroid hormone is essential for virtually every function in the body,
including reproduction and neurodevelopment. Both animal and human
studies have reported that chlorpyrifos may interfere with thyroid
hormone function. In a 2006 study of sub-fertile men, chlorpyrifos
exposure was associated with reduced levels of thyroid stimulating
hormone (TSH) and thyroxine.[^37] In a 2005 study of rat pituitary
cells, which are normally stimulated to grow after exposure to thyroid
hormone, cell growth was inhibited by co-exposure to chlorpyrifos.[^38]
In an earlier study (1998), exposure to chlorpyrifos in ewes was
associated with reduced thyroxine (thyroid hormone) concentrations.[^39]
More troubling, these effects resulted from exposures at levels similar
to those found in the general population, indicating that chlorpyrifos
can reduce thyroid hormone and cause endocrine disruption at
environmentally relevant levels. In addition to causing infertility,
reductions in thyroid hormone concentrations, even at subclinical
levels, can result in permanent neurological effects on the developing
nervous system of a fetus or newborn.[^40]^,^ [^41]

Studies also indicate that chlorpyrifos can affect the reproductive
hormones estrogen and testosterone. Chlorpyrifos is a weak estrogen-like
substance.[^42] Pituitary cells from the rat that are normally
stimulated to grow after estrogen exposure were found to grow after
chlorpyrifos exposure.[^43] This growth was blocked by a potent estrogen
receptor antagonist, suggesting that chlorpyrifos stimulates the growth
of these pituitary cells via the estrogen receptor and is an estrogen
agonist. In human studies, exposure to chlorpyrifos has been shown to be
associated with lower levels of testosterone, poorer sperm quality, and
increased sperm DNA damage.[^44]^,^ [^45]

Gonadotropin-releasing hormone (GnRH) is a hormone released by the
hypothalamus. It acts as a primary regulator of reproduction by
controlling the release of luteinizing hormone and follicle stimulating
hormone from the pituitary gland, thereby ultimately controlling
androgen and estrogen levels. In experiments with a cell line model for
GnRH neurons, exposure to chlorpyrifos was found to alter the
biosynthesis of GnRH, potentially disrupting the entire
hypothalamic-pituitary-gonadal axis.[^46]

According to the IRED, EPA did not consider the endocrine disrupting
effects of chlorpyrifos because the development of an Endocrine
Disruptor Screening Program (EDSP) has not been completed. As a
consequence, it neglects analyzing an entire category of potential
adverse health effects. In fact, the risk assessment omits a group of
studies that, taken together, suggest that chlorpyrifos may be an
endocrine disrupting chemical, capable of interfering with multiple
hormones controlling reproduction and neurodevelopment.

There is precedent for the Agency to consider endocrine disrupting
effects in a human health risk assessment in the absence of a final
EDSP. For example, in the RED for atrazine, the Agency examined the
potential endocrine disrupting effects of atrazine on amphibians,
undermining any agency claim that existing studies of the endocrine
disrupting effects cannot be considered in its human health risk
assessments. Accordingly, given the studies suggesting that chlorpyrifos
has the potential to cause endocrine disrupting effects, EPA should have
quantitatively incorporated these endpoints in its risk assessment of
chlorpyrifos.

## Cancer risks

The 2004 National Institutes of Health Agriculture Health Study, a very
robust prospective epidemiology study of pesticide applicators in the
Midwest, reported chlorpyrifos-specific findings that have been ignored
by EPA despite their high relevance to the risk analyses and
registration decisions. The incidence of lung cancer was statistically
significantly associated with both chlorpyrifos lifetime exposure-days
and chlorpyrifos intensity-weighted exposure days. After adjusting for
other pesticide exposures and demographic factors, "individuals in the
highest quartile of chlorpyrifos lifetime exposure-days (\>56 days) had
a relative risk of lung cancer of 2.18 (95% CI=1.31-3.64), significantly
higher than those with no chlorpyrifos exposure."[^47] These data were
not referenced in the final aggregate assessment of chlorpyrifos or the
OP CRA, but are highly relevant and so should have been.

## Potential adverse effects below 10% cholinesterase inhibition 

The OP CRA evaluated the cumulative toxicity of chlorpyrifos and its
related organophosphate pesticides assuming that if the Agency regulated
so as to allow no more than a 10% level of cholinesterase inhibition
(10% ChEI) in the female adult rodent brain, this would be protective of
all adverse effects at all life stages. That is, the Agency presumed
that there are no other adverse effects that occur with doses lower than
the dose eliciting a 10% ChEI in the female adult rodent brain. However,
scientific studies published both prior to and since the IRED was
completed in 2001 have reported that fetal and newborn exposure to
chlorpyrifos affects diverse cellular functions by mechanisms of
toxicity that are independent of cholinesterase inhibition. This is
important because while the systemic toxicity that results from
cholinesterase inhibition is reasonably well characterized, it does not
explain why rodents exposed pre- and perinatally seem to recover from
cholinesterase inhibition relatively rapidly, yet display persistent and
more severe damage to the central nervous system.[^48] Accumulating
scientific evidence points to non-cholinergic mechanisms that disrupt
multiple brain targets.[^49] Many of these critical targets are
vulnerable even at doses below those that elicit 10-20% cholinesterase
inhibition. Some of the relevant studies are listed below:

-   Scientists first reported in 1994, and then confirmed in 2001 that
    chlorpyrifos inhibited the production of the cellular second
    messenger Cyclic Adenosine Monophosphate (cAMP) in rat brain.[^50]
    This has serious implications for many important cellular functions.
    For example, cAMP is required for normal function of hormones like
    glucagon (increases blood sugar levels) and adrenaline (regulates
    the stress response by increasing heart rate, elevating blood sugar,
    and depressing the immune system). cAMP is also required for
    regulating normal calcium movement in the body. Disruption of normal
    cAMP function may be associated with progression of some cancer
    types, including melanoma.[^51]^,^[^52]

-   Scientists reported in 2007 that in neonatal rats exposed to four
    daily doses of 1 mg/kg chlorpyrifos on days 1-4 after birth
    displayed life-stage and gender-specific alterations in the
    expression of genes important for nerve cell growth, cAMP-related
    cell signaling, programmed cell death (apoptosis), oxidative stress,
    and neurotransmitter synthesis. This dose and treatment regime is
    below the threshold dose that is associated with growth retardation
    and systemic toxicity and elicits less than 20% ChEI in exposed
    newborn rats.[^53]

-   In 2006, scientists reported that chlorpyrifos disrupted serotonin
    pathways in the developing rat brain at doses spanning the threshold
    for cholinesterase inhibition.[^54] Interestingly, the study
    reported altered expression of transcription factors in both the
    forebrain (an area with many cholinergic neurons) and in the
    cerebellum (an area poorly innervated with cholinergic neurons),
    suggesting that there are severe impacts on non-cholinergic targets
    of chlorpyrifos in the brain, presumably through a non-cholinergic
    mechanism of toxicity.

