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Pesticides and children

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 Toxicology and Applied Pharmacology 198 (2004) 152 163
www.elsevier.com/locate/ytaap

Pesticides and children

Vincent F. Garry *
Department of Laboratory Medicine and Pathology and Program in Toxicology, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA

Received 1 October 2003; accepted 24 November 2003

Available online 5 March 2004

Abstract

Prevention and control of damage to health, crops, and property by insects, fungi, and noxious weeds are the major goals of pesticide
applications. As with use of any biologically active agent, pesticides have unwanted side-effects. In this review, we will examine the thesis
that adverse pesticide effects are more likely to occur in children who are at special developmental and behavioral risk. Childrens exposures
to pesticides in the rural and urban settings and differences in their exposure patterns are discussed. The relative frequency of pesticide
poisoning in children is examined. In this connection, most reported acute pesticide poisonings occur in children younger than age 5. The
possible epidemiological relationships between parental pesticide use or exposure and the risk of adverse reproductive outcomes and
childhood cancer are discussed. The level of consensus among these studies is examined. Current concerns regarding neurobehavioral
toxicity and endocrine disruption in juxtaposition to the relative paucity of toxicant mechanism-based studies of children are explored.
D 2004 Elsevier Inc. All rights reserved.

Keywords: Pesticide; Children; Fungi

Introduction systems undergoing development from the fetus through

For many years now, there has been public concern raised
about the potential health effects of pesticides on the devel-
oping fetus and in childhood. Depending on stage of devel-
opment, the fetus is selectively sensitive to particular chemical
toxicants (Schardein, 1993; Wilson and Fraser, 1977).
In the postnatal period and through pubescence, children
are vulnerable to their environment, whether physical,
chemical, or psychological. Less clear is the relative vul-
nerability of pregnancy due to pre-pregnancy germ cell
exposure of adult females and males.
In a recent USEPA summary report (USEPA: EPA/630/
R-03/002, 2002, p. F-36), Locke (2002) defined vulnerabil-
ity applied to risk assessment as a four-component system:
(1) susceptibility or sensitivity of the human or ecological
receptors; (2) differential exposures of the receptors; (3)
differential preparedness of the receptor to withstand the
insult from exposure; (4) differential ability to recover from
these effects. All of these components are pertinent to
* Laboratory Medicine and Pathology, Box 609 Mayo, Minneapolis,
MN 55455. Fax: +1-612-626-3380.
E-mail address: garry001@tc.umn.edu.
childhood.
For example, differences in the chemical biotransforma-
tion capacity of the human fetus and developing child
(Hakkola et al., 1998) can be both protective and potentially
detrimental to normal development (USEPA/630/r-01/004,
2001). Regarding this point, there is little direct information
regarding the specific metabolism of xenobiotics, much less
pesticides, in children or the fetus. Overriding differences in
biotransformation in the fetus is the probable role of
maternal metabolism of xenobiotics affecting the level of
fetal toxicant exposure. Polymorphisms of maternal phase 1
and phase 2 enzymes may play a key role in these exposure
events (USEPA/630/r-01/004, 2001).
A fundamental maxim of pediatric medicine is that
children are not little adults. This observation is
especially relevant to discussion of children and their
exposures to pesticides. Children are at risk for pesticide
exposures from different sources and at levels different
than adults in the same exposure scenario. Childrens
respiratory rate, heart rate, and metabolism are signifi-
cantly different from adults (Bearer, 1995). Food con-
sumption and food consumption patterns place children in
a special dietary pesticide risk category (National Acad-
emy of Sciences, 1993). Hand-to-mouth behavior further

0041-008X/$ - see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.taap.2003.11.027
 V.F. Garry / Toxicology and Applied Pharmacology 198 (2004) 152163
adds to childrens pesticide exposure by the oral route.
Children, being low to the ground, may have greater
exposure to volatile pesticide vapors, particularly those
pesticides that, in the gas phase, have a density greater
than air. One prime example is the grain fumigant
aluminum phosphide (AlP). After enclosed space appli-
cation, AlP is converted to the toxicant gas phosphine,
the active pest control agent. Human phosphine fatality
case reports dealing with children playing on AlP fumi-
gated grain, and another dealing with a fatality of a
pregnant woman living near large tarp covered fumigated
grain piles, illustrate the potential hazard (Garry and
Lyubimov, 2001).
In the US, beginning with the conclusions derived
from the 1993 National Academy of Science report on
pesticides in the diets of infants and children and
culminating in 1996 with revision of the US Federal
Fungicide, Insecticide and Rodenticide Act (FIFRA) to
include the directive In the case of threshold effects, an
additional 10-fold margin of safety for the pesticide
chemical residue and other sources of exposure shall be
applied for infants and children to take into account
potential prenatal and postnatal toxicity (Makris and
Rowe, 1998), the vulnerability of children to the toxi-
cant effects of pesticides was recognized.
In the review to follow, we will first discuss childrens
pesticide exposures in the rural and urban environment.
