Synthesis Report of Research from EPAs Science to Achieve Results (STAR) Grant Program:
FEASIBILITY OF ESTIMATE
PESTICIDE EXPOSURE Ah
DOSE IN CHILDREN'USI^
BIOLOGICAL MEASUREMENTS
DECEMBER 2006
United States
Environmental Protection
Agency
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PREPARED FOR
U.S. EPA, Office of Research and Development
National Center for Environmental Research
Washington, DC
PREPARED BY
ICE International
Fairfax, VA
Under EPA Contract No. 68-C-03-137
Work Assignments 00-05,01-05, and 02-03
EPA/600/S-06/006
U.S. Environmental Protection Agency
Office of Research and Development (8101R)
www.epa.gov
December 2006
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CONTENTS
Disclaimer
II
Executive Summary
III
1.
2.
Background
1.1 History and Objectives of STAR Grants Related to Children's Pesticide Exposures
1.2 Research Covered by This Report
Summaries of Supported Research
2.1 Biomarkers of Pesticide Exposure
2.2 Children's Vulnerability lo Toxic Substances
2.3 Children's Exposure to Pesticides
1
1
1
3
3
6
8
3. Contributions to ORD Research Goals and State of Knowledge
12
3.1 Contributions to ORD Research Goals
12
3.2 Summary of Major Contributions to the State of Knowledge
14
4. Cited References
15
5. Additional Grant Publications
17
Appendix A.
A-l
Cross-Walk of STAR Grant Contributions lo ORD Research Goals and Specific Grant Contributions lo These Goals
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DISCLAIMER
The research described in this document has been funded wholly by the United States Environmental
Protection Agency (EPA) under the Science to Achieve Results (STAR) grants program. The information does
not necessarily reflect the views of the Agency and no official endorsement should be inferred. Mention of
trade names or commercial products does not constitute endorsement or recommendation by EPA for use.
The information presented in this synthesis report is intended to provide the reader with insights about the
progress and scientific achievements of STAR research grants. The report lists the grantees whose research is
discussed, and it also indicates where more detailed peer-reviewed scientific data can be found. This report
is not sufficiently detailed nor is it intended to be used directly for environmental assessments or decision-
making. Readers with these interests should instead consult the peer reviewed publications produced by
the STAR grants and conduct necessary data quality evaluations as required for their assessments.
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EXECUTIVE SUMMARY
This report provides a brief overview of research funded by 12 grants issued through the Environmental
Protection Agency's (EPA) Science to Achieve Results (STAR) program. These grants were all aimed at
advancing the state of knowledge concerning children's exposures to pesticides and the potential adverse
effects of these exposures. Children's pesticide exposures are a major concern to EPA because of exten-
sive evidence that children may be more vulnerable to the effects of pesticide exposures than adults and
because children's exposures to pesticides may be greater than those of adults under typical use scenarios.
The grants reviewed in this report address three related topics:
• Development of improved biomarkers of children's pesticide exposure,
* Studies of the basis for children's vulnerability to pesticides, and
* Development of improved information relating to the nature and magnitude of children's
pesticide exposures.
Biomarkers are physiological or biochemical measurements that can be used to estimate pesticide
exposures and body burdens, which indicate the amounts of pesticides remaining in the body. Three
of the grants reviewed in this document investigated the development of less invasive biomarkers
(analyses of saliva, hair, meconium) that can provide rapid, reliable indications of children's, infants',
and fetal exposures to commonly used pesticides, and have related these biomarkers to indices of early
neurological development.
A second group of grants attempted to determine the most important factors explaining why children are
often disproportionately exposed to pesticides. These studies have confirmed the ubiquity of children's
exposure to household pesticide residues, provided insights into die reasons for high variability of expo-
sures in children, and confirmed the importance of specific behaviors (mouthing in infants and toddlers)
associated with children's exposures.
Finally, three of the grants set out to develop detailed estimates of pesticide exposures for specific groups
of children. These studies evaluated differences in exposures between urban, rural, and agricultural com-
munities, and the effects of ethnicity, socioeconomic factors, and household conditions on the magnitude
of exposures. One of the grants funded research that compared children's and adults' exposures to support
evaluations of the differences in risks between adults and children exposed to pesticides in similar settings.
Research under these grants has added greatly to the available data on children's pesticide exposure pat-
terns and potential risks, confirmed the usefulness of biomarkers of pesticide exposure, and identified
major methodological and data gaps in risk assessment for children exposed to pesticides.
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1.1 and §1 SVUt
to
As part of its mission to improve
public health and increase the
reliability with which risks to the
public health are identified and
measured, the Office of Research
and Development (ORD) at the
Environmental Protection Agency
(EPA) funds extramural research
through the Science to Achieve
Results (STAR) program. The STAR
program is managed by the ORD's
National Center for Environmen-
tal Research (NCER) and provides
grants and fellowships mainly to
academic researchers to address
research goals under ORD's Human
Health Research Strategy (EPA,
2003) and the Human Health
Multi-Year Plan (EPA, 2003). These
documents, and the research goals,
are updated regularly.
A major focus of ORD's research in
the last decade has been to improve
the quality of risk assessments for
children. In addition, the Agency has
been supporting the development
of improved methods for measuring
and estimating children's exposure
to pesticides and other common
environmental contaminants. Recent
research has provided extensive
evidence that children may be more
vulnerable to the effects of pesticide
exposures than adults. Children
may absorb, metabolize, and react
to pesticides differently than adults
because of differences in physiology
associated with specific stages of
development. In addition, children's
behavior patterns differ from
adults—they spend more time in
contact with potentially contami-
nated media such as soil and house
dust. Thus, they may receive higher
exposures and doses than adults in
the same exposure setting. Expo-
sure to pesticides may begin before
birth, and the effects of prenatal
exposure are poorly understood.
Currently available models and data
are not always adequate to assess
children's exposures to pesticides
or to estimate the risks associated
with these exposures.
In addition, passage of the Food
Quality Protection Act (FQPA) of
1996 requires EPA to specifically and
quantitatively consider the special
vulnerability of children in decisions
related to pesticide tolerance setting.
This has provided additional incen-
tive for EPA to improve methods for
characterizing children's exposure
to pesticides, how children metabo-
lize pesticides and other chemicals,
and how the differences between
children's and adults' responses to
pesticide exposure translate into dif-
ferences in health risks.
1.2
To address these concerns, EPA has
issued Requests for Applications
(RFAs) in three major topic areas
related to children's pesticide expo-
sures, as summarized in table 1:
* Development of improved bio-
markers of children's pesticide
exposure,
* Studies of the basis for children's
vulnerability to pesticides, and
* Development of improved infor-
mation relating to the nature and
magnitude of children's pesticide
exposure.
This report provides a brief over-
view of 12 grants funded under the
STAR program in these three general
areas. The projects listed in table 1
were initiated between 1996 and
2001. Progress in research under
these grants, and important research
results, are described in section 2 of
this report. Where projects have not
been completed, progress through
2005 is summarized. Section 3 briefly
discusses how the individual grants
have contributed to the fulfillment
of seven specific ORD research goals
specified in the Human Health
Research Strategy and the Human
Health Multi-Year Plan.
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TABLE 1, STAR GRANT RESEARCH PROJECTS REVIEWED IN THIS SYNTHESIS REPORT
Grant*
Project Title
Principal
Iiwestigator
(PI)
of in
R828611
R8286Q8
R828606
R8286Q9
R828610
Biomarkers and Neurobehavioral Effects of
Perinatal Exposure to Chlorpyrifos (CPF) and Other
Organophosphatc Insecticides
Development of a Physiologically Based Pfaarmacokinetic/
Pharmacodynamic (PBPK-PD) Model to Quantitate
Biomarkers of Exposure for Organophosphate Insecticides
Saliva Biomonitoring for Organophosphorus Pesticide
Exposures in Children
Measurement of Non-Persistent Pesticides in Postpartum
Meconium as a Biomarker of Prenatal Exposure:
A Validation Study
Chlorotriazine Protein Binding: Biomarkers of Exposure
and Susceptibility
to in
R827440
R827444
R827443
Ingestion of Pesticides by Children in an Agricultural
Community on the U.S./Mexico Border
Study of Exposure and Body Burden of Children of Different
Ages to Pesticides in the Environment
Vulnerability of Young Children to Organophosphate
Pesticides and Selected Metals through Intermittent
Exposures in Yuma County, Arizona
of to
R825169 Exposure of Children to Pesticides in Yuma County, Arizona
R825283
R825170
Measuring and Apportioning Children's Exposure to
Pesticides in Urban, Suburban, and Rural Communities
Assessing Levels of Organophosphorus Insecticides Which
Could Expose Children From Pets Treated with Flea Control
Insecticides
Wilkins
Timchalk
Fenske
Whyatt
Tessari
(previously
Andersen)
Shalat
Raymer
O'Rourke
O'Rourke
Sexton
Chambers
Project Period
02/2001-02/2004
(extended to 02/2006)
01/2001-12/2003
(extended to 05/2005)
09/2000-08/2003
(extended to 08/2005)
07/2000-06/2003
(extended to 06/2005)
06/2000-05/2003
(extended to 05/2006)
10/1999-09/2002
(extended to 03/2003)
09/1999-08/2002
05/1999-04/2002
(extended to 09/2004)
10/1996-09/1999
10/1996-09/1999
10/1996-09/1999
R825171
Total Organophosphorus (OP) Pesticide Exposure Among
Children in Urban and Rural Environments
Fenske
09/1996-09/1999
(extended to 09/2000)
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This section provides brief summa-
ries of the progress and findings of
the twelve grants listed in table 1.
Literature publications arising from
the grants are listed in section 4,
and detailed progress reports for
each grant can be found on ORD
NCER's Web site
http://es.epa.gov/ncer/index.html.
2.1
EPA released an RFA entitled "Biomark-
ers for the Assessment of Exposure
and Ibxicity in Children" in 2000. In
2000 and 2001, ORD awarded five
grants to researchers investigat-
ing various aspects of biomarkers
research. The RFA solicited research
that "would establish normative data
for biomarkers, evaluate biomarker
sensitivity in predicting exposure
or health outcomes, and lead to
the development of less invasive
biomarkers.
and Effects of
to (CPf) and
(OP)
This grant funded a large pro-
spective longitudinal study of the
relationships between biomarkers
of exposure to common household
pesticides (chlorpyrifos, diazinon,
other OP pesticides, and synthetic
pyrcthroids) and. indices of infant
neurological development from birth
through 2 years of age.
In spring 2005, mothers and chil-
dren were still being recruited to
reach a target sample of 176 low-risk
PI:
Dr. John Wllklns,
Ohio State University
EPA GRANT
R828611
AMOUNT:
$1,126,423
DURATION:
February 2001 through February 2006
pregnancies. The study involves
an analysis of maternal urine and
blood samples (at study entry and.
postpartum), infant urine samples
(at or before 3 months, then every
7 months to 24 months), and infant
blood samples (12 and 24 months)
for pesticide biomarkers. Infant
neurological development is being
measured at 3, 12, and 24 months
using the Bayley Scales of Infant
Development 2nd Edition (BSID-II)
and Child Development Index (GDI)
tests. Urine and blood samples were
originally to be analyzed for major
metabolites of CPF and. other OP
pesticides, but the ban on household
uses of CPF has caused a shift to
synthetic pyrethroids. Therefore, the
biological samples are also being ana-
lyzed for pyrethroid metabolites. In
addition to biomonitoring, data are
being gathered related to maternal
exposure to cigarette smoke, ethnic-
ity, sociocconomic status, parental
intelligence, family structure, as well
as clinical birth data.