-   Scientists reported in 2006 an observed loss of non-cholinergic
    cerebellum neurons and permanent sensorimotor deficits in adult
    rodents exposed to chlorpyrifos *in utero,* demonstrating
    long-lasting effects from early life exposures to
    chlorpyrifos*.*[^55] In this work, pregnant Sprague-Dawley rats were
    treated with 1.0 mg/kg daily dermal exposures to chlorpyrifos, and
    offspring were evaluated at 90 days after birth, corresponding to a
    human adult age. This study provides evidence that exposures during
    vulnerable windows of development can result in adverse impacts that
    extend into adulthood.

-   In 2007, researchers reported that neonatal rats exposed to four
    daily doses of 1 mg/kg chlorpyrifos on days 1-4 after birth
    displayed regional alterations in the expression of the fibroblast
    growth factor family of genes across the brain and brain stem.[^56]
    The proteins that are coded from these genes play critical roles in
    neural cell development, brain assembly and recovery from neuronal
    injury.

The broad spectrum of neurotoxic effects indicate that chlorpyrifos
toxicity is far more complex than would be predicted if only its direct
impairment of cholinesterase activity were considered.

A review published in 2003 by Duke University Professor Abou-Donia of OP
poisoning incidents includes clinical reports of long-term impairment of
cognitive and neurobehavioral performance associated with long-term
exposure to the pesticides.[^57] Permanent clinical symptoms that have
been reported includes anxiety and deficits in learning, memory, and
concentration. [^58] In addition, individuals exposed to low,
subclinical levels of chlorpyrifos have reported persistent long-term
deficits in concentration, word finding, and short-term memory.[^59] Two
separate studies in 1996 and 1997 reported clinical cases of long-term
cognitive and neuropsychological deficits in sheep dipper workers
exposed to organophosphate pesticides.[^60]^,^ [^61] Dr. Abou-Donia
suggests that the observed long-term effects are more likely to be a
result of neuronal cell damage and death from apoptosis and oxidative
stress, rather than from transient cholinesterase inhibition. [^62]

Neither EPA's aggregate risk assessment (IRED) nor the OP CRA cite or
quantitatively incorporate the results of the aforementioned laboratory
studies and clinical reports. Without quantitatively incorporating
low-dose risks of non-cholinergic effects, EPA's contention that the
acute and chronic dietary point of departures (BMD10) are protective is
unproven and is likely to underestimate significantly the long-lasting
impairments resulting from early life exposure to chlorpyrifos.

EPA ought to heed experts who warned: "the fact that alterations in
neurodevelopment occur with organophosphate exposures below the
threshold for cholinesterase inhibition reinforces the inadequacy of
this biomarker \[cholinesterase inhibition\] for assessing exposure or
outcome related to developmental neurotoxicity."[^63] EPA's own
Scientific Advisory Panel (SAP) in 2002 had raised the same concern,
stating "reliance on a single biochemical assay to measure brain damage
may become problematic."[^64] Accordingly, the Agency must consider
non-cholinergic neurotoxicity in the CRA and IRED assessments when
establishing the safe level (RfD) and allowable commodity tolerances.
Taking into consideration the full toxicity spectrum of chlorpyrifos
will lead to the scientifically-defensible conclusion that it is too
dangerous to be reregistered.

**III. CRA Misrepresents Risks, Fails to Apply FQPA**

The CRA failed to apply any FQPA factor to adjust for early life
exposures, citing a 2000 study that EPA interprets to show no difference
in response between pups and adult rats at the dose estimated to result
in 10% inhibition.[^65]

In addition to relying on limited data, EPA resorted to inaccurate
interpretations of that data to support its decisions. EPA approached
the determination of an FQPA factor by screening for data "which
measured brain cholinesterase inhibition in juvenile and adult rats
following repeat dosing."[^66] For all organophosphate pesticides
*except* chlorpyrifos, EPA then determined a benchmark dose. However,
for chlorpyrifos, EPA used data from a paper by Zheng et al.[^67]
authored and provided by FIFRA SAP member Carey Pope, to identify a 10%
brain cholinesterase inhibition point.[^68] EPA relied solely on this
one study to eliminate the FQPA factor for repeat exposures, stating
that "at this dose, there is no difference in response between pups and
adult rats." However, review of these data in both the original
published manuscript, and as presented in the cumulative risk
assessment, shows that there is an obvious difference between juvenile
and adult responses to chlorpyrifos. (See Figure 1, below.)

![](media/image1.wmf){width="5.247222222222222in"
height="4.969444444444444in"}

In fact, Zheng et al. report that neonates are more sensitive than
adults to chlorpyrifos associated ChEI.

First, the authors observed that after acute chlorpyrifos exposure,
neonates were much more sensitive than adults: "Following acute CPF
\[chlorpyrifos\] exposure, more extensive ChE \[cholinesterase\]
inhibition was noted in neonates than in adults (especially in the
brain) with NOELs based on ChE inhibition in adult tissues being 1 to
≥10-fold higher than in neonates."[^69] These results are consistent
with many other reports in the scientific literature: "It is apparent
from a number of studies that neonatal rats are more sensitive to acute
toxicity following either oral or subcutaneous acute high dosages of CPF
(Atterberry et al, 1997; Moser and Padilla, 1998; Pope and Chakraborti,
1992; Pope et al, 1991)." They also note that signs of toxicity and
lethality generally develop several hours, rather than immediately,
after an acute exposure to chlorpyrifos.

