’

Childhood Leukemia and Primary
Prevention
Todd P. Whitehead, PhD,a,b Catherine Metayer, MD, PhD,a,b
Joseph L. Wiemels, PhD,b,c Amanda W. Singer, PhD,a and Mark D. Miller, MD, MPHb,d

Leukemia is the most common pediatric cancer, affecting 3800
children per year in the United States. Its annual incidence has
increased over the last decades, especially among Latinos.
Although most children diagnosed with leukemia are now
cured, many suffer long-term complications, and primary
prevention efforts are urgently needed. The early onset of
leukemia—usually before 5 years of age—and the presence at
birth of “pre-leukemic” genetic signatures indicate that pre- and
postnatal events are critical to the development of the disease.
In contrast to most pediatric cancers, there is a growing body
of literature—in the United States and internationally—that has
implicated several environmental, infectious, and dietary risk
factors in the etiology of childhood leukemia, mainly for acute
lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and
traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In
contrast, intake of vitamins and folate supplementation during

the preconception period or pregnancy, breastfeeding, and
exposure to routine childhood infections have been shown to
reduce the risk of childhood leukemia. Some children may be
especially vulnerable to these risk factors, as demonstrated by a
disproportionate burden of childhood leukemia in the Latino
population of California. The evidence supporting the associations between childhood leukemia and its risk factors—including
pooled analyses from around the world and systematic reviews—
is strong; however, the dissemination of this knowledge to
clinicians has been limited. To protect children’s health, it is
prudent to initiate programs designed to alter exposure to wellestablished leukemia risk factors rather than to suspend judgment
until no uncertainty remains. Primary prevention programs for
childhood leukemia would also result in the significant co-benefits
of reductions in other adverse health outcomes that are common
in children, such as detriments to neurocognitive development.

Introduction

leukemia (ALL) or acute myeloblastic leukemia
(AML) in the United States (U.S.).1 A small but steady
annual increase from 1975 and 2012 in the ageadjusted incidence rate of childhood leukemia in the
U.S. has resulted in an overall rise of 55% in the annual
number of cases during the past three and a half
decades. Modern treatment protocols cure 80–90% of
children with leukemia with fewer sequelae than

ancer is the second most common cause of
death in children 0–14 years of age, after
accidents. Leukemia is the most common
cancer in children, representing approximately onethird of pediatric cancers. Approximately 3800 children are diagnosed annually with acute lymphoblastic

C

Curr Probl Pediatr Adolesc Health Care 2016;46:317-352

From the aDepartment of Epidemiology, School of Public Health, University of California, Berkeley, CA; bCenter for Integrative Research on Childhood
Leukemia and the Environment, University of California, Berkeley, CA; cDepartment of Epidemiology and Biostatistics, School of Medicine, University of
California, San Francisco, CA; and dWestern States Pediatric Environmental Health Specialty Unit, University of California, San Francisco, CA.
This publication was supported by the cooperative agreement award number 1 U61TS000237-02 from the Agency for Toxic Substances and Disease
Registry (ATSDR), United States. The U.S. Environmental Protection Agency (EPA), United States, supports the Pediatric Environmental Health Specialty
Units (PEHSU) by providing partial funding to ATSDR under Inter-Agency Agreement number DW-75-95877701. This work also was supported in part by
the US National Institute of Environmental Health Sciences (NIEHS), United States, (Grants P01 ES018172 and P50ES018172) and the USEPA (Grants
RD83451101 and RD83615901), as part of the Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE). The California
Childhood Leukemia Study was also supported in part by NIEHS, United States (Grant R01ES009137).
The ideas and opinions expressed herein are those of the authors and do not necessarily represent the official views of the ATSDR, EPA, or NIEHS.
Endorsement of any product or service mentioned by ATSDR, EPA, or NIEHS is not intended nor should it be inferred.
Curr Probl Pediatr Adolesc Health Care 2016;46:317-352
1538-5442/$ - see front matter
& 2016 The Authors. Published by Elsevier Inc. All rights reserved. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.cppeds.2016.08.004