According to the Pi's June 2005
progress report, 117 subjects were
actively enrolled; 104 of these
women have provided, second.
urine specimens and completed
questionnaires. The investigators
collected 83 diaper urine samples
from 2-month-old infants, 70
samples from 9-month-old infants,
46 samples from 16-month-old
infants, and 29 samples from 23-
month-old infants. The researchers
also performed neurological testing
(BSID-II) of 80 3-month-old infants
and 21 24-month-old infants.
The researchers have analyzed
and reviewed 198 maternal urine
samples. In addition, approximately
one-third of the 228 analyzed infant
diaper urine samples have been
reviewed. Organophosphates,
pyrethroids, and cotinine (cigarette
smoke) were detected in several of the
198 maternal urine samples analyzed.
Final results are not yet available.
Development of a Physiologically
Pharmacoklnetic/PharmacodynamlcfPBPK-
PD) to of
Exposure for
The purpose of this research was
to develop and validate an age-
dependent PBPK-PD model for the
OP pesticide CPF. The model was
intended to include age-dependent
changes in metabolism and phar-
macodynamic response to facilitate
quantitative biomonitoring of OP
pesticides.
Research under this grant built on
previous work by these authors on
PBPK-PD modeling of OP pesticide
responses in animals and humans.
Researchers developed analytical
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methods for quantifying CPF metabo-
lites, investigated in vivo and in vitro
mechanisms of CPF metabolism, and
refined the PBPK-PD model to sup-
port the evaluation of noninvasive
biomarkers of exposure.
PI;
Dr. Charles Ttmehalk, Battelle,
Pacific Northwest Division
EPA SHANT NUMBER:
R8
AMOUNT:
$733,174
DURATION:
January 2001 through May 2005
In the first year, grantees used their
previously developed human PBPK-
PD model to evaluate the effect of
the known polymorphism of CPF
oxonase (PON-1, a major detoxify-
ing enzyme) on brain and plasma
metabolite levels and plasma esterase
inhibition (Timchalk et al., 2002).
They found that estimated brain
concentrations of CPF-oxon were
nearly equal for all pheno-
types (QQ, QR, and RR) at low
single doses (~ 5 jug/kg). At
doses (0.5-5.0 ing/kg)
oxon concentrations were signifi-
cantly in medium- (QR)
and low-activity (QQ) plienotypes.
They concluded that at low doses
other detoxifying enzymes will
likely prevent significant toxicity
(as indicated by butyleholines-
terase [BuChE] inhibition), but
at doses, PON-1 polymor-
phism may contribute
cantly to variations in
sensitivity to CPF exposure.
Grantees also investigated the use of
saliva cholinesterase levels as a pos-
sible biomarker for CPF exposures
(Kousba et al., 2003). Fixperimenls
in rats showed that salivary ester-
ase activity is predominantly (>95
percent) BuChE. Kinetic parameters
for salivary esterase inhibition (active
site concentration, Ki for CPF-oxon,
and spontaneous reactivation rate)
derived from the experiments were
incorporated into the PBPK-PD
model. The revised model was able
to reproduce the time course of
salivary BuChE inhibition in rats,
supporting the potential use of saliva
sampling as a noninvasive biomarker
for acute CPF exposures (Timchalk et
al., 2004).
Experiments were conducted to
evaluate the role of intestinal metabo-
lism in modifying the absorbed dose
of CPF after ingestion exposure
(Poet et al., 2003). Production of
major CPF metabolites (CPF-oxon
and trichlorpyridinol [TCPy]) by
microsomc preparations from rat
hepatocytes and intestinal entero-
cytes was tracked using analytical
methods developed for this study.
Kinetic parameters (Km, Vniax) were
measured for the major metabolic
reactions (desulfurization and dearyl-
ization by cytochromes, hydrolysis
by PON-1), and the overall metabolic
capacities of the liver and intes-
tine were compared. The authors
concluded that first-pass metabolism
(primarily detoxification) in the intes-
tine may affect the systemic bioavail-
ability and toxicity of CPF, especially
at low doses.
The project results showed that
the age-dependent rat model is
quantitatively consistent with the
general understanding of OP loxicity
in younger versus older animals.
The model suggested that neonatal
rats are more sensitive to the high-
dose acute effects of OP exposure;
however, at low, environmentally rel-
evant exposure levels, the neonatal
rat model was not substantially more
sensitive than adult rats.
Biomonitoring for Organophosphorus
in
The purpose of this study was to
evaluate the feasibility of quantify-
Pl:
Dr. Richard Fenske,
University of Washington
EPA
R828606
AMOUNT:
$742,597
DURATION;
September 2000 through August 2005
ing children's exposure to the OP
pesticides diazinon and CPF, as
well as a third pesticide from the
synthetic pyrethroid family, perme-
thrin, through saliva biomonitoring
of pesticide levels.
Research performed under this
grant included (1) measurement of
diazinon concentrations in saliva
after intravenous injection in rats,
(2) evaluation of the effects of vary-
ing diazinon doses and salivary flow
rate on diazinon excretion in saliva,
(3) determination of the correlation
between salivary and plasma concen-
trations, (4) measurements of CPF
and diazinon concentrations in the
saliva and urine of children in agricul-
tural communities, and (5) develop-
ment of a pharmacokinetic model for
CPF and diazinon using salivary and
urinary markers.
In the first part of the study, anesthe-
tized rats were injected with various
doses of diazinon. Time-course
samples of plasma and saliva were
obtained through 250 minutes after
dosing. Concentrations of diazinon
were determined using an enzyme-
linked immunosorbent assay (ELISA).
Statistical analyses of the data
revealed that diazinon concentra-
tions were consistently lower in saliva
samples than in plasma samples,
regardless of dose level, sampling
time, or salivary flow rate. The find-
ing suggests that salivary excretion
of diazinon is diffusion-limited,
father than transporter-mediated.
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A correlation was found
between pesticide metabolite
concentrations ill
(Lu et al., 2005). Addi-
tional analysis revealed that the
concentration of diazinon in saliva
reflected the fraction of diazi-
non that did not bind to plasma
proteins. This information allowed
accurate prediction of rela-
tive concentrations of in
saliva, supporting the
of bioiiionitoring as a
noniiivasive for
sampling in the of
human diazinon exposures.
Data from animals dosed with CPF
suggest that CPF is metabolized within
minutes in blood, and therefore, it is
not measurable in saliva.
Permethrin was selected as one of
the chemicals to be measured in
saliva using the ELISA assay; however,
the ELISA assay for permethrin was
not optimized for use in specimen
samples. Additional research is being
conducted to improve the perme-
thrin ELISA assay.
The second part of the study, con-
ducted in Nicaragua, assessed, pes-
ticide exposures for 7 corn farmers
who used CPF, 10 banana plantation
workers who applied diazinon, and
their children. The investigators
conducted urine, blood, and saliva
sampling. Their analysis of the urine
samples indicated exposure to CPF
for the farmers, plantation "work-
ers, and children, but the saliva
samples did not indicate exposure.
This results from the rapid metabo-
lism and clearance of CPF. This
finding was consistent with the
animal studies. The study identified
two important exposure factors:
proximity to spraying and spray
mixture preparation in the home.
The analysis detected exposure to
diazinon among the applicators, but
not among their children. Diaziiion
concentrations in the workers'
were correlated
with the time-matched of
blood. Diazinon concentra-
tions hi also corresponded
with excretion of primary
urinary metabolite of diazinon in
these applicators.
The investigators suggested that
is a
monitoring it
is uoniuvasive, and it
pesticides pesticide
metabolites. The may not
be for compounds
(e.g., CPF), dehydration
among the study subjects can
adversely affect sample collection.
in as a of
The puipose of this research was to
validate a. new noninvasive biomarker
of prenatal exposure to OPs and other
pesticides. The study design involved
measuring the levels of a large num-
ber of pesticide residues in meconium
samples from 100 infants born to Afri-
can American or Dominican women
from Manhattan and die Bronx, New
York. Pesticide levels in meconium
were compared with the results of
continuous indoor and personal air
monitoring during the final 2 months
of pregnancy and "with self-reported
pesticide use (Whyatt et al., 2003).
The study included 102 mother-
newborn pairs. Biologic samples were
collected from the mother during
pregnancy and from die mother and
newborn at delivery and included:
253 repeat spot urine samples col-
lected from the mothers during preg-
nancy; urine samples collected from
the mothers (n=74) and ncwborns
(n=69) after delivery; maternal blood
(ii=95) and umbilical cord blood
(n=69) collected after delivery; and
postpartum meconium (n=85).
Eleven insecticide metabolites were
measured in meconium. Those
detected most frequently were
carbofuranphenol, 1-naphthol, 4-
nitrophenol, 2-isopropoxyphenol,
and TCPy. TCPy levels in meconium
were correlated positively but not
significantly with CPF in the indoor
air samples and were correlated
positively and significantly with TCPy
levels in the prenatal maternal urine
samples, both before and after adjust-
ing for creatinine. TCPy in meconium
also was correlated significantly with
CPF levels in both the maternal blood
and umbilical cord blood samples
collected after delivery.
PI:
Dr. Robin Whyatt,
Columbia University,
Mailman School of Public Health
EPA GRANT NOMBEft
R828809
AMOUNT:
$744,868
DURATION:
July 2000 through June 2005
CPF, diazinon, and propoxur were
frequently detected in continuous air
sampling results from 102 women
between the week 32 of pregnancy
and delivery (at 40-42 "weeks). Levels
of the individual pesticides "were
generally highly correlated (relatively
constant) over time for individual
women but varied greatly among indi-
viduals, with a few "women showing
much higher exposures.
The results from this study
indicate that meconium is a
biomarker of prena-
tal exposure to CPF. CPF, or its
metabolite, TCPy, 'was only
compound was consistently
detected across all environment
biologic matrices in the cur-
rent study. While only a weak
correlation between CPF levels
in indoor air samples and TCPy
levels in meconium was observed,
there was a consistent and highly
observed correlation between
TCPy levels ill other biologic
matrices meconium. Thus,
TCPy appears to provide a vain-
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dosimeter for CPF
exposures during pregnancy.
ChloroMazine Protein Binding:
of Exposure and Susceptibility
The purpose of this research was to
develop analytical methods to char-
acterize the reactivity of chlorotri-
azines with hemoglobin protein, and
evaluate whether binding to hair
proteins can be used as a nonin-
vasive biomarker of triazine expo-
sure. The investigators proposed to
develop an age-specific PBPK model
to assess tissue concentrations of
PI;
Dr, John Tessari
(previously Dr, Meivin Andersen),
Colorado State University
EPA
R828610
AMOUNT:
$710,617
DURATION:
June 2000 through May 2006
chlorotriazines and their metabolites
over time and validate the model
using animal and human data.