The authors also reported that neonates were more sensitive than adults
following repeat exposure scenarios: "With repeat exposures, NOELs based
on ChE inhibition in adults were only 0.2 - 2-fold higher than in
neonates." However, using the endpoint of body weight changes following
repeat doses, the authors noted that "the NOEL for adults was 5-fold
higher than for neonates."[^70]

EPA has mischaracterized these data. Rather, these data support using a
10X FQPA factor based on acute exposures using brain cholinesterase
endpoints, a 2X FQPA factor based on repeat exposures using brain
cholinesterase endpoints, and a 5X FQPA factor based on repeat exposure
using body weight endpoints. EPA has presented an incomplete and
therefore inaccurate interpretation of these data to support for its
decision to remove the FQPA factor altogether.

## IV. Over-Reliance on Registrant Data  {#iv.-over-reliance-on-registrant-data .unnumbered}

Chlorpyrifos is one of the most studied of all the organophosphate
pesticides. And, as demonstrated above, all the evidence of adverse
health effects arising from the exposure to chlorpyrifos supports
banning all uses of chlorpyrifos and revoking all food tolerances. Yet,
despite this plethora of publicly-available data, the Agency cherry
picked the data, ignoring robust, peer-reviewed data in favor of weak,
industry-sponsored data to determine that chlorpyrifos could be
re-registered and food tolerances be retained. EPA's re-registration and
tolerance reassessment decision is not scientifically defensible because
it is based on a strained and biased interpretation of an incomplete
data set.

As with all scientific inquiry, greater confidence is ascribed to
results of studies that are repeatable, supplied by multiple lines of
evidence, and drawn from multiple, well-designed, well-conducted studies
of adequate statistical power. To that end, all of the studies
identified in this petition are published and publicly-available in
peer-reviewed scientific literature, indicating that they were subject
to public and professional scrutiny and are therefore likely to be
reliable. These data showing adverse impacts of chlorpyrifos and other
organophosphate pesticides on fetal and childhood development from
non-cholinergic effects satisfy all three prongs for strong scientific
validity because they a) arise from multiple laboratories (independent
lines of evidence), b) are based on studies *in vitro*, in whole
animals, and in humans (multiple lines of evidence), and c) show
agreement across studies regarding the reported adverse outcomes
(repeatability) and the mechanisms of action (biological plausibility).
These data fulfill the scientific criteria for establishing causality,
highlighting the breadth of robust data available to, yet ignored by,
the Agency regarding chlorpyrifos.

Where EPA should have relied on its strongest scientific evidence, it
led off with its weaker database and relied on the odd claim of scant
organophosphate data to justify its decision not to refine the
intra-species factor. More egregiously, despite having data on
chlorpyrifos, the Agency chose to ignore that data and retain a weak
intra-species factor for chlorpyrifos. As illustrated by the PON1 study
discussed in the previous section, the Agency chose to ignore strong
evidence of harm at doses below those that inhibit cholinesterase,
despite evidence of susceptibility in exposed children.

**V. EPA Failed to Incorporate Inhalation Routes of Exposure**

In its aggregate assessment, EPA considered exposures from food,
drinking water, and residential uses of chlorpyrifos. However, for some
populations that include children and pregnant women, inhalation of
chlorpyrifos-contaminated air may be one, if not the most, significant
source of chlorpyrifos exposure. Although EPA was advised of these
public data prior to 2006, it failed to incorporate quantitatively this
scientific evidence of air exposures into the aggregate assessment.[^71]

Available monitoring data show that for volatile and semi-volatile
pesticides (vapor pressure \> 10^-7^ mm Hg at 20-25°C), post-application
drift typically accounts for 80-95% of the total off-site airborne
pesticide movement. Chlorpyrifos falls solidly into this category of
pesticides, with a vapor pressure of 10^-5^ mm Hg. Air monitoring
studies conducted by the California Air Resources Board (ARB) and by
communities working with PANNA indicate that post-application
volatilization typically peaks between two and 24 hours after the start
of an application for volatile and semi-volatile pesticides and may
persist for days above levels of concern. ARB published its work on air
monitoring for chlorpyrifos in 1998.[^72] PANNA published its
chlorpyrifos air monitoring results for Lindsay, California in July
2006, before the finalization of the OP CRA.

**A. State of California Data Documents Air Contamination**

The California ARB has documented widespread presence of chlorpyrifos in
the air using both near-field and ambient air monitoring.

### Near-Field Monitoring

The California ARB measured air concentrations of chlorpyrifos near an
orange grove treated with chlorpyrifos, with the application taking
place during two separate events separated by a day.[^73] Three-day,
time-weighted average concentrations at the monitoring stations ranged
from 5,312 to 8,112 ng/m^3^ (depending on the location of the monitoring
station). See Figure 1. Translation of these concentrations into
Reference Exposure Levels (RELs) that take into account breathing rate
and body weight indicated that these concentrations exceeded the acute
24-hour REL for a one-year-old child by a factor of 31 to 48 and the
acute 24-hour REL for adults by a factor of 1.4 to 2.1.[^74]
Concentrations of chlorpyrifos were still above both the adult and child
RELs at the downwind site at the end of the monitoring period, at 4,900
ng/m^3^ (29 times the child REL and 1.3 times the adult REL). These data
indicate that those who live, work, or go to school near application
sites risk acute nervous system toxicity from airborne exposure to this
pesticide. The developing fetus, infants and children are especially at
risk because their nervous systems are still developing.

![](media/image2.wmf){width="4.459027777777778in" height="3.23125in"}

**Figure 1:** Chlorpyrifos air concentrations peaked approximately 2.5
hours after the end of the first application and again during the second
application. Substantial volatilization continued for several days after
application and exceeded 24-hour RELs for both adults and children for
much of the sampling period.