Later, we will consider childrens cancer and birth defects in
relation to pesticide exposure of both parent and child. The
plausibility of pesticide-related postnatal neurologic and
neurobehavioral effects will be considered. The possible
role of endocrine disruption will be summarized.
Childrens pesticide exposure
Background
As stated before, children have multiple sources and
routes of pesticide exposure that differ from adults. Mea-
surement of exposure and, in particular, source components
of pesticide exposure is the primary goal of exposure
assessment. To achieve that goal investigators commonly
employ epidemiological survey methods (Cooper et al.,
2001), combinations of survey with visual observation
(Freeman et al., 2001), ambient air monitoring and urine
or blood serum analysis for pesticide levels. Less common
are measurements in breast milk and umbilical cord blood.
Pesticide residuals indoors (food, carpet, dust) and outdoors
(soil, water, air) and surrogate measures of exposure (skin
surface and breathing zone measurements) may be
employed to provide detail regarding source. In this review,
more current works dealing with available information on
pesticides in common use will be considered. Exposures of
children living in the rural environment will be compared to
children living in the urban environment.
153
Urban setting
Landrigan et al. (1999) examined and reviewed some of
the major issues surrounding pesticide exposure of inner city
children in the US. These authors noted that organophos-
phates, carbamates, and pyrethroids are the principal insec-
ticides in common use in the US, and are a major concern for
children in the urban environment. In New York City (NYC),
at the time of the review, chlorpyrifos (CPF) and cyfluthrin, a
pyrethroid, were the most common pesticides in use by the
New York City housing authority. Pesticides were used
periodically in 16 000 housing units owned and operated
by the housing authority to control insect and other infesta-
tions. These housing units serve economically disadvantaged
families. The pesticide products were applied in these
residences on a monthly basis. Whyatt et al. (2003) exam-
ined pesticide levels in plasma from an NYC minority cohort
of 230 mother and infant pairs. Seven pesticides were
detected in up to 83% of the plasma samples obtained,
including organophosphate insecticides and fungicides. Ma-
ternal plasma levels were correlated with cord blood levels
for most of the seven pesticides indicating placental transfer
of nonpersistent pesticides [insecticides (chlorpyrifos, diaz-
inon, bendiocarb, propoxur); fungicides (dicloran, captan,
folpet)] from the pregnant woman to the fetus. Personal air
monitoring data for chlorpyrifos, diazinon, and propoxur
was correlated with levels of these insecticides in plasma and
cord blood. Birth outcome in this population (Perera et al.,
2003) was also examined. Plasma CPF levels correlated with
decreased birth weight.
Biologic monitoring survey (Lu et al., 2001) of organ-
ophosphate exposure among preschool children in the
Seattle, WA, area (urban and suburban) demonstrated that
99% of spot urine samples obtained in spring and fall
contained at least 1 dialkylphosphate (DAP) metabolite
[dimethylphosphate, dimethylthiophosphate (DMTP),
dimethyldithiophosphate, diethylphosphate, diethylthio-
phosphate (DETP),diethyldithiophosphate] of the parent
organophosphate. DMTP and DEPT were the predominate
metabolites. No significant differences in the level of OP
metabolites were found in spring-fall age, gender, or
income comparisons. The authors speculated that diet
might be a significant source of OP exposure for children.
Work by Wilson et al. (2003), who examined aggregate
exposures of nine preschool children at daycare and in the
home, found that diet was a major contributor to pesticide
exposure. Biologic monitoring of OP metabolite levels in
urine from children ages 5 7 (n = 195) living in the
municipality of Siena, Italy (Aprea et al., 2000), showed
that children had significantly higher levels of urinary OP
metabolites than adults from the same region. On the basis
of survey results and interviews, the authors concluded that
childrens diet and activities might be major sources of OP
exposure.
In this connection, detailed OP exposure assessment of
urban and suburban preschool children with and without an
154 V.F. Garry / Toxicology and Applied Pharmacology 198 (2004) 152163
organic diet (Curl et al., 2003) is of interest. In these studies,
24-h urine collections from 18 children with an organic diet
were compared to urine collected from 21 children on a
conventional diet and examined for five OP metabolites.
Children with an organic diet had significantly lower urinary
levels of dimethyl metabolites ( P = 0.0003) than children
with a conventional diet. The median values reported for
dimethyl OP metabolites differed by a factor of 6 (0.03 vs.
0.17 Amol/l). Diethyl metabolites did not differ across
groups. Along similar lines, MacIntosh et al. (2001) con-
ducted longitudinal food sample collections over 1 years
time from 75 persons residing in Maryland. The OP
malathion was found in 75% of samples tested while CPF
was found 38% of the time in solid food samples. Higher
levels of insecticide were found in summer than winter. The
high levels of urinary OP metabolite obtained in a popula-
tion-based sample of children from urban Minnesota and
surrounding suburban-rural communities in summer raise
the possibility that OP exposures in these juxtaposed com-
munities, apart from diet, may also include regional agri-
cultural sources of exposure (Adgate et al., 2001).