Atrazine (ATRA) is a high-volume
pesticide that has been found in a
number of drinking "water supplies.
Available biomarkers of exposure
have been limited primarily to
metabolites in urine, and the details
of ATRA absorption, metabolism,
and excretion were not well char-
acterized before this work. A major
achievement under this grant was
the development of an analytical
method capable of detecting low
levels of ATRA and its metabolites
in serum (Brzezicki et al., 2003).
Previous efforts to study the pharma-
cokinetics of ATRA had been limited
by the lack of a metabolite-specific
method, and were primarily based
on radiotracer data. The analytical
method included cleanup, liquid-
liquid extraction, and derivalizalion
with methyl bromide/tetrabutyl-
ammonium chloride. The method
demonstrated clean separation of
ATRA and its major metabolites with
a level of quantisation (LOQ) of 100
ng/ml for all species. It was validated
using spiked serum samples as well
as an in vivo metabolite analysis
after single-dose administration to
Sprague-Dawley rats.
The investigators also developed
a detailed PBPK model for ATRA
(McMullin et al., 2003) in adult rats.
The model simulated the metabo-
lism, transformation, and elimination
of two major classes of metabolites,
the chlorinated triazines and glutathi-
one conjugates. Modeled processes
included gastrointestinal absorption,
metabolism by cylochrome P450
isozymes, conjugation by glutathione
(GSH), and. the binding of chlorotri-
azines to hemoglobin and serum
proteins. Development of the model
involved extensive research on chlo-
rotriazine-globin binding rates and
mechanisms. The PBPK model was
validated against previous multiple-
dose radiotracer studies of total ATRA
metabolites and against data from a
single-dose time course study in rats.
The latter study used the previously
developed analytical method to
quantify ATRA and its metabolites in
serum over time. The model was able
to accurately fit both the single- and
multiple-dose data. The importance
of reactions with
serum proteins was confirmed
and the rate constants for hemo-
globin and serum binding and
elimination were estimated. The
slow gastrointestinal absorption of
ATRA, followed by rapid metabo-
to 2-chloro-4,6-diamiuo-l,3>5'
(DACT) were confirmed
as of ATRA
pharmacokinetics.
According to the Pi's June 2005
progress report, the research team
was investigating methods for pre-
Ireatment, digestion, and extraction
of hair and the formation of other
protein-atrazine adducts.
2,2 to
In 1999, EPA released the REA
"Children's Vulnerability to Toxic
Substances in the Environment."
This request focused on research
that quantified children's exposure
to chemicals by examining factors
contributing to exposure, such as
frequency, duration, activity patterns,
temporal variation, and individual
physiological differences. Develop-
ment of predictive exposure models
incorporating these factors were also
encouraged and funded.
by in
on the U.S./
Border
The purpose of this research was to
evaluate children's exposure to OP
pesticides in households within rural,
agricultural communities along the
U.S./Mexico border. The research
attempts to determine the influence
of hygiene practices and behavior
patterns of children on pesticide
dose level.
Research under this grant included
(1) collection of environmental and
urine samples and analysis for the
presence of pesticides and pesticide
residues, (2) statistical analyses to
evaluate the associations between
pesticide levels in environmental
samples and pesticide body burdens,
and (3) observation and analyses of
children's mouthing behaviors.
PI;
Dr. Stuart Shalat, University
of Medicine and Dentistry
of New Jersey
EPA
R827440
AMOUNT;
$710,231
DURATION:
October 1999 through March 2003
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Environmental sampling revealed
detectable levels of pesticides in
house dust in 75 percent of the 29
homes studied; however, no correla-
tion was found between levels of
pesticides in house dust and pesti-
cide metabolite levels in urine. Half
of the hand-wipe samples taken from
the children in the study contained
levels of pesticides above the detec-
tion limit. There a.
association between pesticide lev-
els on children's pes-
ticide metabolite levels ill urine.
Researchers conjectured tills
associated with
frequent hand-to-mouth behav-
iors. 'Video recordings of the partici-
pants' behavior will be analyzed to
help substantiate this hypothesis.
Dimethyl phosphate (DMP) and
diethyl thiophosphate (DETP) were
the most commonly detected metab-
olites that were found in 100 percent
and 96 percent of the subjects,
respectively. The pesticides methyl
parathion and azinophos-methyl
were detected in both hand and dust
samples taken, consistent with die
detection of its metabolite, DMP, in
urine samples.
No association was found between
total
of pesticides on children's
hands. This result suggests that
hand surface area may not be
useful as a sealing factor in risk
assessments. Age was inversely
and significantly correlated with
estimated dose levels, while gen-
not to be predictive
of body burden.
All of the urine samples contained
concentrations of at least one
pesticide metabolite above the limit
of detection. Ninety-five of those
samples contained more than one
metabolite above the detection limit
(Shalat et al., 2003).
Study of and Body of
of Different Ages to in
the
Grantees set out to evaluate whether
children incur more frequent and
higher exposures to pesticides than
adults living in the same house-
hold. Secondary objectives included.
evaluating pediatric environmental
exposure rates and dose distributions
in relation to demographic variables.
PI:
Dr, James Raymer,
Research Triangle Institute
EPA SRAHT
B827444
AMOUNT:
$819,063
DURATION:
September 1999 through August 2002
Research under this grant builds on
previous work of these authors on
the National Human Exposure Assess-
ment Study (NHEXAS) by using the
same study population to examine
exposures to CPF, diazinon, ATRA,
and malatliion (MDA). The research
involved (1) developing a means of
collecting infant urine samples, (2)
collecting and analyzing environ-
mental and urine samples, and (3)
correlating observed behavioral and
demographic data with measured
exposures.
After encountering difficulties finding
detectable levels of pesticide residues
of target analytes to study in Rice
and Goodhue Counties, Minnesota,
grantees moved the study to Moore
County in western Minnesota.
Pesticide and pesticide metabolites
were measured in indoor air, exhaled
breath, domestic "water, surface
wipes, house dust, dermal rinses, and
body suits.
Many pesticides and pesticide
metabolites were found in the first
morning urine samples from both
children and adults. Estimates of
mean exposures were dominated
by a few highly exposed individuals.
revealed sig-
nificant differences between the
metabolite levels present in the
urine of children and adults. Spe-
cifically, the grantees determined
levels of the CPF metabolite
TCPy in children's hydrolyzcd
were on average
two levels detected ill
adults. Similarly, levels of ATRA
metabolite 2-
isopropyl-6-methyl-4-pyrimidlnol
(IMP) detected in nonhydrolyzed
urine samples averaged to be two
and seven times greater, respec-
tively, in children than in adults.
No other significant differences
between adults* and children's
pollutant exposure or body bur-
dens were identified.
There were
ill levels of
found in children's urine samples
from differing age groups. Non-
hydrolyzed urine sample analysis
revealed that children birth to 3
years old excreted 16 times more
of the diazinon metabolite IMP
(mean=245 ng/ml) children
4 to 12 (mean=l4 ng/iiil).
of younger
cohort contained
twice as CPF-oxon
(mean=0.46 ng/iiil), a CPF
metabolite, than that of the 4- to
12-year-old group (mean=0.17 ng/
ml) on the third day of the study.
Conversely, of chil-
dren 4 to 12 years old contained
significantly concentrations
of TCPy ATRA of
birth to 3 years old. Con-
of ATRA ill the nonliy-
drolyzed urine of children 4 to 12
(mean=0.076 ng/ml) were signifi-
cantly higher than levels found in
the younger group (mean=0.004
ng/ml) on the second day of
the study. The following day,
seven level of TCPy
found ill nonhydrolyzed
-------
of children 4 to 12 years
old (mean=0.54 ng/nil)
of the younger children
(mean=0.078 ng/nil).
of FOMJ to
and
through Intermittent Exposures in
The two major objectives of this
effort were to evaluate the routes
and amounts of OP pesticide and
metal exposure among young
children and identify activities that
result in increased children's expo-
sure to contaminants in the home.
Activities under this grant included
(1) collection and analysis of samples
of exposure media, (2) collection and
analysis of pediatric urine samples,
(3) collection and analysis of dermal
hand-wipe samples, (4) administra-
tion of questionnaires about general
household conditions and parental
occupation, and (5) analyses of
recorded activities and play areas
of children to identify pesticide
exposure pathways. Environmental
samples were analyzed for nine OP
pesticides (including CPF, diazinon,
and MDA) and heavy metals; urine
samples were also analyzed for OP
metabolites.
PI:
Dr. Mary Kay O'Rourke,
University of Arizona
EPA
R827443
AMOUNT:
$712,313
DURATION:
May 1999 through September 2004
The results of household dust and
pediatric urine samples of children
living in agricultural communities
were used as screening tools to
identify potential participants with
elevated pesticide exposure or risk of
exposure. The recruited population
of 217 was narrowed to 45 children
who were then divided into low and
high exposure groups matched by
age and gender. The levels of metals
in urine samples were generally low
and showed no evidence of expo-
sures above expected background
levels. The investigators therefore
abandoned their planned analyses of
heavy metal exposures.
Preliminary revealed a
of behavior
were associated with
pesticide exposures. Children
with the highest exposure levels
were males who spent the greatest
amount of time playing outdoors.
Similarly, children who played
extensively in laundry rooms and
entry ways
of pesticide metabolites hi
who did play, or
played less, ill areas.
Video analyses completed to date
indicate that the number of hand-to-
mouth, hand-to-food, and mouthing
activities in a given time period are
more accurate predictors of expo-
sure than the time a child spends
touching a contaminated item or
surface. Repeated wipes from hands
of the same child over a short time
frame (hours) reflected the same
concentration and loading value
repeatedly. This suggests that
frequent hand washing does little
to reduce children's exposures in
the household if chemical con-
tamination is readily accessible.
Additional preliminary analy-
ses to a
method for predicting exposure
to using a urinary
assay quantifying the presence of
an endogenous metabolite.
23
to
EPA awarded four grants as a result
of the RFA entitled "The Exposure
of Children to Pesticides" that was
released in 1996. This REA requested
research proposals that would
enhance development of pediat-
ric pesticide exposure assessment
methods by characterizing the effect
of age and behavioral factors on pes-
ticide exposure. Additional research
priorities set by this RFA included
development of methods for assess-
ing cumulative exposures from one
or multiple pathways.
of to
in County,
The purpose of this study was to
compare the OP pesticide exposure
and exposure pathways in children
living in agricultural communities
to those living in nonagricultural
communities in Arizona. Creatinine
levels were used to normalize urinary
biomarker data of the dialkylphos-
phates, which are common OP
pesticide metabolites. Major study
findings were reported in O'Rourke
et al. (2000).
PI:
Mary Kay O'Rourke
University of Arizona
EPA GRANT NUMBER:
R825169
AMOUNT:
$596,039
DURATION:
1996 through September 1999
Communities in Arizona within 15
miles of the U.S./Mexico Border (46
percent from San Luis, 49 percent
from Somerton, and 5 percent from
Gadsden/Yuma) were selected from
the NHEXAS, 1990 census tract, and
the Arizona. Border Survey (ABS), to
create the Children's Exposure to
Pesticide Survey (CPS) for this study.