ARB only conducted a single application site monitoring study for
chlorpyrifos; however, the fact that the application occurred in two
distinct time periods provides essentially two applications in one
study. The similar peak concentrations observed for the two applications
under different wind conditions (30,950 ng/m^3^ vs. 27,700 ng/m^3^)
suggest that peak air concentrations may be quite predictable based on
the vapor pressure of the pesticide, a fact consistent with other work
in the peer-reviewed literature.[^75]

The breakdown product chlorpyrifos oxon was observed in 100% of the
samples, but the toxicity of this substance was not taken into account
in this analysis because no RELs are available for comparison. However,
because the oxon is more acutely toxic than the parent compound,
neurotoxic effects associated with breathing air contaminated with both
chlorpyrifos and its oxon at the measured levels will be greater than
chlorpyrifos concentrations alone would suggest.

### Ambient Monitoring

During the summer of 1996, the ARB sampled seasonal concentrations of
chlorpyrifos in ambient air in Tulare County, California by placing
monitoring stations on several schools that were somewhat distant from
direct applications but located in regions of high use.[^76] Monitoring
occurred over the course of four and a half weeks, which serves as an
estimate of sub-chronic exposure. Average concentrations over the full
time frame of the monitoring study were below both adult and child
sub-chronic RELs, averaging 38% of the one-year-old child REL over all
sites. See Figure 2. The maximum measured 24-hour concentrations equaled
or exceeded the 24-hour acute child REL at four of the five monitoring
sites and ranged from 23% to 485% of the 24-hour acute child REL. The
monitoring report was published by ARB in 1998, but was not incorporated
into EPA's aggregate assessment.

![](media/image3.wmf){width="4.356944444444444in"
height="3.079861111111111in"}

**Figure 2:** Chlorpyrifos concentrations in air in Tulare County, CA in
Summer 1996 measured by the CA ARB. Averages are for 4 days per week of
sampling over the 4-week period. Monitoring sites included ARB, the ARB
office in downtown Visalia; JEF, Jefferson Elementary School in Lindsay;
KAW, Kaweah School in Exeter; SUN, Sunnyside Union Elementary School in
Strathmore; UCL, University of California, Lindcove Field Station.

Using these ARB data, scientists at the California Department of Health
Services concluded in a peer-reviewed paper in 2002 that short-term
chlorpyrifos exposure estimates exceeded the acute REL for 50% of
children in the exposed general populations.[^77] The researchers noted
that farm workers and their children likely experience higher exposures
and risks than individuals in the general population. Furthermore,
"\[p\]esticide exposures and risks are characterized for the communities
around the air monitoring locations. However, the potential for
exposures in other residential areas clearly exist . . ." In addition,
the authors indicate that census data suggest "a potential for exposures
and risks, similar to those calculated in this risk assessment, for
hundreds of thousands of people in California." [^78]

**B. Community Air Monitoring Shows Widespread Contamination**

Since 2004, PANNA has been working with rural communities to conduct air
monitoring at people's homes, schools and workplaces.[^79] Chlorpyrifos
is one of the primary pesticides that has been found in these
communities. Data collected in Lindsay, California in June and July of
2004, 2005, and 2006, and in Washington State in 2006 demonstrate that
daily exposure to chlorpyrifos can be substantial, and regularly exceeds
the "acceptable" 24-hour acute dose for a one-year-old child established
by the EPA. This information has been transmitted to EPA staff through
personal communications with staff, presentations at public meetings,
and in Spray Drift Work Group meetings. The 2004 and 2005 results from
the Lindsay, California study were published on July 14, 2006.[^80]

Of the 104 samples collected in Lindsay, California during the summer of
2004, 11% were above the 24-hour acute and sub-chronic child REL. The
highest concentration observed for a 24-hour period was 1,340 ng/m^3^
(7.9 times the 24-hour acute child REL). Of the 108 samples in the same
area during the next summer (2005), 23% were above the 24-hour acute and
sub-chronic child REL. The highest concentration observed for a 24-hour
period in 2005 was 1,120 ng/m^3^ (6.6 times the 24-hour acute child
REL). These data are consistent with results obtained by the ARB for
ambient air monitoring conducted in 1996 (see above).

Although the observed 24-hour average concentrations were below the
adult RELs, adults living in the houses where the monitoring stations
were located experienced symptoms of acute OP poisoning. This
observation suggests the following: 1) the NOELs EPA determined from
industry toxicology studies are inaccurate and do not reflect the true
toxicological endpoints; and/or 2) using a 24-hour averaging time does
not protect people from poisoning resulting from shorter-term exposures
at higher concentrations. In any case, it is clear that inhalation
exposure is high enough to cause acute poisonings of bystanders and that
EPA's failure to account for inhalation exposures in its aggregate risk
assessment is a serious flaw in the risk assessment process.

**C. Inhalation Exposure to Chlorpyrifos Far Exceeds Dietary Exposure**

In areas of high chlorpyrifos use, inhalation is the primary source of
exposure, dwarfing all other sources. A comparison of dietary exposure
estimated by EPA for the most-exposed (99.9^th^ percentile) children to
inhalation exposure reported by ARB and PANNA from measurements in
several different locations and seasons is illuminating.

The highest acute dietary exposures for infants are estimated by EPA to
result in a dose that is 50% of the acute Population Adjusted Dose
(PAD). In contrast, inhalation exposures estimated from ARB monitoring
data indicate that infants living very close to an application site
during the day the application takes place are exposed to a dose that is
over 75 times higher than the acute PAD. The ambient air monitoring
conducted in Lindsay, California and the Yakima Valley in Washington
State[^81] indicate that the highest 24-hour exposures (comparable to
the 99.9^th^ percentile acute dietary exposure) would result in a dose
that ranges from 404--793% of the acute PAD. These data show that EPA is
failing to account for the vast majority of exposure when it assumes
inhalation exposure is zero for rural residents in areas of high
chlorpyrifos use.