To summarize, diet seems to be a predominate factor in
the OP exposure of urban and suburban children. However,
indoor household use of OPs such as chlorpyrifos can also
be a significant short duration high level exposure hazard
(Davis and Ahmed, 1998). In regard to other pesticides
classes and groups, there is little information regarding
source and amount of urban childrens exposure. For exam-
ple, one study from the urban Frankfurt/Main region of
Germany cited diet as the major source of pyrethroid
exposure. The authors made this determination from quan-
titative measurement and analysis of urinary pyrethroid
metabolite excretion patterns (Schettgen et al., 2002). An-
other study of 2,4-D applications to residential lawns in
Midwest US estimated that childrens post-application non-
dietary ingestion may be 1 10 Ag/day from contact with
floors and 0.2 30 Ag/day from contact with table tops. In
comparison, dietary ingestion of 2,4-D was said to be about
1.3 Ag/day (Nishioka et al., 2001).
Finally, implementation of the US Food Quality Protec-
tion Act (1996) by USEPA is expected to lead to reduction
of the overall level of pesticide residuals in food. Included in
this effort is review of tolerances of pesticide levels in foods
and efforts directed at increased protections for infants and
children through additional acute, chronic, and neurotoxic-
ity testing (USEPA/735/R/99001, 1999).
Rural/agricultural setting
Childrens pesticide exposure in the rural setting is a
many faceted series of events that can carry with it the
possibility of cumulative exposure over the pesticide use
season. Track in from outdoor pesticide applications, play-
ing in pesticide-treated fields, inadvertent aerial applica-
tions, and pesticide drift are parts of the picture of pesticide
exposure of rural children. Seasonal shift in the pesticides
applied in temperate climates [herbicides in spring, insecti-
cides in summer, and fungicides in fall (Garry et al., 2003)]
adds further complexity to the overall significance of these
exposure events. For example, Koch et al. (2002) conducted
serial measurements of levels of OP metabolites in urine of
44 children from the agricultural community during the
pesticide use and nonuse seasons. Urinary dimethyl and
diethyl DAP levels were significantly elevated during the
spray months compared to nonspray months. Male children
had significantly higher levels of urinary OP metabolites
than females. Surprisingly, age, parental occupation, or
residential proximity to the fields were not factors in these
results. The authors suggested that the ultimate source of
exposure of these children was the result of airborne
pesticide dispersal from multiple sites within the agricultural
region. In a study of 109 children from the same or similar
agricultural region(s), Fenske et al. (2000) found that during
the spray season, children whose parents worked as orchard
applicators or field workers showed 56% of the OP doses
for the spray season that exceeded the USEPA chronic
dietary reference dose versus 44% for nonagricultural work-
ers. These findings further suggest that children residing in
this agricultural region are at increased risk for exposure to
OPs during the spray season regardless of parental em-
ployment. Ambient air monitoring data from agricultural
regions of California (Lee et al., 2002) demonstrated that
pesticide vapor pressure was a major predictor of childrens
inhalation risk.
The take home pathway of agricultural pesticide
exposed farmers and farm workers can be another signifi-
cant factor in rural childrens exposures to pesticides. Curl et
al. (2002) showed in a study of organophosphate exposure
of 213 farm workers and 211 children that house dust
contains on average 0.53 Ag/g azinphosmethyl (an OP)
and 0.75 Ag/g in vehicle dust. Dimethyl DAP, a metabolite
of the OP, in urine from parents (0.09 Amol/g) and children
(0.14 Amol/g) were, on average, nearly identical. Urine
concentrations of OP metabolites from parent and child
from the same household were positively correlated. Similar
findings were reported for children living in an agricultural
community along the US/Mexican border (Shalat et al.,
2003) and in the farming community of rural El Salvador
(Azaroff, 1999). Track in, household dust, and regional
ambient air are common sources of rural childrens exposure
to organophosphates whether their parents were engaged in
agriculture or not. Whether this pattern of rural childrens
exposure extends to other pesticide use groups (herbicides,
fungicides, fumigants) is uncertain.
Children, pesticides, and acute toxicity
According to Blondell (1997), the risk of pesticide
poisoning is elevated among children, non-whites, males,
and residents of poor, southern US states. In Minnesota
(Olson et al., 1991), of 1428 case files reported through the
Minnesota Regional Poison Control center, the mean age of
 V.F. Garry / Toxicology and Applied Pharmacology 198 (2004) 152163
all reported instances of pesticide poisoning (adults and
children) was 5 years, with 50% of cases being below age 3.
Most reported intoxication was due to insecticides. Studies
from North and South Carolina (Sumner and Langley, 2000)
on hospitalizations following pesticide exposure showed
that 30% involved children and most of these were toddlers.