.All children were Latino, most house-
holds were bilingual, 51 percent were
male, and 49 percent were female.
Spanish "was the preferred language
in 97 percent of the homes surveyed.
Study subjects were recruited in two
ways, a population-based probability
design and from families enrolled
-------
in services catering to children, with
children that displayed bladder
control (2 to 6 years old). A total of
154 children participated in the study
(O'Rourke el al., 2000). Descriptive
questions were submitted to each
household, and a two-visit screening
was used to develop a 1-day record of
typical activities and duration and a
1-day record of all food and bever-
ages consumed. A first morning
void urine sample and dust sample
were taken during the screening stage
as well. Urinary OP, OP metabolites,
and creatinine were analyzed.
A total of 154 urine samples were
collected with a mean urinary creati-
nine concentration of 0.90 g/L. The
urinary creatinine data appeared to
be lower than expected for the first
bladder voiding. After questioning the
families about their children's urinary
behavior, 16 percent of the children
were known to wet the bed and ~50
percent may have used the toilet in
the night. Differences in seasonal
creatinine excretions -were observed.
when comparing autumn and spring
(Mann-Whitney, P=0.038) and sum-
mer and autumn values (Mann-Whit-
ney, P=0.04l). Additional compari-
sons of the data to the larger data set
from the 1996 National Health and
Nutrition Examination (NHANES) III
(DHHS, 1996) survey indicated racial
differences, with African-American
children having statistically higher
creatinine values (mean=0.94 g/L;
n = 173; P=0.0000) as compared to
Caucasian children (mean=0.78 g/L;
n = 285). Ethnic differences were
observed -with non-Hispanic chil-
dren displaying a significant increase
in crealinine (0.86 g/L; n = 287;
P=0.005) as compared to Hispanic
children (mean=0.77g/L; n=190).
Metabolites of OP pesticides, dialkyl-
phosphates, were measured in the
urine of 121 children "who were 6
years or younger with valid, creatine
analyses. Thirty-three percent of
the subjects had detectable levels of
at least one metabolite, and many
contained multiple metabolites. The
dialkylphosphate distribution -was
as follows: 5 percent of the sam-
ples contained diethylphosphates
(DEPs), 25 percent dimcthylphos-
phates (DMPs), 26 percent dimeth-
ylphosphorothioates (DMTPs), and
3 percent dimethylphosphordithio-
ates (DMDTP). Theoretical absorbed
daily doses (ADDs) were calculated
for three children that excreted
the highest amount of biomarker,
assuming that a single pesticide
was metabolized and that all of the
metabolite had cleared. CPF and
diazinon are both used in the Yuma
area. and. could, be responsible for
the DEP metabolites. At the highest
DEP excretion, the ADD for diazi-
non was 126 times the permissible
reference dose. DMP and DMTP are
associated with methyl parathion
metabolism, and the theoretical
ADDs were 385 and. 61 times the
reference dose, respectively. When
exposure to
OPs, floor dust to be
major medium through which
young children are (68.8
percent), followed by solid food
(18.8 percent) beverage (10.4
percent). Air and water (modeled
from ABS and NIIEXAS data) eon-
tribute less than 2 percent to the
total aggregate exposure.
to in
and
The purpose of this research grant
was to determine children's actual
exposure to pesticides, and. to assess
if current regulatory decisions
(e.g., the Food Quality Protection
PI:
Dr, Ken Sexton,
University of Minnesota
EPA BRANT NUMBER:
R825283
AMOUNT:
$745,572
DUiATlON:
October 1996 through September 1999
Act of 1996) are either protective of
children's health or cost effective.
The study focused on collecting
NHEXAS data for exposure to 4
primary pesticides (CPF, diazinon,
MDA, and ATRA), 14 secondary pesti-
cides, and 13 polyaromatic hydrocar-
bons (PAHs). The study was a part
of NHEXAS.
Children (102 children/families, 3 to
12 years old.) were recruited, from
the urban Minneapolis/St. Paul area
and rural Goodhue and Rice Coun-
ties. Analytical samples taken were as
follows: 6-day integrated personal-
indoor air; 4-day integrated food and
beverages samples (duplicate diet);
hand rinses; first morning urine
voids; indoor and outdoor air; drink-
ing water; surface wipes; and soils
(Quackenboss et al., 2000). Ques-
tionnaire data, were also collected,
diary data of the child's activities
were maintained, and. a subset of
children were videotaped to quantify
children's hand-to-mouth activities.
Pesticide products were found in
97 percent of the homes with an 88
percent self-reported, use (Adgate et
al., 2000). The population-weighted
mean numbers of products used and
stored, in a household, in the prior
year "were 3.1 and 6.0, respectively.
These results were at least twice the
national averages reported in two
previous major studies. However, no
differences were observed between
urban and rural communities,
socioeconomic and/or racial/ethnic
factors. CPF and its metabolites
were the most commonly measured
compounds found in the samples
analyzed, from personal air (95.0
percent), indoor air (91.5 percent),
and. dust samples (61.6 percent).
Levels of MDA were detected in
54.1, 67.0, and 0.0 percent of these
samples, respectively. Diazinon
was detected in 64.1, 68.0, and 7.1
percent of personal air, indoor air,
and house dust samples, respectively.
ATRA, CPF, and diazinon were all
detected in fewer than 16 percent
-------
of outdoor air and soil samples. CPF
was detected in 57 percent of food
samples; detection frequencies for
MDA, ATRA, and diazinon were 46, 8,
and 3 percent, respectively (Sexton et
al., 2003).
Hand-to-mouth behavior was the
most observed exposure pathway in
children. The 3- to 4-year-old chil-
dren displayed the most frequent
hand-to-mouth actions, however,
the activity was also seen in older
children at a lower frequency. There
were few handwashings preceding
food handling and consumption for
all age groups with females washing
their hands more frequently than
males (Adgate et al., 2001 and
Freeman et al., 2001).
ATRA, CPF, and MDA were detected
in greater than 30 percent of the
households in dust and hand washing
samples. The median range of CPF
and/or metabolites found in the dusl
samples were 0.07-0.42 ng/cm2 (lioy
et al., 2000). CPF and/or metabolites
were found in over 50 percent of the
hand samples with a median amount
of 0.03 ng/hand and a maximum of
2.14 ng/hand.
Urinary metabolites were analyzed
from at least three first morning
voids over a five day period in 90
children that were in households that
reported frequent use of pesticides.
Urinary pesticide metabolites (not
adjusted for creatinine) percent
detected "were 96.6 percent CPF
(6.9 ftg/g or 59-0 ju>g/g, median and
maximum, respectively), 46.6 percent
MDA, and 4.4 percent ATRA; diazi-
non was not analyzed. Interchild
variability (carbamates and related
compounds [1-NAP], CPF and related
compounds [TCPy], and MDA)
indicated a larger sample size "was
needed to better assess exposure for
the general population.
average variability ranges were
1.3 times the weighted popula-
tion mean for 1-NAP, 1.5 times the
weighted population for
MDA, and approximately equal
weighted population for
TCPy suggesting single measure-
ments are insufficient to charae-
relative of
long-term exposure to the parent
compound (Clayton et al., 2003).
of Organophosphorus
From with Flea Control
The objective of this project was
to measure potential pesticide
exposures to dog owners and iheir
children from flea-dipped or collar-
treated dogs. Major findings can be
found in Boone et al. (2001).
The researchers recruited dogs from
the general population. These dogs
were treated with commercial, non-
prescription flea control dips (CPF
or phosmet) or collars (tetrachlorvin-
phos or CPF) and were nibbed on
the midline back area for five minutes
•with a cotton glove. The glove was
extracted and analyzed for pesticide
residues. Pesticide residue samples
were taken at 4 hours, and then at
7, 14, and 21 days after application.
Collared animals were sampled from
the neck area with and without the
collar. The CPF-dipped animals were
split into two groups (12 dogs/group)
to assess if die pesticide accumulated
over time; one group of dogs was
shampooed before each reapplica-
tion; a second group was not bathed.
Plasma butyrylcholinesterase and
acctylcholincsterase activity were
assayed in the dogs, and their own-
ers' urine "was analyzed for pesticide
metabolites.
The transferable OP pesticide
residues from the CPF and phosmet-
dipped dogs were found to peak
shortly after flea dip administra-
tion. CPF residues decreased by 87
percent after 1 week, 92 percent by
week 2, and 97 percent by week 3,
with similar residue attenuation in
the phosmet-dipped dogs. There was
no evidence of CPF accumulation
from one dipping to the next in the
nonshampoocd dogs. Considerable
individual variablity was observed;
however, fur length was not consid-
ered a factor in the variability. Plasma
butyrylcholinesterase activity in the
nonshampooed CPF treated dogs was
inhibited 50-75 percent throughout
the study and acetylcholinesterase
was inhibited by 11-18 percent,
PI:
Dr. Janice Chambers,
Mississippi State University
EPA
R825170
AMOUNT:
$5i7,804
October 1996 through September 1999
with no appreciable cholinesterase
inhibition observed with the phosmet
dipped or shampooed group of CPF-
dipped dogs.
The tetrachlorvinphos and CPF col-
lars both yielded the least transfer-
able residues from the backs of the
dogs. The highest residues were
found in the neck area "when the
tetrachlorvinphos collar was in place.
The data suggest the pesticide does
not migrate from the neck down
the back. An appreciable degree of
individual variation in the residues
detected "was observed with no
correlation to fur length. There was
negligible inhibition of the plasma
cholineslerase in dogs with lelra-
chlorvinphos collars. In contrast,
the CPF collar pesticide residues
were considerably lower than those
obtained with tetrachlorvinphos
collars; however, the plasma cholin-
esterase activities in the dogs were
inhibited about 60 percent compared
to pretest activities throughout the
sampling period.
Urine
and children (aged 3 to 12 years)
hi households with dogs
used collars indicated that TCPy
levels when the col-
lars wefe placed on the dogs.
The magnitude of in
TCPy levels was highly variable
-------
both children,
and adjusting the TCPy levels for
urinary concentrations
did not significantly reduce the
variability. Because of high
variability, the difference between
precollar postcollar TCPy lev-
els in urine, while large for some
individuals, 'was mot statistically
significant for the study group
as a whole.
Total
in and
Rural Environments
The primary objectives of the research
conducted under this grant were to
characterize the geographic, temporal,
age-related, and gender-related vari-
ability in total OP pesticide exposure
in children living in certain areas of
Washington State and to determine
the relative contributions of environ-
mental sources to the children's total
OP pesticide body burdens.
Two biologic monitoring experiments
were conducted to measure pesticide
metabolites in 2- to 5-year-old chil-
dren's urine. Samples were analyzed
for OP pesticide metabolites and six
dialkylphosphates (DAP). The first
study evaluated 110 children with
sampling in the spring and fall, and
the other involved 44 children from
agricultural areas of Washington State
whose urine "was sampled monthly
over 21 months. In addition to the
first two efforts, the third field study
was conducted to evaluate biomark-
ers in 13 children with higher poten-
tial OP pesticide exposure as judged
based on behavioral surveys and resi-
dential location. Samples of inhaled
air (24-hour), soil, house dust, drink-
ing water, 24-hour duplicate diet,
and 24-hour urine were analyzed.