**VI. Exporting Hazards**

Unless chlorpyrifos is banned, and all tolerances cancelled,
chlorpyrifos will continue to be used, often unsafely, in other
countries thus creating a health and environmental hazard in those
countries and on contaminated food re-entering the US. Although
chlorpyrifos is listed as a "restricted use" pesticide in the US, it is
exported in high volume: 7 to 9 million pounds annually since 1997
(8,570,694 in 2000).[^82] Between 1997 and 2000, nearly 65 million
pounds of severely restricted or forbidden pesticides in the US were
exported; more than 22 tons per day -- and more than half were exported
to developing countries for agriculture use.[^83] The International
Labor Organization estimates that 60 to 90% of children estimated to be
working in Africa (80 million), Asia (152 million), and Latin America
(17 million) work in agriculture. These children are exposed to toxic
pesticides in the fields, from drinking and washing water, through
contaminated clothing, and in their homes.[^84] The U.N. Commission on
Human Rights stated that "\[a\]llowing the export of products recognized
to be harmful is immoral."[^85] The mitigation requirements in this IRED
include respirators with an organic-vapor removing cartridge and a
pesticide-approved prefilter, chemical-resistant outer-clothes,
enclosed-cab machinery, emergency equipment readily available, and
storage containments for discarding single-use chemically-resistant
over-clothes. It is inconceivable that these are "readily available" to
mixers, loaders, applicators, and fieldworkers in developing countries.
US labeling requirements will have no mitigation effects for these men,
women, and children workers. Cancellation of these dangerous pesticides
is the most prudent and health-protective solution.

# VII. Conclusion {#vii.-conclusion .unnumbered}

Just a few months prior to the August, 2006 release of the CRA, the
Local Presidents of EPA Unions representing scientists, risk managers,
and related staff took the unusual step of sending a letter to
Administrator Johnson expressing significant concerns about the EPA's
risk analyses for organophosphates and identifying undue influence of
pesticide registrants on its decision-making processes for these
pesticides.[^86] Particular concerns raised by the EPA Union leaders
included the failure of EPA adequately to address exposures to infants
and children who live near treated fields, including the children of
farm workers. Moreover, the letter alerted Administrator Johnson that
Pesticide Program staff "feel besieged by political pressure exerted by
Agency officials perceived to be too closely aligned with the pesticide
industry and former EPA officials now representing the pesticide and
agricultural community; and by the USDA...."[^87] The letter concluded
that "until EPA can state with scientific confidence that these
pesticides will not harm the neurological development of our nation's
born and unborn children, there is no justification to continue to
approve the use of the remaining OP \[organophosphate\] and carbamate
pesticides."[^88]

Separately, NRDC also voiced serious concerns about the limitations of
the data set used by EPA for the aggregate and cumulative
assessments.[^89] Many of these concerns were discussed at length by the
FIFRA SAP and reported in 2002. Two members of the panel "felt strongly
that the studies presented by the Agency have limited application to
understanding the effects of OP insecticides, specifically in
children."[^90] The SAP was also concerned about the failure to fully
incorporate pre- and post-natal effects of organophosphates associated
with children's brain function. The SAP reported that "\[n\]ot to
include data on these outcomes excludes important variables in the
assessment and therefore introduces important specification error.
Wilson's work and the work of many others have shown that
*systematically measured behavior may demonstrate toxicological effects
at lower doses than those that yield phenotypic or biochemical
alterations*."[^91] Significantly, the SAP concluded that EPA's
assessment contained "substantial measurement and specification errors,
and as a consequence, underestimates the risk of OPs for child health."
[^92] In its final determinations, EPA failed to acknowledge these
important limitations and chose not to adjust the uncertainty factors.

Without incorporating published literature describing the chronic
impacts of long-term, low-level doses of organophosphate pesticides,
particularly early-life exposures, EPA is making critical decisions
about chlorpyrifos based on only a fragment of the whole story. Together
with the decision to ignore robust data, this approach of deliberately
selecting for the weakest data dumbs down the Agency's registration
decision to the lowest common denominator.

Robust data shows that any use restriction on chlorpyrifos would still
not be health-protective and that all food tolerances must be revoked.
EPA's decision to reregister chlorpyrifos and retain food tolerances
violates FIFRA and the FFDCA. EPA failed to consider important studies
and improperly disregarded others. Furthermore, the Agency relied on a
biased selection of available, weak data, in favor of the robust data,
leading to an unsupported risk assessment.

As a result of EPA's actions, NRDC and PANNA members and their children
are being exposed to unsafe levels of chlorpyrifos, and will continue to
be as long as the chlorpyrifos registrations and food tolerances
challenged in this petition remain in effect. We therefore request that
EPA expedite its consideration of this petition in every way possible.
If EPA intends to solicit public comment before making a decision on
this petition, we request that the Agency do so promptly. EPA's past
history of significant delay in responding to pesticide petitions and
tolerance objections filed by NRDC constitutes a pattern and practice of
unlawful agency inaction that harms NRDC and PANNA and its members.

Based on all of the foregoing comments, NRDC and PANNA petition EPA to
revoke all tolerances and cancel all registrations for the pesticide
chlorpyrifos. We reserve the right to supplement this petition based on
new information.

Respectfully submitted,

![](media/image4.png){width="2.2916666666666665in" height="0.8125in"}

Mae C Wu, Esq.

Jennifer Sass, Ph.D.

Natural Resources Defense Council

1200 New York Ave., NW, Suite 400

Washington DC, 20005

\(202\) 289-6868

\(202\) 289-1060 (fax)

![](media/image5.png){width="2.7805555555555554in"
height="0.8854166666666666in"}

Susan E. Kegley, Ph.D.

Pesticide Action Network, North America

49 Powell Street, Suite 500,

San Francisco CA 94102

Dated: 12 September 2007

cc: Administrator Stephen Johnson

General Counsel Roger Martella

James Gulliford

Debbie Edwards

Pete Caulkins

Bob Perliss

Tom Myers

[^1]: "Chlorpyrifos Facts." EPA website,
    \<[www.epa.gov/oppsrrd1/REDs/factsheets/chlorpyrifos_fs.htm](../www.epa.gov/oppsrrd1/REDs/factsheets/chlorpyrifos_fs.htm),
    8 Mar 2007. All home uses of chlorpyrifos have been canceled "except
    ant and roach baits in child-resistant packaging." All uses for
    termite control were required to be phased out by December 31, 2005.
    IRED, p.71

[^2]: As chemical weapons, the production and stockpiling of
    organophosphate nerve agents are outlawed by the United Nations'
    1993 Convention on the Prohibition of the Development, Production,
    Stockpiling and Use of Chemical Weapons and on Their Destruction.
    ¶71(b)..