Over the last 20 years, pesticide mortality has decreased in
the US. Intentional poisonings represent the greatest fraction
(Langley and Sumner, 2002). Pesticide poisonings reported
from Milan, Italy (Davanzo et al., 2001), noted that 48%
occurred in children under age 5 and most occurred in the
home setting; organophosphate and pyrethroid insecticides
were most frequently involved. The reported childrens
pesticide intoxication experience from Zimbabwe (Dong
and Simon, 2001) and Israel (Weissmann-Brenner et al.,
2002) again indicates that insecticides are the most common
class of pesticide involved. Ingestion, especially by male
children, seems to be the most common route of intoxication
for children under age 5. Recent examination of this issue
by USEPA made the suggestion that protective measures,
including reducing the concentration of the active ingre-
dients, improved packaging and storage need to be consid-
ered (Spann et al., 2000). In this connection, studies in
animals indicate that young animals that were more sensi-
tive than adults to high concentrations of insecticides, were
not more sensitive to lower concentrations of OP or pyre-
throid insecticides than adults (Sheets, 2000).
Recent experiences with large-scale illicit commercial
applications of the organophosphate methyl parathion in
Midwestern US residences further illustrate the risk of
childrens pesticide intoxication (McCann et al., 2002;
Rubin et al., 2002a). The median detectable level of p-
nitrophenol (Hryhorczuk et al., 2002), a principal metab-
olite of methyl parathion, in urine from children in
residence younger than age 3, was 93.9 ppb compared
with 41.6 ppb among people older than 3 years (Rubin et
al., 2002b). Illicit use and misuse of pesticides is a
nagging, persistent concern.
Pesticide persistence and children
Historically, organochlorine pesticides, for example,
DDT and dioxin contaminants in chlorophenoxy herbicides,
have been a concern in regard to environmental persistence,
bio-accumulation, and toxicity related to longer-term ad-
verse health effects, including cancer and adverse reproduc-
tive effects such as birth defects (Birnbaum, 1995). For
children, the principal route of exposure for these chemicals
is through ingestion from breast milk and diet (Berlin et al.,
2002; Fitzgerald et al., 2001; Koopman-Esseboom et al.,
1995; Patandin et al., 1999; Sauer et al., 1994). In general,
levels of dioxins in breast milk have been decreasing in
recent times (LaKind et al., 2000, 2001; Schecter et al.,
1998). Geographic variation in organochlorine levels has
been reported in studies of human breast milk from lactating
women residing in the arctic and subarctic regions of Russia
155
(Polder et al., 2003). Similar geographic variation was noted
in historical residenc based studies from California (James
et al., 2002). In another study, organochlorine levels in
offspring were found to vary directly with the age of the
mother (Lackman et al., 1999) pointing to cumulative
historic maternal exposure as a major part of the infants
total exposure.
Recent studies of preschool children from the Nether-
lands (Huisman et al., 1995; Vreugdenhil and Weisglas-
Kuperus, 2000) demonstrated that alteration of markers of
neurobehavioral development and immunologic status were
related to higher body burdens or prenatal exposures to
dioxins/PCBs. These works imply that more subtle neuro-
behavioral toxicity can occur in children subject to current
dioxin/PCB exposure levels. More careful study of this
question is needed.
Childrens health and pesticides
Reproductive effects
Overview
Reproductive toxicity begins with parental exposure to
toxicants. Preconception, conception, prenatal, and postnatal
periods are all windows of opportunity for adverse repro-
ductive outcomes. No observable phenotypic effect, shift in
sex ratio, birth anomaly, miscarriage, stillbirth, prematurity,
low birth weight, developmental and neurobehavioral ab-
normalities, and reduced fertility are major reproductive
endpoints considered in examination of reproductive toxicity.
Postnatal chemical exposures, particularly during growth
spurts and pubescence, are other avenues offering a window
of opportunity for an adverse developmental outcome.
Timing of exposure, duration, dose and susceptibility, or
genotype of parent and fetus or child can play a role in the
outcome observed. For each adverse reproductive effect,
there appears to be a critical window of exposure. These
concepts in reproductive and developmental human toxicity
were discussed in detail in a series of workshops conducted
by USEPA held in June 2000 (Lemasters et al., 2000;
Selevan et al., 2000) and will not be further considered
here. Our review will be confined to observations of adverse
reproductive outcomes in humans and their possible asso-
ciation with use and exposure to pesticides.
Antenatal prenatal exposure
Semen studies. Concern regarding paternally mediated
reproductive toxicity began in the 1970s with observations
in workers exposed to the nematocide 1,2-dibromopropane
(DBCP). These studies demonstrated that DBCP production
workers, as well as pesticide applicators who used DBCP,
had reduced sperm counts related to the length of exposure
to the nematocide (Glass et al., 1979; Whorton et al., 1977).
Some people were oligospermic or azospermic and infertile.
156 V.F. Garry / Toxicology and Applied Pharmacology 198 (2004) 152163
After removal from exposure, long-term (11 years) follow-
up studies conducted among 30 azospermic and 17 oligo-
spermic workers showed that 73% of the azospermic work-
ers had evidence of spermatogenesis recovery and all 17 of
the oligospermic workers were normospermic (Olsen et al.,
1990). Subsequent pregnancies and children born to the
spouse of DBCP-exposed humans were seemingly unaffect-
ed by prior DBCP exposure (Goldsmith et al., 1984;
Potashnik and Abeliovich, 1985). On the other hand, the
sex ratio of children born to the spouses of the DBCP-
exposed workers was reduced (more female births than male
births (Goldsmith, 1997).