.Another study measured DAP levels
in urine from preschool children of
urban and suburban communities
that consumed a conventional diet or
an organic diet.
In the first field study, no differences
in DAP levels were observed when
comparing values from spring and
fall, urban or suburban communi-
ties, gender, age, family income,
or housing type. Children whose
parents reported pesticide use in
the garden had significantly higher
levels of dimethyl and diethyl DAPs
in their urine (Lu et al., 2001). In the
second field effort, a strong temporal
PI:
Dr. Richard Fenske,
University of Washington
EPA
R825171
AMOUNT;
$800,145
DURATION:
September 1998 to September 2000
trend in OP pesticide exposure was
observed with DAP concentrations
displaying an elevation in months
•when OP pesticides were sprayed.
Boys had significantly higher DAP
metabolite levels in their urine than
did girls. No differences were found
based on child age, parental occupa-
tion, or residential proximity to fields
(Koch et al., 2002). The data were
analyzed by a mixed-effects analysis
of variance (ANOVA) model dial
compared the within- and betwecn-
child variance and standard devia-
tion in urinary DMTP concentration
during both die spray and nonspray
months. The results of this analysis
demonstrated that, regardless of time
of year, the within-child component
of variability is much greater than
the bctwecn-child component for
this population. These results show
urinary DMTP concentra-
tion varied more front day-to-day
child-to-child in tills
population. In the third field effort,
azinphosmethyl, CPF, malathion,
methidathion, methyl parathion, and
phosmct were detected in the food
of these children. Azinphosmelhyl
(10 percent) -was die compound
found most frequently, particularly in
foods or beverages containing apples
or apple juice. No detections were
found to be above legal tolerances for
residues on produce. However, the
acute population-adjusted reference
dose (aPAD) for CPF of 1.7 mg/kg/day
was exceeded by one child -who con-
sumed 10 cherry tomatoes that con-
tained 30 ng/g azinphosmethyl and
350 ng/g CPF. This child's cumulative
daily dose of CPF equivalents was
estimated to be 2.5 mg/kg/day (Fen-
ske et al., 2002). Diaziiion and CPF
were commonly detected in indoor
air. Most housedust samples con-
tained one or more OP pesticide. OP
pesticides were virtually non-detect-
able in drinking water and soil. Clear
were noted in
exposure pathways for the rural
agricultural children Seattle
metropolitan area children, with
metabolite levels ill suburban
children being correlated with
reported household pesticide
(Lu et al., 2004).
When four urine samples were
collected from each child over the
course of a 24-hour period, the data
were highly variable, suggesting a
single spot sample is not a reliable
predictor of an individual child's
exposure. First morning void samples
were found to be the best predictors
of total daily metabolite excretion
(Griffith et al., submitted and Kissel
et al., 2005). In the
study, children with organic diets
were found to
lower median dimethyl DAP levels
conventional diets. No differences
ill occupational or household pes-
ticide use were reported between
two (Curl et al., 2003).
The researchers also developed a
novel method for determination
of OP pesticide concentrations
in household and vehicle dust.
This method used size exclusion
chromatography (SEC) as a cleanup
method for the analysis of organo-
phosphorus pesticides diazinon,
methyl parathion, CPF, MDA, phos-
met, and azinphosmelhyl (Moate
et al., 1999).
-------
3.1
All of the research contained in
this report has helped to reduce
uncertainties in risk assessment by
providing better data on children's
aggregate exposures and estima-
tion of exposure factors, improving
knowledge of children's pesticide
exposure in agricultural communi-
ties, helping to identify principles
for the use of scaling factors in risk
assessment, and developing and
validating biomarkers of exposure
and dose. For convenience, grants
are referred to in this section by the
name of the first PI listed on the
grant proposal. (Richard Fenske and
Mary Kay O'Rourke were the PI on
more than one grant; these grants
are also referred to by number).
Four of the grants (Fenske 825171,
O'Rourke 827443 and 825169, and
Sexton) specifically involved mea-
surements of aggregate pesticide
exposures from multiple sources
in different selected populations
of children. Fenske looked at
multipathway exposures in children
in Washington State in relation to
urban/rural residence, household.
and agricultural pesticide usage,
versus parental and other house-
hold variables. Both of O'Rourke's
grants evaluated pesticide expo-
sures in predominantly Hispanic
rural communities near the U.S./
Mexico border in relation to pesti-
cide levels in soil, house dust, and
activity patterns. Sexton evaluated
exposure patterns of children in
urban and rural Minnesota com-
munities. Multipathway aggregate
exposures (air, soil, dust, diet, sur-
faces) -were measured using urinary
metabolites as biomarkers.
Slialat evaluated the factors con-
tributing to children's ingestion
exposures to OP pesticides, also in
New Mexico. O'Rourke (825169)
estimated OP exposures in children
in Arizona, and evaluated the relative
contributions of dermal and inges-
tion pathways to total exposure.
Whyatt's analysis of meconium
samples and maternal exposure
levels will help characterize prena-
tal OP pesticide exposure patterns
among minority infants in New York
City. Wilkens' longitudinal study is
examining maternal, prenatal, and
postnatal biomarkers of exposuure
that support analysis of aggregate
exposures to OP and pyrethoid
pesticides and may reveal age-related
exposure differences. His -work will
also attempt to correlate biomarkers
of exposure with impaired develop-
ment in the exposed, infants.
Along with Sexton, both Shalat
and O'Rourke (827443) evaluated
children's mouthing behaviors and
found that they contributed sig-
nificantly to aggregate exposures.
Raymer evaluated, levels of pesticide
metabolites in urine from popula-
tions in rural Minnesota, finding
that metabolite levels were much
higher in children than in adults,
and higher in younger children than
in older children in similar exposure
settings. Chambers developed a
method for measuring the poten-
tial dermal exposures and doses in
children and adult dog owners who
use pesticide flea dips or collars
and found, that such exposures may
contribute significantly to household
pesticide exposures. These results
are directly applicable to pesticide
risk assessments.
Many of these grants provided infor-
mation about children's exposures,
body burdens and dose levels that
could be used in conjunction with
other data for comparison with
adults' exposure patterns. Raymer's
research specifically documented
higher children's pesticide exposures
and doses and higher exposures
in younger children than in older
children in similar exposure settings.
"Wilkins is engaged in a long-term
study of maternal, prenatal, and
postnatal pesticide exposures and
body burdens. Whyatt's study is also
evaluating and comparing indices
of maternal and prenatal exposure.
Finally, the PBPK modeling efforts of
Tinichalk and Tessari provide frame-
works that may ultimately be used
to compare children and adult body
burdens of CPF and ATRA, respec-
tively. Chambers compared adults'
and children's levels of urinary pesti-
cide metabolites in households with
CPF-collared dogs.
-------
Research under many of the grants
has indirectly provided information
that could be used in development
of scaling factors for risk assessment
(thai is, for adjusting between adults
and children). Data from the research
that evaluated relationships between
children and adult exposures and
body burdens (Raymer, Whyalt)
may find direct application in risk
assessments for pesticide exposures.
Data being developed, by WUkins on
indices of maternal and infant body
burdens of pesticides might also
be used. Shalat evaluated methods
for evaluating dermal and ingestion
exposures based on children's body
(hand) size and behavior patterns,
and O'Rourkc (827443) investigated
the behavior and physical determi-
nants (including gender) of chil-
dren's pesticide exposure patterns.
In addition, the PBPK models devel-
oped by Timchalk and Tessari are
intended to help elucidate relation-
ships between adult and children's
exposures, absorbed doses, and
adverse effects.
Grants involving PBPK modeling
helped to understand differences
between children and adults. Tim-
chalk and Fenske (828606) devel-
oped and/or refined PBPK models
for OP pesticides to improve their
applicability in human health risk
assessments for adults and children.
Timchalk developed analytical
methods and conducted in vivo
and in vitro experiments on CPF
metabolism to improve a previously
developed PBPK-PD model. Studies
of enzyme polymorphism on CPF
metabolism, and on the role of first-
pass metabolism in the intestine on
absorbed dose, were used to improve
the ability of the model to replicate
serum time-course data. In addi-
tion, the refined, model "was used to
establish the utility of saliva, esterase
inhibition as a useful biomarker of
CPF exposure.
Fenske (828606) used. data, from
rat studies to develop a pharmaco-
kinetic model for diazinon and. its
metabolites. The model confirmed
the utility of saliva metabolite levels
as indicators of exposure.
Tessari developed the first
metabolite-specific PBPK model for
ATRA. Tessari's model incorporates
dealkylation by cytochromc
P450 isozymes and. glutathione
conjugation, as well as binding to
hemoglobin and serum proteins.
The model is intended for use in
evaluating hair protein adducts
as biomarkers of exposure and
as potential risk indicators. This
model may help to better elucidate
the as yet poorly understood
pharmacodynamic mechanisms of
ATRA and its metabolites in humans.
The five studies funded under the
biomarkers RFA were specifically
devoted to biomarker identification
and validation, and all attempt to
improve risk assessment through
biomarker use, and to develop more
convenient, less invasive biomarkers
of exposure. Wilkiiis conducted a.
detailed, evaluation of a wide range
of maternal and neonatal biomark-
ers of pesticide exposure as predic-
tors of infants' neurodevelopmental
impairment. Fenske (828606) and.
Timchalk used animal experiments
and PBPK modeling to evaluate the
usefulness of diazinon metabolites
and cholinesterase levels, respec-
tively, in saliva as noninvasive indica-
tors of pesticide exposures and risks.
Whyatt evaluated the use of OP
metabolite levels in mcconium as
a noninvasive indicator of prenatal
pesticide exposures. The PBPK model
developed, by Tessari could be used.
in pesticide risk assessments and is
also intended for use in validating
hair protein adducts as a noninvasive
biomarker of ATRA exposure. Five
studies that measured children's
exposures (Raytner, Shalat,
O'Roitrke—both grants, Sexton,
and Fenske 825171) evaluated
correlations between environmen-
tal samples, noninvasive personal
exposure samples (hand rinses and
wipes), and more conventional bio-
markers (urine metabolite analyses).
"WilMns, Sexton, O'Rourkc—both
grants, and Fenske (R825171) sup-
ported development and validation
of urinary metabolites as biomarkers
of exposure to pesticides.
In summary, these research grants
contributed to our knowledge of
children's pesticide exposures,
including pathways, types of
pesticides, and age-related differ-
ences. This research also helps
us understand differences in
exposure between children and
adults. Finally, it has increased
our understanding of children's
pesticide exposures in agricultural
communities.
This research will be beneficial for
risk assessments, for models that help
quantify biomarkers of exposure, and
for the identification and validation
of novel biomarkers.
-------
3.2 if
te tie tf
All three of the RtAs resulted in
research that contributed significantly
to the state of knowledge related to
children's pesticide exposures and
risks. Major contributions include:
for the of
and in
* Novel Biomarkers. Three studies
investigated novel, noninvasive
biomarkers of children's expo-
sure, including saliva (diazinon
metabolites, and cholineslerase
inhibition by CPF), meconium
(third-trimester cumulative ex-
posure to OP pesticides), and
hair protein adducts (ATRA and
metabolites).