[^3]: 7 U.S.C. § 136a.

[^4]: 7 U.S.C. § 136a(c)(5)(C).

[^5]: 21 U.S.C. §§ 345a(b) & (c).

[^6]: *Id.* § 346a(b)(2)(A)(i).

[^7]: *Id.* § 346a(b)(2)(A)(ii).

[^8]: *Id.* § 346a(a)(1).

[^9]: *Id*. § 346a(b)(2)(C).

[^10]: *Id*. §§ 346a(b)(2)(C)(ii)(I) & (II).

[^11]: *Id*. § 346a(b)(2)(C)(i)(II).

[^12]: *Id*. §§ 346a(b)(2)(C)(i)(I) & (III).

[^13]: EPA, Fact Sheet: Protecting Children from Pesticides (Jan. 2002)
    (www.epa.gov/pesticides/factsheets/kidpesticide.htm) ("The 1996 Food
    Quality Protection Act set tougher standards to protect infants and
    children from pesticide risks.")

[^14]: 21 U.S.C. § 346a(b)(2)(C).

[^15]: *Id.* (emphasis added).

[^16]: J. Sass and S. Kegley. Call with EPA to discuss chlorpyrifos.
    From HED: Jack Housenger, Anna Lowit, and Tom Moriarty; from RD:
    Venus Eagle; from SRRD: Pete Caulkins, Margaret Rice, and Tom Myers;
    from OGC: Mark Dyner and Jon Fleuchaus. July 17, 2007

[^17]: Philip J. Landrigan and others, Pesticides In The Diets Of
    Infants And Children (Washington, D.C.: National Academy Press,
    1993), 9.

[^18]: 66 Fed Reg 57073 (Nov 14, 2001) Organophosphate Pesticide;
    Availability of Chlorpyrifos Interim Risk Management Decision
    Document. IRED at 64-68.

[^19]: Memo from Debra Edwards to Jim Jones, re: Finalization of Interim
    Reregistration Eligibility Decisions (IREDs) and Interim Tolerance
    Reassessment and Risk Management Decisions (TREDs) for the
    Organophosphate Pesticides, and Completion of the Tolerance
    Reassessment and Reregistration Eligibility Process for the
    Organophosphate Pesticides, July 31, 2006.

[^20]: J. Sass and S. Kegley. Call with EPA to discuss chlorpyrifos.
    From HED: Jack Housenger, Anna Lowit, and Tom Moriarty; from RD:
    Venus Eagle; from SRRD: Pete Caulkins, Margaret Rice, and Tom Myers;
    from OGC: Mark Dyner and Jon Fleuchaus. July 17, 2007

[^21]: IRED at 17

[^22]: IRED at 16

[^23]: Makris S, Raffaele K, Sette W, Seed J. A retrospective analysis
    of twelve developmental neurotoxicity studies submitted to the USEPA
    Office of Prevention, Pesticides, and Toxic Substances (OPPTS).
    Draft 11/12/98. Available at
    http://www.epa.gov/scipoly/sap/meetings/1998/december/neuro.pdf

[^24]: Lee, BW, London, L, Paulauskis, J, Myers, J, Christiani, DC**.**
    Association Between Human Paraoxonase Gene Polymorphism and Chronic
    Symptoms in Pesticide-Exposed Workers. J Occup Environ Med, 2003
    Feb; 45(2)

[^25]: Costa LG, Richter RJ, Li WF, Cole T, Guizzetti M, Furlong CE.
    Paraoxonase (PON 1) as a biomarker of susceptibility for
    organophosphate toxicity. Biomarkers. 2003 Jan-Feb;8(1):1-12.
    Review.

[^26]: Furlong CE, Holland N, Richter RJ, Bradman A, Ho A, Eskenazi B.
    PON1 status of farmworker mothers and children as a predictor of
    organophosphate sensitivity. Pharmacogenet Genomics. 2006
    Mar;16(3):183-90.

[^27]: Furlong CE, Holland N, Richter RJ, Bradman A, Ho A, Eskenazi B.
    PON1 status of farmworker mothers and children as a predictor of
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[^28]: CRA at Section I.B page 55

[^29]: Organophosphorus Cumulative risk assessment -- 2006 Update,
    available at \<
    <http://www.epa.gov/pesticides/cumulative/2006-op/index.htm>\>, 55.

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    Whitehead R, Tang D, Whyatt RW. Impact of prenatal chlorpyrifos
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    inner-city children. Pediatrics. 2006 Dec;118(6):e1845-59. Epub 2006
    Nov 20.; Perera FP, Rauh V, Whyatt RM, Tang D, Tsai WY, Bernert JT,
    Tu YH, Andrews H, Barr DB, Camann DE, Diaz D, Dietrich J, Reyes A,
    Kinney PL. A summary of recent findings on birth outcomes and
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    outcomes in a multiethnic population. Environ Health Perspect. 2003
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[^31]: Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R,
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[^32]: Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB,
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[^33]: Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB,
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[^35]: EPA, Fact Sheet: Protecting Children from Pesticides (Jan. 2002)
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[^36]: EPA. Human health risk assessment: Chlorpyrifos. June 8, 2000. p
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[^46]: Gore AC 2002 Organochlorine pesticides directly regulate
    gonadotropin-releasing hormone gene expression and biosynthesis in
    the GT1-7 hypothalamic cell line. Mol Cell Endocrinol.
    192(1-2):157-70.