In other studies (Garry et al., 2003), a shift in sex ratio of
children born to pesticide applicator families was noted
among applicators who applied fungicides in addition to
herbicides and insecticides. Reproductive hormone analyses
conducted in conjunction with this epidemiological study
showed that more female children were born to applicators
with lower testosterone levels. Lower testosterone levels
were also correlated with the extent of fungicide use.
Altogether, these data imply a relationship between repro-
ductive hormone levels, use of certain pesticides, and
gender of children born to pesticide applicators.
From a different perspective, in situ hybridization studies
of human sperm chromosomes (Recio et al., 2001) demon-
strated that agricultural workers who applied or worked with
organophosphate insecticides had significantly increased
sperm chromosome nullisomy involving the sex chromo-
somes. The authors hypothesized that interference with
sperm chromosome segregation by OPs may lead to in-
creased risk for genetic syndromes such as Turners syn-
drome. G-banded chromosome studies of peripheral
lymphocytes from pesticide applicators showed an increased
prevalence of sex chromosome abnormalities in pesticide
applicators who applied herbicides, insecticides, and fungi-
cides (Garry et al., unpublished observations) compared to
control subjects. These unpublished data lend some support
to the foregoing (Recio et al., 2001) hypothesis. Current use
of pesticides has also been associated with decreased sperm
quality (Swan et al., 2003). Increased serum pp-DDE levels
have been tentatively associated with abnormal sperm
motility. Altogether, these data begin to provide needed
mechanistic information regarding male-mediated reproduc-
tive toxicity.
Miscarriages (spontaneous abortions). Descriptive epide-
miological studies showed links between preconception
herbicide use (Arbuckle et al., 2001) and increased frequen-
cies of miscarriages. Similarly, Garry et al. (2002a) noted a
significantly increased miscarriage rate among the spouses
of male applicators who applied herbicides in the spring.
Other work (Petrelli et al., 2000) also showed that the
spouses of pesticide applicators had increased numbers of
miscarriages compared to control subjects. Comparison of
miscarriage rates of conventional pesticide applier house-
holds to applier households, where the applier used inte-
grated pest management technique, demonstrated that
miscarriages occurred significantly more often in conven-
tional applier households (Crisostomo and Molina, 2002).
The recorded miscarriage risk (OR) among pesticide applier
families in the studies reported above varied from 1.5 to
over 3.0 suggesting some consistency in the observed
adverse reproductive outcomes.
Birth defects. The assessment of birth anomalies as a birth
outcome is limited by the accessibility of a population,
numerous ethical and privacy concerns, and reporting ac-
curacy. As mentioned earlier, pesticide use and exposure in
the agricultural setting can involve direct and indirect
exposure to each family member. As a general rule, expo-
sure to reproductive toxicants during the first trimester of
pregnancy is associated with an increased risk for structural
birth defects, usually recognizable at birth or within the first
year of life. For this reason, structural birth defects will be
considered in some detail with reference to pesticide use.
A Minnesota (MN) statewide study of birth defects
occurring among pesticide applicator families and the gen-
eral population (Garry et al., 1996) divided the state into
specific crop growing regions. Significantly increased
numbers of birth defects occurred in the western portion
of the state where wheat, sugar beets, and potatoes were the
primary crops [odds ratio (OR) = 1.5; 95% confidence
interval (CI), 1.3 1.6]. The birth defect rates were com-
pared to the rate reported for urban and forested areas of the
state. Specific birth defect categories (circulatory/respirato-
ry, urogenital and musculoskeletal/integumental) showed
significant increases, more so in families of pesticide
applicators from the western MN [Red River Valley
(RRV) region]. Conceptions in the spring led to the highest
level of birth defects in the RRV, but not elsewhere in the
state. RRV agricultural practice included intensive use of
chlorophenoxy herbicides and fungicides as well as aerial
applications of these products to small grains, sugar beets,
and potatoes.
In an expanded ecological study of birth defects occur-
ring in four major wheat-producing states in the US,
Schreinemachers (2003) demonstrated that high wheat crop
production (85% of the acreage was treated with chlorophe-
noxy herbicides) was associated with significantly increased
risk of cardiovascular/respiratory birth defects [odds ratio
(OR) = 1.65; 95% confidence interval (CI), 1.07 2.55]. A
stronger effect was observed for the subcategory, which
excluded heart malformations (OR = 2.03; 95% CI, 1.14
3.59). A large study from the Norwegian birth registry
(Kristensen et al., 1997) demonstrated an association be-
tween grain farming and increased risk for limb reduction
birth defects (OR = 2.5; CI, 1.06 5.9). In more detailed
work (interview, pedigree analysis, medical records verifi-
cation, and specific pesticide use information) from a
smaller sample of the Minnesota Red River Valley farm
cohort, Garry et al. (2002b) showed that an increased risk
 V.F. Garry / Toxicology and Applied Pharmacology 198 (2004) 152163
for birth and developmental abnormalities among pesticide
applicator families was associated with use of the fumigant
phosphine (OR = 2.48; CI 1.2 5.1) and use of the herbicide
glyphosate (OR = 3.6; CI, 1.3 9). Given the small sample
size (1535 live births, 72 children with birth defects), these
results need to be considered with caution.