Curr Probl PediatrAdolesc Health Care, October 2016

317

 FIG. Incidence of childhood leukemia in California by race-ethnicity, 1988–2012. Adapted with permission from Giddings et al.7

previous regimens. Still, even with improved treatments,
the immediate and long-term consequences of childhood
leukemia continue to exact a heavy toll.2,3 The impacts
and costs of childhood leukemia extend beyond the care
of the sick child; affecting family, friends, and the
community. Long-term and late-appearing secondary
effects include detriments to neurocognitive development, mental health, endocrine system function, and
general health.4 To avoid these risks completely, it
would be beneficial to prevent the disease altogether.
Though new genetic risk factors are likely still to
be discovered, to date only a small fraction (less
than 10%) of childhood leukemia cases can be
attributed to the influence of genetics, including to
genetic syndromes such as Down’s.5,6 Moreover,
the aforementioned increase in childhood leukemia
incidence—which is not fully explained by diagnostic trends—indicates that causal factors for
childhood leukemia have become more prevalent
in the last few decades. Since genetic factors do not
change on this time scale, it is probable that
environmental factors play a significant role in the
etiology of childhood leukemias and their recent
upward trends.6 These facts underscore the importance

318

of developing an approach to primary prevention of
childhood leukemia focused on reducing exposure to
environmental risk factors for the disease.
Children of Latino (also referred to as Hispanic)
descent have a higher incidence of leukemia than
whites, African-Americans or Asian-Americans nationally and in California, a highly-populated and ethnically
diverse State. Moreover, over the past 25 years, childhood leukemia incidence has been rising in California
at a faster pace in Latino children, compared to white
children (Fig),7 suggesting that Latino children (or
parents) are even more vulnerable to and/or more
exposed to harmful environmental factors than others.
Exposure to carcinogens has generally been considered a non-threshold event and modeled in a linear
fashion. However, there are chemicals for which a
supra-linear dose–response curve has been observed,
indicating that the risk from low-dose exposure may
actually be proportionally greater than would be
expected with a linear dose–response curve.8 One such
example is the known leukemogen, benzene, which is
metabolized to active intermediary compounds. This
finding is consistent with other exposures of concern to
pediatric environmental health, such as lead, where a

Curr Probl PediatrAdolesc Health Care, October 2016

 non-linear dose–response relationship has resulted in
worse-than-anticipated health effects from low-dose
environmental exposures that were presumed to be
safe.9 As such, findings from observational studies—
where participants are exposed to chemicals at environmental levels as opposed to higher dose occupational
levels—are critical to avoid underestimating risk.
Research into environmental, infectious, and dietary
causes of childhood leukemia has been limited,
amounting to only a small fraction of the total Federal
funding for childhood leukemia research (e.g., 3–7%
of National Institutes of Health and 1% of National
Cancer Institute total funding in 2010–2011).10 Funding for treatment/outcome-related studies has been far
greater than for those studies examining etiology. The
dramatic increases in children cured clearly justifies the
expenditures made to improve treatment, but research
on etiologic factors that may lead to prevention is
also important. Despite limited funding, evidence
demonstrating associations between environmental,
infectious, and dietary exposures and the risk of
developing childhood leukemia is accumulating.
This issue provides an overview of key biological
concepts in childhood leukemia research and summarizes
the environmental, infectious, and dietary risk factors for
childhood leukemia that have been identified in epidemiologic studies from around the world. Our purpose is
not to conduct a systematic review of the field of
childhood leukemia epidemiology—an endeavor which
could fill an entire book—but rather to provide a concise
perspective of the subject for the benefit of clinicians and
policy makers. The literature cited in this issue spans a
wide gamut. Whenever possible, the authors emphasize
relevant findings from well-designed meta-analyses of
published data and from large international collaborations
that have pooled and analyzed individual-level data from
multiple studies. In some instances, both pooled analyses
and meta-analyses (including unpublished data) were
conducted in parallel. Because most of these comprehensive studies fulfill criteria for systematic reviews, they
provide the strongest evidence of associations between
childhood leukemia and its risk factors. However, when
warranted by the novelty of the research, the authors also
discuss “one-off” findings of particular interest. The
authors are associated with the California Childhood
Leukemia Study (CCLS) and the Center for Integrative
Research on Childhood Leukemia and the Environment
(CIRCLE) at the University of California, Berkeley. This
research group, begun by Patricia Buffler, PhD, has
studied environmental causes of childhood leukemia for