[^47]: Lee et al, Cancer Incidence Among Pesticide Applicators Exposed
    to Chlorpyrifos in the Agricultural Health Study, Journal of the
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[^48]: Slotkin TA, Cousins MM, Tate CA, Seidler FJ. Persistent
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[^49]: Pope CN. Organophosphorus pesticides: do they all have the same
    mechanism of toxicity? J Toxicol Environ Health B Crit Rev. 1999 Apr
    Jun;2(2):161-81. Review.

[^50]: Huff RA, Corcoran JJ, Anderson JK, Abou-Donia MB. Chlorpyrifos
    oxon binds directly to muscarinic receptors and inhibits cAMP
    accumulation in rat striatum. J Pharmacol Exp Ther. 1994
    Apr;269(1):329-35; Huff RA, Abu-Qare AW, Abou-Donia MB. Effects of
    sub-chronic in vivo chlorpyrifos exposure on muscarinic receptors
    and adenylate cyclase of rat striatum. Arch Toxicol. 2001
    Oct;75(8):480-6.

[^51]: Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA,
    Bastian BC,Springer C, Marais R. In Melanoma, RAS Mutations Are
    Accompanied by Switching Signaling from BRAF to CRAF and Disrupted
    Cyclic AMP Signaling. Cancer Res. 2006 Oct 1;66(19):9483-91.

[^52]: Abramovitch R, Tavor E, Jacob-Hirsch J, Zeira E, Amariglio N,
    Pappo O, Rechavi G, Galun E, Honigman A. A pivotal role of cyclic
    AMP-responsive element binding protein in tumor progression. Cancer
    Res. 2004 Feb 15;64(4):1338-46.

[^53]: Slotkin TA, Seidler, FJ. 2007. Comparative developmental
    neurotoxicity of organophosphates in vivo: Transcriptional responses
    of pathways for brain cell development, cell signaling, cytotoxicity
    and neurotransmitter systems. Brain Res Bull, May 30;72(4-6):232-74.
    Epub 2007 Jan 25.

    Crumpton TL, Seidler FJ, Slotkin TA. Developmental neurotoxicity of
    chlorpyrifos in vivo and in vitro: effects on nuclear transcription
    factors involved in cell replication and differentiation. Brain Res.
    2000 Feb 28;857(1-2):87-98.

[^54]: Slotkin TA, Tate CA, Ryde IT, Levin ED, Seidler FJ.
    Organophosphate insecticides target the serotonergic system in
    developing rat brain regions: disparate effects of diazinon and
    parathion at doses spanning the threshold for cholinesterase
    inhibition. Environ Health Perspect. 2006 Oct;114(10):1542-6

[^55]: Abou-Donia MB, Khan WA, Dechkovskaia AM, Goldstein LB, Bullman
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    alone, and in combination produces persistent sensorimotor deficits
    and Purkinje neuron loss in the cerebellum of adult offspring rats.
    Arch Toxicol. 2006 Sep;80(9):620-31. Epub 2006 Feb 16.

[^56]: Slotkin TA, Seidler FJ, Fumagalli F. Exposure to organophosphates
    reduces the expression of neurotrophic factors in neonatal rat brain
    regions: similarities and differences in the effects of chlorpyrifos
    and diazinon on the fibroblast growth factor superfamily. Environ
    Health Perspect. 2007 Jun;115(6):909-16. Epub 2007 Feb 27.

[^57]: Abou-Donia, MB. Organophosphorus ester-induced chronic
    neurotoxicity. Arch Environ Health, 2003; 58(8): 484-497

[^58]: *Id.*

[^59]: Kaplan JG, Kessler J, Rosenberg N et al. Sensory neuropathy
    associated with Dursban (chlorpyrifos) exposure. Neurology 1993;
    43:2193-2196

[^60]: Beach JR, Spurgeon A, Stephens R, et al. Abnormalities on
    neurological examination among sheep farmers exposed to
    organophosphate pesticides. Occup Environ Med, 1996; 53(8): 520-525

[^61]: London L, Myers JE, Neil V, et al. An investigation into
    neurological and neurobehavioral effects of long-term agrochemical
    use among deciduous fruit farm workers in the Western Cape, South
    Africa. Environ Res, 1997; 73(1-2):132-145

[^62]: Abou-Donia, MB. Organophosphorus ester-induced chronic
    neurotoxicity. Arch Environ Health, 2003; 58(8): 484-497

[^63]: Slotkin TA, Tate CA, Ryde IT, Levin ED, Seidler FJ.
    Organophosphate insecticides target the serotonergic system in
    developing rat brain regions: disparate effects of diazinon and
    parathion at doses spanning the threshold for cholinesterase
    inhibition. Environ Health Perspect. 2006 Oct;114(10):1542-6.

[^64]: Transmittal of Meeting Minutes of the FIFRA Scientific Advisory
    Panel Meeting Held June 26-27, 2002. Released on July 19, 2002, 26.

[^65]: *Id.*

[^66]: Organophosphorus Cumulative risk assessment -- 2006 Update,
    available at \<
    <http://www.epa.gov/pesticides/cumulative/2006-op/index.htm>\>, 59.

[^67]: Zheng Q, Olivier K, Won YK, Pope CN. 2000. Comparative
    cholinergic neurotoxicity of oral chlorpyrifos exposures in
    preweaning and adult rats. Toxicological Sciences, 55(1): 124-132

[^68]: Oklahoma State University, Fig I.B-3, Cumulative Risk Assessment
    at 63

[^69]: Zheng Q, Olivier K, Won YK, Pope CN. 2000. Comparative
    cholinergic neurotoxicity of oral chlorpyrifos exposures in
    preweaning and adult rats. Toxicological Sciences, 55(1): 124-132

[^70]: Zheng Q, Olivier K, Won YK, Pope CN. 2000. Comparative
    cholinergic neurotoxicity of oral chlorpyrifos exposures in
    preweaning and adult rats. Toxicological Sciences, 55(1): 124-132

[^71]: PANNA provided EPA with the results of the ARB monitoring
    demonstrating problematic exposure from volatilization drift for
    multiple pesticides on several occasions, including in several
    formal comment letters to EPA on molinate (Docket ID \# OPP-34232,
    included here by reference), several legal petitions,^?^ in comments
    submitted to US EPA for the OP CRA docket in October of 2006 (Docket
    ID \# EPA-HQ-OPP-2006-0618), and in a presentation to EPA staff
    (EFED and HED) on May 9, 2002. PANNA published a report presenting
    and analyzing the ARB data in May of 2003. S.E. Kegley, A. Katten,
    and M. Moses, *Secondhand Pesticides: Airborne Pesticide Drift in
    California*, Californians for Pesticide Reform (San Francisco, CA
    2003),

[^72]: *Report for the Application and Ambient Air Monitoring of
    Chlorpyrifos (and the Oxon Analogue) in Tulare County during
    Spring/Summer 1996,* California Air Resources Board, Test Report
    #C96-040 and \# C96-041, April 7, 1998,
    http://www.cdpr.ca.gov/docs/empm/pubs/tac/chlrpfs.htm.