In a detailed case/control study of subjects with and
without transposition of the great vessels, Loffredo et al.
(2003) showed an increased risk for transposition of the great
arteries in association with maternal herbicide exposure. A
case referent study (Restrepo et al., 1990) of children with
and without birth defects showed that pesticide use was
associated with integumental (hemangiomas) defects.
With further regard to maternal exposure to pesticides in
early pregnancy, several epidemiological studies suggest
that maternal employment in agriculture or gardening may
be a risk factor for birth defects (Engel et al., 2000;
Nurminen, 1995; Rojas et al., 2000; Weidner et al., 1998).
Few studies involving direct or indirect measurement of
pesticide levels in human tissue and their possible correlation
with birth defects have been conducted. Among the few
studies, Hosie et al. (2000) examined fat samples from 48
patients, 18 of whom had undescended testes, for levels of
persistent organochlorine chemicals, including DDT metab-
olites. Significantly higher organochlorine levels were
detected in fat tissue from patients with undescended testes.
In another study, male children of mothers who had 85 Ag/l or
higher levels of DDE in serum seemed to be at increased risk
for crypt-orchidism and polythelia (Longnecker et al., 2002).
From the data discussed above, it is evident that epidemio-
logical studies frequently demonstrate statistical associations
between birth defects and pesticide use or exposure. The
biologic basis for these associations needs evaluation at the
analytic chemical, cellular, and molecular levels.
Pesticides and childhood cancer
In an earlier comprehensive review of childhood cancer,
Zahm and Ward (1998) presented a detailed analysis of the
available epidemiological data for or against association
between pesticides and childhood cancer. In their review,
the authors included case reports and case-control studies.
Individual case-control studies reported tended to have few
subjects and fewer exposed subjects. The studies were
further limited by nonspecific pesticide exposure informa-
tion. Nonetheless, linkage between childhood leukemia and
parental exposure or use of pesticides was frequently
reported in the studies reviewed. Most studies reviewed
also suggested an association between childhood brain
cancer and parental pesticide exposure. Fewer studies sug-
gested possible relationships between neuroblastoma,
Ewings sarcoma, and non-Hodgkin lymphoma in childhood
and pesticide use.
More recent studies seem to portray similar relationships
between pesticides and childhood cancers. Feychting et al.
(2001) demonstrated an increased risk of nervous system
157
tumors among children whose father was exposed to pesti-
cides [relative risk (RR) = 2.4; 95% CI, 1.3 4.4]. In
contrast to some earlier case-control studies (Zahm and
Ward, 1998), an ecological study conducted by Reynolds
et al. (2002) showed no association between overall child-
hood cancer risk and pesticide use within an agricultural
region of California. However, in this region, childhood
leukemia was significantly elevated [RR = 1.48; 95%, CI
1.03 2.13] where use of the pesticide propargite was
extensive. Most recently, Van Wijngaarden et al. (2003)
reported that paternal use of herbicides [OR = 1.6; 95% CI,
1.0 2.7] or fungicides [OR = 1.6; 95% CI, 1.0 2.6] was
associated with increased risk of a specific brain tumor
(astrocytoma) among their children.
In sum, it appears from the foregoing that specific
childhood cancers are weakly but consistently associated
with pesticide use and in particular paternal pesticide use.
In their review, Zahm and Ward (1998) also noted that
many of the childhood cancers associated with pesticide
exposure were the same types of cancers repeatedly associ-
ated with pesticide exposure among adults. This interesting
parallel raises several questions. Thomas (1995) and Olshan
et al. (2000) suggested that exposures to pesticides during
vulnerable periods of childhood might lead to increased
cancer risk as an adult. On the other hand, recent work by
Ma et al. (2002) pointed out that the risks for childhood
leukemia were significantly increased (OR = 2.8; 95% CI,
1.4 5.7) by use of professional pesticide control services in
the home from 1 year before birth to 3 years after birth.
Exposure during year 2 was associated with the highest risk
(OR = 3.6; 95% CI, 1.6 8.3). Odds ratio for exposures to
insecticides were highest with exposures during pregnancy
(OR = 2.1; 95% CI, 1.3 3.5).
With regard to cancer in general and childhood cancer in
particular, gene environment interaction becomes a major
concern. Population-based case-control studies (Infante-
Rivard et al., 1999) showed interaction between CYPA1M1
and CYP1AM2 mutations and the occurrence of acute
lymphocytic leukemia when women were pregnant or their
children had been exposed to insecticides. Other gene
polymorphisms examined in this reported work failed to
show evidence of gene chemical toxicant interaction.