* PHPK Validation and Support of
Biomarkers. Some of the stud-
ies discussed above included
the evaluation and validation of
biomarkers as part of comprehen-
sive PBPK frameworks that may
be used in future risk assessments
for children's exposure to pesti-
cides. These studies also suggest
mechanistic and methodological
approaches for future validation of
children's biomarkers of exposure.
to
in the
• Ubiquity of Pesticide Contami-
nation and Exposure. Studies
under tills EFA found uniformly
high frequencies of pesticide
contamination in household
surface wipes, con-
firming the ubiquity of house-
hold sources of children's pesti-
cide exposure. The frequency of
detection of pesticide metabolites
in urine approached 100 percent
in some populations.
• High Variability in Children's
Pesticide Exposures. Levels of
household pesticide contamina-
tion and biomarkers of children's
exposure were found to be highly
variable among households and
individuals, with most subjects
experiencing low exposures, while
a few were highly exposed. The
most highly exposed children
were found to have received
estimated pesticide doses
exceeded health-based criteria
ill two instances. These studies
demonstrated the need to thor-
oughly characterize population
exposures to avoid potentially
hazardous exposures, even
where most exposures arc low.
• Importance of Mouthing and
Other Behaviors. Results of several
studies established quantitatively
what had been suspected but
not conclusively established, that
mouthing behavior in young
children is an important factor
in determining total household
exposure to pesticides. One study
showed that this risk is not
reduced by normal hygiene
practices, a finding that has
important implications for the
design of strategies to reduce
children's pesticide exposures.
of to
* Estimation of Aggregate Expo-
sures. Grants under this RFA
funded four major studies of co-
horts of children in different areas
of the country, in different ethnic
groups, and in urban, rural, and
agricultural areas.
* Sources of Exposure. The studies
addressed the relative importance
of different sources of exposures,
behaviors that contributed to
exposures, and socicconomic,
parental, and household variables.
* Relative Exposures of Children
and Adults. Two of the studies
compared children's and adults'
exposure patterns, exposure lev-
els, and biomarkers of exposure
in such a way that inferences can
be drawn regarding potential risk
differences by age.
In summary the grants evaluated in
this report have resulted in a num-
ber of important advances in the
state of knowledge relating to chil-
dren's pesticide exposures. Research
under these grants has added greatly
to the available data on children's
pesticide exposure patterns and
potential risks, the usefulness of
biomarkers of pesticide exposure,
and identified major methodological
and data gaps in risk assessment for
children's pesticide exposures.
-------
Adgate JL, Barr DB, Clayton CA,
Eberly LE, Freeman NC, Lioy
PJ, Needham LL, Pellizzari ED,
Quackenboss JJ, Roy A, and
Sexton K. (2001). Measurement
of children's exposure to pesti-
cides: Analysis of urinary metab-
olite levels in a probability-based
sample. Environmental Health
Perspectives, 109(6) :583-590.
Adgate JL, Kukowski A, Stroebel C,
Shubat PJ, Morrell S, Quacken-
boss JJ, Whitmore RW, Sexton
K. (2000). Pesticide storage
and use patterns in Minnesota.
households with children. Jour-
nal of Exposure Analysis and
Environmental Epidemiology,
10(2): 159-167.
Boone JS, Tyler JVC; and Chambers
JE. (2001). Transferable resi-
dues from dog fur and plasma
cholinesterase inhibition in
dogs treated "with a flea control
dip containing chlorpyrifos.
Environmental Health Perspec-
tives, 109:1109-1114.
Brzezicki JM, TessariJD, Andersen
ME, and Cranmer BK. (2003).
Quantitative identification of
atrazine and its chlorinated
metabolites in plasma.. Journal
of Analytical 'toxicology, 20
(November/December) :569-5 73.
Clayton AC, Pellizzari ED, Whitmore
RW, Quackenboss JJ, Adgate J,
and Sefton K. (2003). Distribu-
tions, associations, and partial
aggregate exposure of pesticides
and polynuclear aromatic hydro-
carbons in the Minnesota Chil-
dren's Pesticide Exposure Study
(MNCPE S). Journal of Exposure
Analysis and Environmental
Epidemiology, 13(2): 100-111.
Curl CL, Fenske RA, and Elgethun
K. (2003). Organophosphorus
pesticide exposure of urban and
suburban preschool children
with organic and conventional
diets. Environmental Health
Perspectives, 111(3)=377-382.
DHHS (United States Department
of Health and Human Ser-
vices). (1996). National Center
for Health Statistics. Third
National Health and Nutrition
Examination Survey, 1988-1994.
NHANES III Laboratory Data File
(CD-ROM). Public Use Data File
Documentation Number 76200.
Centers for Disease Control and
Prevention, Ilyattsville, MD.
Environmental Protection Agency
(EPA). (2003). Human Health
Research Strategy. Office of
Research and Development,
September.
EPA (2003). Human Health Multi-
Year Plan. Office of Research
and Development, April.
Fenske RA, Kedan G, Lu C, Fisker-
Andersen JA, and Curl CL.
(2002). Assessment of organo-
phosphorus pesticide expo-
sures in the diets of preschool
children in Washington State.
Journal of Exposure Analysis
and Environmental Epidemiol-
ogy, 12:21-28.
Freeman NC, Jimenez M, Reed KJ,
Gurunathan S, Edwards RD,
Roy A, Adgate JL, Pellizzari ED,
Quackenboss J, Sexton K, and
Lioy PJ. (2001). Quantitative
analysis of children's microactiv-
ity patterns: The Minnesota chil-
dren's pesticide exposure study.
Journal of Exposure Analysis
and Environmental Epidemiol-
ogy, 11(6):501-509.
Griffith W, Curl CL, Fenske RA, Koch
D, and Lu CA. Organophospho-
rus pesticide metabolite levels
in pre-school children in an agri-
cultural community: Within- and
bctwecn-child variability in a lon-
gitudinal study. Environmental
Health Perspectives (Submitted).
Kissel JC, Curl CL, Kedan G, Lu CA,
Griffith W, Rarr DB, Needham
LL, and Fenske RA. (2005).
Comparison of organophospho-
rus pesticide metabolite levels
in single and multiple daily
urine samples collected from
prc-school children in Washing-
ton State. Journal of Exposure
Analysis and Environmental
Epidemiology 15 (2) = 164-171.
-------
Koch D, Lu C, Jolley L, Fenske R.
(2002). Longitudinal biological
monitoring of organophospho-
rous pesticide exposure among
children living in an agricultural
community. Environmental
Health Perspective 110(8):
829-833-
Kousba AA, Poet TS, and Timchalk C.
(2003). Characterization of the
in vitro kinetic interaction of
chlorpyrifos-oxon with rat sali-
vary cholinesterase: A potential
biomoni Coring matrix. Toxicol-
ogy, 188(2) =219-232.
Lioy PJ, Edwards RD, Freeman N,
Gurunathan S, Pellizzari E,
Adgate JL, Quackenboss J, and
Sexton K. (2000). House dust
levels of selected insecticides
and a herbicide measured by
the EL and LWW samplers and
comparisons to hand rinses
and urine metabolites. Jour-
nal oj Exposure Analysis and
Environmental Epidemiol-
ogv, 10(4)=327-340.
Lu C, Kedan G, Fisker-Andersen, J,
Kissel JC, and Fenske RA. (2004).
Multi-pathway organophos-
phorus pesticide exposures of
pre-school children living in
agricultural and nonagricultural
communities. Environmental
Research, 96(3)=283-289.
Lu C, Irish RM, and Fenske RA.
(2003). Biological monitoring of
diaziiion exposure using saliva
in an animal model. Journal of
Toxicology and Environmental
Health, Part A, 66:2315-2325.
Lu C, Knutson D, Fisker-Anderson
J, Fenske R. (2001). Biological
monitoring survey of organo-
phosphorus pesticide exposure
among pre-school children in
the Seattle metropolitan area.
Environmental Health Perspec-
tive 109(3) :299-303.
McMullinTS, BrzezickJM, Cranmer
BK, Tessari JD, and Andersen
ME. (2003). Pharmacokinetic
modeling of disposition and
time-course studies with
[C-14] atrazine. Journal of Toxi-
cology and Environment Health,
Part A, 66(10) =941-964.
Moate TF, Lu C, Fenske RA, Hahne
RM, and Kalman DA. (1999).
Improved cleanup and determi-
nation of dialkyl phosphates in
the urine of children exposed to
organophosphorus insecticides.
Journal of Analytical Toxicol-
ogy, 23(4)=230-236.
O'Rourke MK, Lizardi PS, Rogan SP,
Freeman NC, Aguirre A, and
Saint CG. (2000). Pesticide expo-
sure and crcatininc variation
among young children. Journal
of Exposure Analysis and Envi-
ronmental Epidemiology, 10(6
Pt 2) =672-681.
Poet TS, Wu H, Kousba AA, and
Timchalk C. (2003). In vitro rat
hepatic and enterocyte metabo-
lism of the organophosphate
pesticides chlorpyrifos and
diazinon. Toxicological Sciences,
72(1): 193-200.
Quackenboss JJ, Pellizzari ED,
Shubat P, Whitmore K»; Adgate
JL, Thomas KW[ Freeman NC,
Stroebel C, Lioy PJ, Clayton AC,
and Sexton K. (2000). Design
strategy for assessing multi-
pathway exposure for children:
The Minnesota. Children's Pesti-
cide Exposure Study (MNCPES).
Journal of Exposure Analysis
and Environmental Epidemiol-
ogy, 10(2): 145-158.
Sexton K, Adgate JL, Eberly LE, Clay-
ton CA, Whitmore RW Pellizzari
ED, Lioy PJ, and Quackenboss
JJ. (2003). Predicting children's
short-term exposure to pesti-
cides: Results of a questionnaire
screening approach. Environ-
mental Health Perspectives,
) = 123-128.
Shalat SL, Donnelly KC, Freeman NC,
Calvin JA, Ramesh S, Jimenez M,
Black K, Coutinho C, Needham
LL, Barr DB, and Ramirez J.
(2003). Non-dietary ingestion
of pesticides by children in an
agricultural community on the
US/Mexico border: Preliminary
results. Journal of Exposure
Analysis and Environmental
Epidemiology. 13:42-50.
Timchalk CT, Poet S, Kousba AA,
Campbell JA, and Lin Y. (2004).
Non-invasive biomonitoring
approaches to determine dosim-
etry and risk following acute
chemical exposure: Analysis
of lead and organophosphate
insecticide in saliva.. Journal of
loxicology and Environmental
Health, Part A. 67:635-650.
Timchalk C, Kousba. A, and Poet TS.
(2002). Monte Carlo analysis of
the human chlorpyrifos-oxonase
(PON1) polymorphism using a
physiologically based pharmaco-
kinetic and pharmacodynamic
(PBPK-PD) model. Toxicology
Letters, 135(1) =5 1-59.
Whyatt RM, Barr DB, Camann DE,
Barr JR, Andrews HE, Hocpner
LA, Kinney PL, and Perera
FP. (2003). Measurement of
contemperary-use pesticides
in personal air samples during
pregnancy and blood samples
at delivery among urban minor-
ity mothers and ncwborns.