[^73]: *Report for the Application and Ambient Air Monitoring of
    Chlorpyrifos (and the Oxon Analogue) in Tulare County during
    Spring/Summer 1996,* California Air Resources Board, Test Report
    #C96-040 and \# C96-041, April 7, 1998,
    http://www.cdpr.ca.gov/docs/empm/pubs/tac/chlrpfs.htm.

[^74]: In order to compare observed concentrations of chlorpyrifos in
    air with concentrations likely to be associated with adverse
    effects, the US EPA inhalation NOAELs for acute and sub-chronic
    exposures to chlorpyrifos of 0.1 mg/kg-day (based on plasma and red
    blood cell cholinesterase inhibition)? were used to calculate
    Reference Exposure Levels (RELs) for a sensitive receptor, a
    one-year-old infant weighing 7.6 kg, breathing on average 4.5 m^3^
    of air per day. This calculation takes into account the 10-fold
    intraspecies, 10-fold interspecies and 10-fold FQPA uncertainty
    factors used by US EPA for chlorpyrifos.

    $\begin{array}{r}
    \text{Acute REL }(\text{ng/m}^{3}) = \frac{\text{Inhalation NOEL }(\text{mg/kg-day})´\text{10}^{6}\text{ng/mg}´\text{body wt}\text{.}(\text{kg})}{(\text{UF}_{\text{inter}}´\text{ UF}_{\text{intra}}´\text{ UF}_{\text{FQPA}})´\text{breathing rate }(\frac{m^{3}}{\text{day}})} = \frac{0\text{.}\text{1 mg/kg-day}´\text{10}^{6}\text{ng/mg}´7\text{.}\text{6 kg}}{(\text{10}´\text{ 10}´\text{ 10})´4\text{.}5\frac{\text{ m}^{3}}{\text{day}}} = \text{170}\text{ ng/m}^{3} \\

    \end{array}$The calculated concentration is the equivalent of a
    concentration in air below which no adverse effects on
    cholinesterase inhibition are anticipated by US EPA. Note, however,
    that the developmental neurotoxicity observed for chlorpyrifos (see
    Section 1 above) is not mediated by cholinesterase inhibition and
    may occur at lower doses.

[^75]: JE Woodrow, JN Seiber, LW Baker, Correlation Techniques for
    Estimating Pesticide Volatilization Flux and Downwind
    Concentrations, *Envi. Sci. Tech.,* **1997,** 31: 523-529.

[^76]: *Report for the Application and Ambient Air Monitoring of
    Chlorpyrifos (and the Oxon Analogue) in Tulare County during
    Spring/Summer 1996,* California Air Resources Board, Test Report
    #C96-040 and \# C96-041, April 7, 1998,
    http://www.cdpr.ca.gov/docs/empm/pubs/tac/chlrpfs.htm.

[^77]: S. Lee, R. McLaughlin, M. Harnly, *et al.*, Community exposures
    to airborne agricultural pesticides in California: Ranking of
    Inhalation Risks, *Env Health Persp,* 2002, 110: 1175--84.

[^78]: S. Lee, R. McLaughlin, M. Harnly, *et al.*, Community exposures
    to airborne agricultural pesticides in California: Ranking of
    Inhalation Risks, *Env Health Persp,* 2002, 110: 1175--84.

[^79]: *Drift Catcher Results*, Pesticide Action Network,
    www.panna.org/campaigns/driftCatcherResults.html

[^80]: K Mills and SE Kegley, *Air Monitoring for Chlorpyrifos in
    Lindsay, California, June-July 2004 and July-August, 2005,*
    Pesticide Action Network North America (San Francisco, CA, July 14,
    2006).

[^81]: C Dansereau, SE Kegley, K Tupper, A Wang and M. Perez, *Poisons
    on the Wind: Community Air Monitoring for Chlorpyrifos in the Yakima
    Valley*, Farm Worker Pesticide Project and Pesticide Action Network
    North America (San Francisco, CA December 2006).

[^82]: Smith, C. 2001. Pesticide exports from U.S. ports, 1997-2000.
    *Int J Occ Environ Health,* 7(4): 266-274. Table 6, data from
    California EPA.

[^83]: article by C. Smith according to customs records

[^84]: US Newswire. 2001. U.N. human rights investigator deems U.S.
    export of banned pesticides 'immoral'. December 17, 16 :09.
    http://www.usnewswire.com

[^85]: U.N. Special Rapporteur Fatma Zora Ouhachi-Vesely. In : US
    newswire, December 17, 2001. op cit.

[^86]: Union Letter to EPA Administrator. May 24, 2006
    http://www.nrdc.org/media/docs/060525.pdf

[^87]: Union letter at 3

[^88]: Union letter at 3

[^89]: NRDC comments on the Revised Cumulative Risk Assessment of the
    Organophosphate Pesticides. Docket OPP-2002-0230. April 28, 2002

[^90]: Transmittal of Meeting Minutes of the FIFRA Scientific Advisory
    Panel Meeting Held June 26-27, 2002. Released on July 19, 2002, 26.

[^91]: *Id* (emphasis is added).

[^92]: Transmittal of Meeting Minutes of the FIFRA Scientific Advisory
    Panel Meeting Held June 26-27, 2002. Released on July 19, 2002
    (emphasis is added).