Curr Probl PediatrAdolesc Health Care, October 2016

25 years. In this article, we identify many of the major
epidemiologic investigations of childhood leukemia
worldwide and we rely on our collective expertise to
highlight the literature that we believe will be most
instructive to clinicians and policy makers. However, we
acknowledge that particular emphasis has been paid to
the work of our research group and its collaborators in the
Childhood Leukemia International Consortium (CLIC).

Natural History of Leukemia as a
Disease
Development of Blood Cells and the Formation
of Leukemia
Hematopoiesis is a process involving extreme cellular blast growth, which produces 1011 blood cells per
day throughout life. The activity of certain cell differentiation stages (defined by cell surface markers and
the potential of the progeny) varies throughout life due
to different needs of the organism. These changes in
the activity of blood cell types over the course of
development are reflected in the distinct types of blood
cells with the propensity for cancer in childhood and
adulthood.
Although the maternal immune system protects the
child before and shortly after birth (with maternal
antibodies), the child’s immune system must begin its
education immediately after birth. This education of
the adaptive immune system requires exposures to
immune stimuli (e.g., infections) leading to the formation of billions of naïve pre-B and pre-T cells.
Leukemias in children arise from these naïve, preantigen stages, typically leading to primitive precursor
blast cell leukemic populations. That is, the majority of
childhood leukemias are of the pre-B cell or, to a lesser
extent, pre-T-cell phenotype (exhibiting cell surface
markers of normal pre-B or pre-T cells) and appear as
clonal outgrowths of normal pre-B or pre-T cells
“frozen” at a particular stage of differentiation.
Through the adaptive formation of antibodies and
T-cell receptors that respond to specific antigens, a
stable long-lived repertoire of cells is developed by the
time a child reaches young adulthood. The pre-B and
pre-T stages decrease in frequency after adolescence,
exemplified by the involution of the thymus and the
reduction in size of the pre-B cell population in the
bone marrow. As a result, adults typically contract
hematopoietic cancers (lymphomas and leukemias) in
post-antigen-stimulated B and T-cells and the myeloid