Environmental Health Perspec-
tives, 11 1(5) =749-756.
-------
Chambers, EPA Grant Number:
R825170
Booiie JS, Tyler }W, and Chambers,
JE. (2001). Transferable resi-
dues from dog fur and plasma
cholinesterase inhibition in dogs
treated with a flea control dip
containing chlorpyrifos. Envi-
ronmental Health Perspectives,
109:1109-1114.
Fenske, EPA Grant Number:
R825171
Curl CL, Fenske RA, and Elgethun
K. (2003). Organophosphorus
pesticide exposure of urban and
suburban preschool children
with organic and conventional
diets. Environmental Health
Perspectives, 111 (3) :377-382.
Fenske RA, Kcdan G, Lu C, Fiskcr-
Andersen JA, and Curl CL.
(2002). Assessment of organo-
phosphorus pesticide expo-
sures in the diets of preschool
children in Washington Stale.
Journal of Exposure Analysis
and Environmental Epidemiol-
ogy', 12:21-28.
Fenske RA, Lu C, Simcox NJ, Loewen-
herz C, Touchstone J, Moate TF,
Men EH, Kissel JC. (2000).
Strategies for assessing children's
organophosphorus pesticide
exposures in agricultural com-
munities. Journal of Exposure
Analysis and Environmental
Epidemiology, 10:662-671.
Griffith W, Curl CL, Fenske RA, Koch
D, and Lu CA. Organophospho-
rus pesticide metabolite levels
in pre-school children in an agri-
cultural community: Within- and
bctwcen-child variability in a. lon-
gitudinal study. Environmental
Health Perspectives (Submitted).
Kissel JC, Curl CL, Kedan G, Lu CA,
Griffith W; Barr DB, Needham LL,
and Fenske RA. (2005). Com-
parison of organophosphorus
pesticide metabolite levels in
single and multiple daily urine
samples collected from pre-
school children in Washington
State. Journal of Exposure
Analysis and Environmental
Epidemiology,
15(2) = 164-171.
Koch D, Lu C, Jolley L, Fenske R.
(2002). Longitudinal biological
monitoring of organophospho-
rous pesticide exposure among
children living in an agricultural
community. Environmental
Health Perspective 110(8):
829-833.
Lu C, Kedan G, Fisker-Andersen, J,
Kissel JC, and Fenske RA. (2004).
Multi-pathway organophos-
phorus pesticides exposures
of pre-school children living in
agricultural and nonagricultural
communities. Environmental
Research, 96(3) =283-289.
Lu C, Knutson D, Fisker-Anderson
J, Fenske R. (2001). Biological
monitoring survey of organo-
phosphorus pesticide exposure
among pre-school children in
the Seattle metropolitan area.
Environmental Health Perspec-
tive 109(3) :299-'303.
Moate TF, Lu C, Fenske RA, Hahne
RM, and Kalman DA. (1999).
Improved cleanup and determi-
nation of dialkyl phosphates in
the urine of children exposed to
organophosphorus insecticides.
Journal of Analytical Toxicology,
23(4):230-236.
Fenske, EPA Grant Number:
R828606
Lu C, Rodriguez T, Funez A, and
Fenske RA. (2006). The assess-
ment of occupational exposure
to diazinon in Nicaragua.!!
plantation workers using saliva
biomonitoring. Annals of the
New York Academy of Sciences,
1076:355-365.
Lu C, Showlund-Irish R, and Fenske
R. (2003). Biological monitoring
of diazinon exposure using saliva
in an animal model. Journal of
Toxicology and Environmental
Health, 66=2315-2325.
Rodriguez T, Younglove L, Lu C, Funez
A, Weppner S, Barr DB, and
Fenske RA (2006). Biological
monitoring of pesticide exposure
among applicators and their chil-
dren in Nicaragua. International
Journal oj Occupational and
Environmental Health, 12(4)=
312-320.
-------
Sexton, EPA Grant Number:
R825283
Adgate JL, Barr DB, Clayton CA,
Eberly LE, Freeman NC, Lioy
PJ, Needham LL, Pellizzari ED,
Quackenboss JJ, Roy A, and
Sexton K. (2001). Measurement
of children's exposure to pesti-
cides: Analysis of urinary metab-
olite levels in a. probability-based
sample. Environmental Health
Perspectives, 109(6)=583-590.
Adgate JL, Kukowski A, Stroebel C,
Shubat PJ, Morrell S, Quacken-
boss JJ, Whitmore RW, Sexton
K. (2000). Pesticide storage
and use patterns in Minnesota
households with children. Jour-
nal of Exposure Analysis and
Environmental Epidemiology,
10(2)=159-167.
Clayton AC, Pellizzari ED, Whitmore
RW Quackenboss JJ, Adgate J,
Sexton K. (2003). Distributions,
associations, and partial aggre-
gate exposure of pesticides and
polynuclear aromatic hydrocar-
bons in the Minnesota Chil-
dren's Pesticide Exposure Study
(MNCPES). Journal of Exposure
Analysis and Environmental
Epidemiology, 13(2)=100-111.
Freeman NC, Jimenez M, Reed KJ,
Gurunathan S, Edwards RD,
Roy A, Adgate JL, Pellizzari ED,
Quackenboss J, Sexton K, and
LioyPJ. (2001). Quantitative
analysis of children's microac-
tivity patterns: The Minnesota.
Children's Pesticide Exposure
Study. Journal of Exposure
Analysis and Environmental
Epidemiology, 11 (6) =501-509.
Lioy PJ, Edwards RD, Freeman N,
Gurunathan S, Pellizzari E,
Adgate JL, Quackenboss J, and
Sexton K. (2000). House dust
levels of selected insecticides
and a herbicide measured by
the EL and LWW samplers and
comparisons to hand rinses
and urine metabolites. Jour-
nal of Exposure Analysis and
Environmental Epidemiology.
10(4) =327-140.
Quackenboss JJ, Pellizzari ED,
Shubat I> Whitmore K»; Adgate
JL, Thomas KW[ Freeman NC,
Stroebel C, Lioy PJ, Clayton AC,
and Sexton K. (2000). Design
strategy for assessing multi-path-
way exposure for children: The
Minnesota Children's Pesticide
Exposure Study (MNCPES).Jowr-
nal of Exposure Analysis and
Environmental Epidemiology,
10(2) = 145-158.
Sexton K, Adgale JL, Eberly LE, Clay-
ton CA, Whitmore RW, Pellizzari
ED, Lioy PJ, and Quackenboss
JJ. (2003) Predicting children's
short-term exposure to pesti-
cides: Results of a questionnaire
screening approach. Environ-
mental Health Perspectives,
Shalat, EPA Grant Number:
R827440
Shalat SL, Donnelly KG, Freeman NC,
Calvin JA, Ramesh S, Jimenez M,
Black K, Ooutinho C, Needham
LL, Barr DB, and Ramirez J.
(2003). Non-dietary ingestion
of pesticides by children in an
agricultural community on die
US/Mexico border: Preliminary
results./owraa/ of Exposure
Analysis and Environmental
Epidemiology, 13:42-50.
Tessari (previously Andersen),
EPA Grant Number: K828610
Brzezicki JM, Tessari JD, Andersen
ME, and CranmerBK. (2003).
Quantitative identification of
atrazine and its chlorinated
metabolites in plasma. Journal
of Analytical Ibxicology, 20
(November/December) =569—573.
McMullin TS, Andersen ME, Nagahara
A, Lund TD, Pak T, Handa RJ,
andllannemanWII. (2004). Evi-
dence that atrazine and diami-
nochlorolriazine inhibit the
estrogen/progesterone induced
surge of luteinizing hormone
in female Sprague-Dawley rats
without changing estrogen
receptor action, lexicological
Sciences, 79=278-286.
McMullin TS, BrzezickJM, Cranmer
BK, Tessari JD, and .Andersen
ME. (2003). Pharmacokinetic
modeling of disposition and
time-course studies with [C-
14] atrazine. Journal of 'loxicol-
ogy and Environment Health,
Part A, 66(10) =941-964.
Tessari JD and Cranmer BK. Analytical
determination of atrazine and its
chlorinated metabolites in rodent
brain tissue. Journal of Analyti-
cal Toxicology (Submitted).
-------
Timchalk, EPA Grant Number:
R828608
Kousba AA, Poet TS, and Timchalk C.
(2003). Characterization of the
in vitro kinetic interaction of
chlorpyrifosoxon with rat sali-
vary cholinesterase: A potential
biomonitoring matrix. Ibxicol-
oSF,188(2):219-232.
PoetTS, Wu H, Kousba AA, and
Timchalk C. (2003). In vitro rat
hepatic and enterocyte metabo-
lism of the organophosphate
pesticides chlorpyrifos and
diazinon. Toxicological Sciences,
72(1):193-200.
Timchalk CT, Poet S, Kousba AA,
Campbell JA, and Lin Y (2004).
Non-invasive biomonitoring
approaches to determine dosim-
etry and risk following acute
chemical exposure: Analysis
of lead and organophosphate
insecticide in saliva. Journal of
Toxicology and Environmental
Health, Part A, 67:635-650.
Timchalk C, Kousba. A, and Poet TS.
(2002). Monte Carlo analysis of
the human chlorpyrifos-oxonase
(PON1) polymorphism using a
physiologically based pharmaco-
kinetic and pharmacodynamic
(PBPK-PD) model. Toxicology,'
Letters, 135(l)=51-59.
Whyatt, EPA Grant Number:
K828609
Bradman A and Whyatt RM. (2005).
Characterizing exposures to
nonpersistent pesticides during
pregnancy and early child-
hood in the National Children's
Study: A review of monitoring
and measurement technologies.
Environmental Health Perspec-
tives, 113(8):1092-1099.
Fenske RA, Bradman A, Whyatt RM,
Wolff MS, and Barr DB. (2005).
Lessons learned for the assess-
ment of children's pesticide
exposure: Critical sampling
and analytical issues for future
studies. Environmental Health
Perspectives 113(10): 1455-1462.
Whyall RM, Camann DE, Perera FP,
Rauh VA, Tang D, Kinney PL, Gar-
finkel R, Andrews II, Iloepner
L, and Ban- DB. (2005). Bio-
markers in assessing residential
insecticide exposures during
pregnancy and effects on fetal
growth. Toxicology and Applied
Pharmacology, 206(2):246-254.
Whyatt RM, Rauh \ Barr DB, Camann
DE, Andrews HE, Garfinkel R,
Hoepner LA, Diaz D, Dietrich
J, Reyes A, Tang D, Kinney PL,
and Perera FR (2004). Prenatal
insecticide exposure and birth
weight and length among an
urban minority cohort. Envi-
ronmental Health Perspectives,
Whyatt RM, Barr DB, Camann DE,
Barr JR, Andrews HE, Hoepner
LA, Kinney PL, and Perera
FP (2003). Measurement of
contemporary-use pesticides
in personal air samples during
pregnancy and blood samples
at delivery among urban minor-
ity mothers and newborns.
Environmental Health Perspec-
tives, 11 1(5) =749-756.