Altogether, epidemiological studies reviewed above have
provided a beginning for understanding of the relationships
between parental and childrens exposures to pesticides and
the occurrence of childhood cancer. The general lack of
specificity of these studies point out the need for laboratory-
based studies with specific toxicological endpoints to fin-
gerprint exposure effect relationships.
Children and neurologic/neurobehavioral effects of
pesticides
A number of editorials and reviews (Kaufman, 2003;
Kimmel and Makris, 2001; Schettler, 2001; Tilson, 1998;
Weiss, 2000) identified the need to examine neurobehavio-
158 V.F. Garry / Toxicology and Applied Pharmacology 198 (2004) 152163
ral and neurodevelopmental status of children exposed to
toxicants, including pesticides. Studies evaluating possible
neurological and neurobehavioral effects of pesticides in
children are indeed rare. In this connection, neurobehavioral
studies conducted among children exposed to polychlori-
nated biphenyls have parallel interest (Darvill et al., 2000;
Rice, 2000; Schantz and Widholm, 2001). These studies
consistently showed PCB dose-related interference with
cognitive function during early childhood. On the basis of
structural similarities, the foregoing data infer that members
of the organochlorine class of insecticides might have
similar toxicant effects. Neurobehavioral studies conducted
among adults and children inadvertently exposed to chlor-
dane, an organochlorine insecticide, in an apartment com-
plex (216 exposed and 174 control subjects) showed an
association between protracted impairment of neurophysio-
logical and psychological function (Kilburn and Thornton,
1995) and exposure to chlordane. Perinatal exposure studies
of animals treated with heptachlor (Moser et al., 2001), an
organochlorine insecticide, and longer-term follow-up stud-
ies after exposure had ceased, demonstrated persistent
treatment-related neurobehavioral abnormalities in exposed
rats.
In a limited neurodevelopmental study of rural Yaqui
Indian preschool children, lowland Indian children who
had been exposed to multiple pesticides were compared to
upland children who had limited pesticide exposure (Guil-
lette et al., 1998). Levels of pesticide exposure were
inferred from other published studies of the same popula-
tion. Children of lowland Indians (N = 34) demonstrated
more deficiencies in gross and fine motor coordination,
short-term memory, and draw a person neurodevelop-
mental parameters than did upland Yaqui Indian (N = 17)
children.
In contrast, and pertinent to this review, are several
detailed animal studies dealing with neurodevelopmental
effects of organophosphates and, in particular, the organo-
phosphate chlorpyrifos (CPF). For example, administration
of a single high dose CPF during gestation demonstrated
more extensive neurotoxicity in the rat dam relative to the
fetus (Chanda et al., 1995). On the other hand, repeated low
level CPF exposure of the rat dam during gestation may
invoke extensive neurochemical and neurobehavioral
changes in developing rats in the absence of maternal
toxicity (Chanda and Pope, 1996). Further, administration
of CPF late in the gestation of developing rats (GD 17 20)
leads to long-term changes in cognitive performance that are
gender selective (Levin et al., 2002). Early postnatal studies
of CPF exposures in rats were found to depress locomotor
activity (Carr et al., 2001). Mechanistic studies (Qiao et al.,
2002, 2003) suggest a wide window of vulnerability of
cholinergic systems to CPF extending from the late prenatal
period through the early postnatal period of rat develop-
ment. In toto, these neurodevelopmental studies in the rat
suggest that CPF is a potential neurobehavioral toxicant.
Other studies indicate that different cholinesterase inhibiting
insecticides do not demonstrate enhanced neurodevelop-
mental sensitivity during the postnatal period (Moser, 1999).
Susceptibility to OP intoxication and neurodevelopment
may have a basis other than anticholinesterase effects.
Polymorphisms of paraoxonase (PON), an enzyme involved
in the detoxification of organophosphorothioate (OP) insec-
ticides, showed very low levels of activity in the human
newborn period (Chen et al., 2003). In the same review and
study, enhanced OP sensitivity was demonstrated in para-
oxonase activity-deficient adult (knockout) mice (Furlong et
al., 2000).
In perhaps the most thought provoking recent work,
Winrow et al. (2003) demonstrated that inhibition of neu-
ropathic target esterase (NTE) activity, either genetically or
by OPs that inhibit NTE, results in a neurological hyperac-
tivity phenotype in mammals (mice). Possible linkage of
attention deficit/hyperactivity disorders in children to pesti-
cide exposure in early childhood was hypothesized by these
authors. This limited review of neurodevelopmental toxi-
cants and their possible effects in children clearly indicate
the need to conduct toxicogenomics studies together with
neurobehavioral assessments of children and their exposures
to pesticides.