Whyatt RM, Camann DE, Barr DB,
Barr JR, Andrews IIP, Iloepner
LA, Kinney PL, and Perera FP
(2002). Pesticides levels in
48-hour personal air samples
during pregnancy and in blood
samples at delivery from urban
minority mothers and newborns.
Proceedings of the 9th Interna-
tional Conference on Indoor
Air Quality and Climate (Ed. H.
Levin), 4:877-882.
-------
-------
More detailed tabular summaries of the contributions of each grant to meeting EPA ORD's Annual Pcrfomancc
Goals (APGs) or Annual Performance Measures (APMs) in the areas of children's exposure and risk assessment are
provided in this appendix. The first column of table A-l below lists these seven major research goals. Each column of
the table identifies with a star the grants -whose research has contributed significantly to the achievement of these goals.
TABLE A-l. CROSS-WALK OF STAR GRANT CONTRIBUTIONS TO ORD RESEARCH GOALS
Multi-Year
APG 44. Provide better data on children's
aggregate exposures and estimation of
exposure factors
APM 188. Provide information supporting the
comparison of children's and adult exposures
and body burdens
APM 187. Improve knowledge of children's
pesticide exposure in agricultural communities
APG 45. Help identify principles for the use of
scaling factors in risk assessment
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK)
models to quantify biomarkers of exposures to
organophosphate pesticides
APM 376. Provide biomarkers and
pharmocokinetic data that can be used in
pesticide risk assessments under the Food
Quality Protection Act
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Blornartors
of
Exposure
a
=3
&
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XD
SO
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*
*
*
*
*
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Objective, Human Multi-Year Plan
EPA
and leurobeha¥loral Effects of Perinatal Eiposure to
Chlorpf rltos and Other Qrganophospnate
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
The study "will provide biomarkcrs that indicate
maternal, prenatal, and early aggregate exposures to a
range of commonly used household pesticides.
APM 188, Provide information supporting the
comparison of children's and adult exposures and
body burdens
Relative body burdens of household pesticides may
be estimated from the study results.
APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
N/A
APG 45. Help identify principles for the use of scaling
factors in risk assessment
The study results may support estimates of scaling
factors for use in estimating pre- and postnatal
pesticide exposures.
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N/A
APM 376. Provide biomarfcers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
The study will provide information concerning the
relationships between biomarkers of specific pesticide
exposures and adverse effects on neurological
development, which may be applied in children's risk
assessments.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
The study can provide validation data in support of
urinary metabolite analysis as biomarkers of exposure
in infants, particularly for synthetic pyrethroids.
-------
ibjectlwe, Multi-Year
EPA (Tlmchalk) of a
PBPK-PD to of for
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
N/A
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
Refined PBPK-PD model can be used to investigate
differences in metabolism, adverse effects associated
with age differences, enzyme polymorphisms.
.APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
APG 45. Help identify principles for the use of scaling
factors in risk assessment
Refined PBPK-PD model can be used to investigate
differences in metabolism, adverse effects associated
with age differences, enzyme polymorphisms.
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
Developed data and PBPK model supporting the use
of metabolite and cholinesterase measurement in
saliva, as biomarkers of OP pesticide exposure.
APM 376. Provide biomarkers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Refined PBPK-PD model can be used in risk
assessments for OP residues in foods as required
under the FQPA.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Developed data, supporting the use of metabolite and
cholinesterase measurement in saliva as biomarkers of
OP pesticide exposure.
-------
Multi-Ykar
EPA
for in
APG 44. Provide better data, on children's aggregate
exposures and estimation of exposure factors
N/A
APM 188. Provide information supporting the
comparison of children's and, adult exposures and
body burdens
N/A
APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
N/A
APG 45. Help identify principles for the use of scaling
factors in risk assessment
N/A
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
Developed exposure model using metabolites in
saliva as biomarkers of pesticide exposure; could
be integrated into PBPK model for estimation of
exposures or target organ dose.
APM 376. Provide biomarkers and pharmocokinelic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Developed pharmacokinelic data on OP pesticide
diazinon. Developed data supporting the use of saliva
as a biomonitoring of OP pesticide exposure.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Developed data supporting the use of metabolite
measurement in saliva as a biomarker of risk for OP
pesticide exposure.
-------
Multi-Ykar
EPA {Whyatt) of ion-
In
APG 44. Provide better data, on children's aggregate
exposures and estimation of exposure factors
Will help demonstrate prenatal exposure patterns of
minority infants to OP pesticides.
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
Meconium analyses may turn out to be useful
biomarkers of cumulative (time-integrated) exposures
and body burdens during pregnancy.
APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
N/A
APG 45. Help identify principles for the use of scaling
factors in risk assessment
The results could ultimately be used to help evaluate
age-specific (including prenatal) variations in
exposure and body burden that could be used in risk
assessment.
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N,A
APM 376. Provide biomarkers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Meconium levels may shed light on prenatal exposure
levels that could be used in risk assessment under the
FQPA.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Meconium could be a useful noninvasive biomarker
of cumulative exposure to OP pesticides and other
chemicals.
-------
ibjeetlwe, Multi-Year
EPA
of and
Susceptibility
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
N/A
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
Future development of the atrazine PBPK model
could be used to evaluate age-specific differences in
pharmacokin e tic s.
.APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
APG 45. Help identify principles for the use of scaling
factors in risk assessment
Future development of the atrazine PBPK model
could be used to evaluate age-specific differences in
pharmacokin e tic s.
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N/A (Atrazine is not an OP)
APM 376. Provide biomarkers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
The atrazine PBPK model could provide a framework
for assessing potential children's sensitivity to atrazine
exposure, as required under the FQPA.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Further development of the model will allow
evaluation of the feasibility of using hair protein
adducts as a noninvasive biomarker for quantifying
atrazine exposures.
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ibjectlwe, Mnltl-Year
EPA
of by In an
on the U.S./ilexico
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
Quantified levels of household exposures and
determined dose levels.
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
N/A
APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
Developed direct measurements of pesticide body
burden and excretion rates in children living in rural
areas.
APG 45. Help identify principles for the use of scaling
factors in risk assessment
Data collected indicative of variations inpediatric
pesticide exposures and body burdens between age
groups.
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N/A
APM 376. Provide biomarkers and phannocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Refined estimates of children's exposures and doses
of OP pesticide metabolites that can be used in
risk assessments for pesticide residues in foods as
required under the FQPA,
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
N/A
-------
ibjeetlwe, Multi-Year
EPA R827444 of
and of of to
in the
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
Quantified levels of household exposures to
pesticides.
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
Developed data establishing that children have higher
body burdens of OP pesticide metabolites than adults.
APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
Developed direct measurements of pesticide body
burden and excretion rates in children living in rural
areas.
APG 45. Help identify principles for the use of scaling
factors in risk assessment
Data collected indicative of variations inpediatric
pesticide exposures and body burdens between age
groups.
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N/A
APM 376. Provide biomarkers and phannocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Refined estimates of children's exposures and doses
of OP metabolites that can be used in risk assessments
for pesticide residues in foods as required under the
FQPA.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Developed new noninvasive method for evaluating
infant dermal contact exposures (body suits). Study
provides data to support urinary metabolite analysis
as biomarkers of exposure in children.
-------
ibjectlwe, Multi-Year
EPA
of to OP and
in Yutna, AZ
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
Quantified levels of household exposure factors and
determined exposure levels of children.
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
N/A
.APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
Developed direct measurements of pesticide residues
in children living in agricultural areas.
APG 45. Help identify principles for the use of scaling
factors in risk assessment
Data collected indicative of variations in pediatric
pesticide exposures and body burdens between
genders.
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N/A
APM 376. Provide biomarkers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Identified a urinary metabolite as a biomarker of
exposure.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Developed data, supporting the use of metabolite
measurement in urine as a biomarker of risk for OP
pesticide exposure.
-------
Multi-Ykar
EPA (O'Rourfce) of
to In
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
Quantified levels of pesticide exposure from dust,
food, and beverages that were correlated with urine
samples taken from children in Arizona from urban
and agricultural areas.
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
N/A
APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
Agricultural migrant communities in Yuma, Arizona,
•were compared to urban area.
APG 45. Help identify principles for the use of scaling
factors in risk assessment
N/A
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N/A
APM 376. Provide biomarkers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Data collected on urinary metabolites (DAPs)
from children in Yuma, Arizona, from urban and
agricultural areas.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Urinary samples normalized with creatininc. Study
supports the use of urinary metabolites as biomarkers
of exposure in children.
-------
Objective, Human Multi-Year Plan
EPA
Measuring and Apportioning Children's Exposure to
in Urban, Suburban, and Rural Communities
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
Quantified levels of pesticide exposure from dust,
hand washing, indoor and outdoor air, food, and
beverages, which "were correlated, "with OP metabolites
from urine samples taken from children in Minnesota
from urban and agricultural areas.
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
N/A
APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
Assessed rural/agricultural communities of Goodhue
and Rice Counties for pesticide exposure and
metabolism.
APG 45. Help identify principles for the use of scaling
factors in risk assessment
N/A
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N/A
APM 376. Provide biomarkers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Dietary exposure assessed through analyzing food
and beverage OP content and correlated with urinary
metabolites (DAPs) for children in Minnesota from
urban and agricultural areas.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Study provides data, that support the use of urinary
metabolites as biomarkers of exposure.
-------
Multi-Ykar
EPA 821170
of
From Flea Control
APG 44. Provide better data on children's aggregate
exposures and estimation of exposure factors
Quantified levels of pesticide exposure from dog flea
controls.
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
Compared urinary pesticide metabolites for
chloropyrifos in households with chloropyrifos
collared dogs.
.APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
APG 45. Help identify principles for the use of scaling
factors in risk assessment
N/A
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
APM 376. Provide biomarkers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
N/A
.APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
N/A
-------
ibjectlwe, Multi-Year
EPA Total
In
and
APG 44. Provide better data on children's aggregate
exposures and. estimation of exposure factors
Quantified levels of pesticide exposure from dust,
personal air, drinking water, and food, which was
correlated with urine samples.
APM 188. Provide information supporting the
comparison of children's and adult exposures and
body burdens
N/A
APM 187. Improve knowledge of children's pesticide
exposure in agricultural communities
Assessed urban/agricultural communities of
Washington State for pesticide exposure and
metabolism.
APG 45. Help identify principles for the use of scaling
factors in risk assessment
N/A
APM 182. Development of physiologically based
pharmacokinetic/pharmacodynamic (PBPK) models to
quantify biomarkers of exposures to organophosphate
pesticides
N/A
APM 376. Provide biomarkers and pharmocokinetic
data that can be used in pesticide risk assessments
under the Food Quality Protection Act
Six dialkylphosphates were analyzed in children's
urine from various ages, genders, time points,
geographical areas, and from children who consumed
different diets. Duplicate diets were analyzed for 15
OP pesticides.
APM 206. Develop less invasive biomarkers for
assessing children's exposures and risks
Study can provide data to support urinary metabolite
analysis as biomarkers of exposure in children.
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Office of Research and Development (8101R)
Washington: DC 20460
EPA/600/S-06/006
December 2006
www.epa.gov
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