Endocrine effects
The hypothesis that environmental exposure to endocrine
disruptive agents generates adverse health effects rests
mainly on findings in wildlife and laboratory animal studies
(Colburn et al., 1993; Kavlock and Ankley, 1996). In
humans, environmental chemical disruption of sex hormone
cycles and altered levels of sex hormones are tenuously
connected with adverse reproductive outcomes, including
birth defects (e.g., hypospadias in males, urogenital defects),
neurobehavioral developmental disturbances (i.e., IQ with
PCBs), cancers involving the reproductive tract of the next
generation (clear cell carcinoma of the vagina with diethyl-
stilbestrol), leukemia in offspring (carbamate pesticide pro-
poxur), testicular cancer, and perhaps miscarriages in
association with farm thiocarbamate use (70% are fungi-
cides and 30% are herbicides) by male partners (Birnbaum
and Fenton, 2003; Cooper and Kavlock, 1997; Giesy et al.,
2000; Hatch et al., 1998; Mittendorf, 1995; Porterfield,
1994; Safe, 2000; Savitz et al., 1997; Skakkeback, 2002;
Winneke et al., 1998).
More subtle and perhaps more important to the devel-
oping fetus, child, and adult are endocrine disorders arising
out of alteration of thyroid function (Howdeshell, 2002;
Porterfield, 2000). If thyroid modulation of organ and
tissue form and function are changed, physical and mental
retardation and congenital births defects in children, in-
cluding alterations of the cardiovascular system and mus-
culoskeletal defects (Porterfield, 1994; Sher et al., 1998;
Wartofsky, 1998), are more likely to occur. In the hypo-
thyroid pubescent child, routine clinical studies demon-
strate alterations of the menstrual cycle and onset of
 V.F. Garry / Toxicology and Applied Pharmacology 198 (2004) 152163
menarche, obesity, and failure to develop secondary sex
characteristics appropriately.
A number of pesticide products are thought to interfere
with thyroid function [acetanilide, ethylene bisdithiocarba-
mates (EBDCs), nitroanilines, organophosphates, and syn-
thetic pyrethroids]. The reported molecular mechanism of
action in terms of thyroid toxicant activity of each of these
pesticide classes may differ significantly (Brucker-Davis,
1998; DeVito et al., 1999; Hurley, 1998). Possible syner-
gistic interactions anywhere in the hypothalamic pituitary
endocrine organ axis (Brucker-Davis, 1998) among pesti-
cides used in combination add further complexity. Measur-
able adverse health outcomes due to exposures to endocrine
disrupting agents can be diverse.
At the governmental level, programmatic progress toward
development of effective research tools has been made to
reduce the uncertainty that surrounds determination of endo-
crine disruptive effects in populations (Daston et al., 2003).
At present, few studies have measured potential adverse
endocrinologic effects of pesticides on children. One study
(Krstevska-Konstantinova et al., 2001) made a tentative
association between plasma levels of organochlorine pesti-
cides and precocious puberty (N = 39 girls; 1 boy). Another
study (Colon et al., 2000) examined the question of premature
breast development and showed significantly high levels
of phthalates in serum from affected patients (N = 41) and
none in control subjects (N = 35). One human ecologic-based
study-referenced organochlorine pesticide levels in fat tissue
from children made a tentative association between intensity
of agriculture and frequency of cryptorchidism (Olea et al.,
1999). No studies were found that examined thyroid function
in children in relation to their exposure to pesticides.
In the context of this review, the following quote (Rogan
and Ragan, 2003) seems applicable: Although endocrine
disruption in humans by pollutant chemicals remains largely
undetermined, the underlying science is sound and the
potential for such effects is real. Hormones and hormone
effects are low-dose, receptor-driven actions, dependent on
local and distant feedback. Normal hormone activities take
place over a relatively narrow concentration range. Chem-
ical interference with hormone actions, particularly during
neurodevelopment, and consequent effects on cognitive
behavior are a current concern (Schantz and Widholm,
2001; Weiss, 2002). The appropriateness of toxicological
screening for detection of endocrine-active compounds
continues to be a point of much concerted query and
discussion (Nilsson, 2000; OConnor et al., 2002).
Future directions
Much of the research data reviewed here is necessarily
descriptive. It is an appropriate effort for epidemiologist and
an ancillary role for toxicologist.
With the rise of genomics and toxicogenomics and the
introduction of sensitive immunoassay and analytic methods
159
capable of being used to measure toxicants levels in
humans, mechanism-based human studies are at the horizon.
With these tools, population toxicologists can assess differ-
ences and similarities between childrens and adults re-
sponse to pesticide exposure. We can identify childrens
susceptibility to toxicant effects of pesticides. More impor-
tantly, we will be able to better quantify childrens risk. In
the meantime, it seems prudent to minimize childrens
exposure to pesticides wherever possible.
Acknowledgments
The author would like to thank Ms. Leanna Erickson
for her assistance in the preparation of this review. Special
thanks to Joan Nephew and the staff of the Institute of
Environmental Assessment for providing administrative
and clerical assistance. Work in this laboratory was
supported by the University of Minnesota Medical School,
Minnesota State Legislature special appropriation, and
NIEHS ESO 8161.
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