319

 lineage predominates in adult tumors. Distinct from
common translocations for ALL and AML, respecadult leukemias, the unique properties of childhood
tively. Studies using cord blood from healthy children
leukemia cells are likely to be important for underwithout cancer indicate that these translocations may
standing the environmental sensitivities for leukemooccur at a rate of 1% or more in the general
genesis in this age group.
population,20,21 while the disease is much more rare.
Childhood leukemia, like all cancers, is a product of
two or more molecular changes in a stem-like cell that
Mutational Mechanisms in Leukemia
has the ability to divide while maintaining an immature
state. Because they are formed from blood cells,
Recent investigations into the precise molecular
leukemias have an inherent capacity for mobilization
attributes of leukemia point largely to three pathways:
in the bloodstream and extravasation. Precursor blood
(1) aberrations in a small number of lineage-specific
cells also have an enormous capacity for “blast-like”
transcription factors such as ETV6, RUNX1, IKZF1, and
growth, and an ability to travel throughout the body
PAX5 (2) defects in receptor protein tyrosine kinases
without restriction. These attributes are among the six
and their downstream pathways (i.e., RAS/MEK/ERK),
11
“hallmarks of cancer,” and the fact that hematopoiand (3) epigenetic modifiers. Mutations may involve
translocations that comprise fusion genes, copy number
etic precursors harbor these “cancer-like” attributes
alterations (most common are deletions), single nucleomay explain why leukemias seem to need far fewer
tide mutations, and broad changes in epigenetic features
genetic aberrations for tumor progression compared to
solid tumors, which need to evolve additional metasuch as DNA methylation aberrations. The molecular
formation of the initiating transstatic capacities via genetic
locations may provide some
mutations. This simplicity may
also help explain the short
The development of childhood clues as to their causes. In the
past several years, many translatency of childhood cancers.
The genetic simplicity of leu- leukemia is a multi-step process; location breakpoints were shown
kemia combined with the young initiation occurs in utero for most to be induced by enzymatic
age of onset has allowed leukemias, whereas progression mutagenic processes—normally
researchers to delineate—within into acute disease usually takes utilized by the immune system to
diversify antibody and T-cell
the lifetime of the child—the
place after birth.
repertoire—which were abertiming of the formation of charrantly targeted to oncogenes
acteristic genetic aberrations.12
and genomic enhancers.22 These types of translocations
These changes appear to occur within two time frames
—prenatal initiating events that induce some cellular
are common in hematopoietic cancers that form after
changes, and postnatal genetic and epigenetic events
birth in response to antigenic stimulation. Interestingly,
that allow the emergence of acute disease. This
leukemia translocations including the most common in
research was made possible by the availability of
children such as ETV6-RUNX1 do not show signs of
archived newborn blood spots that are routinely
such activity and their origin remains a mystery. The
collected at birth by heel prick from neonates (e.g.,
lack of a clear endogenous path toward translocation
by the State of California Newborn Screening Proformation points to exogenous causes such as in utero
gram), including from children with leukemia. Several
environmental exposures, and points again to the
translocations commonly found in leukemias that were
oncologic immaturity of childhood leukemia blasts.
assessed using archived newborn blood spots, includEnvironmental causes may also interact with endogeing t(12;21) ETV6-RUNX1, t(8;21)RUNX1-MTG8, inv
nous mutagenic mechanisms in children after birth.
(16)CBFB-MYH11, have indicated a clear presence of
Many of these postnatal secondary rearrangements
the mutations in neonatal blood at birth in children who
show the clear involvement of the activity of the
contract leukemia later in life.13–16 Several other
enzymes that create antibody diversity, that is, recombinase activating gene (RAG) and adenosine deaminase
mutations, including t(1;19)TCF3-PBX1, FLT3, and
17–19
(AID) in the formation of secondary deletions and
RAS mutations clearly occur postnatally.
The mutations associated with leukemia are generally
mutations.23 Illegitimate targeting of these endogenous
enzymes has long been known to be stimulated by
insufficient to cause disease by themselves. This is the
exposures as diverse as pesticides and smoking. As
case for ETV6-RUNX1 and RUNX1-MTG8, the most

320

Curr Probl PediatrAdolesc Health Care, October 2016

 such, there is evidence that postnatal environmental
exposures may initiate childhood leukemia via the
stimulation of endogenous mutagenic mechanisms
including recombinase activating gene activity.24,25
Apart from the chromosome breakage events mentioned above, additional mutations include point mutations and epigenetic modifications. Point mutations are
caused by electrophilic chemicals that are either exposed
to bone marrow cells directly or else they are metabolically activated, and their metabolites are exposed to bone
marrow cells. Many oxidized reactive metabolites are
produced from chemicals circulating in the bone marrow
due to the presence of highly metabolically active cells
such as neutrophils (containing myeloperoxidase, for
instance) and the high levels of heme iron. Metabolites
that adduct to DNA can directly cause miscoding
mutations if unrepaired, or can result in repair-induced
strand breaks. There is little current evidence that point
mutations such as those found in RAS are caused by
environmental chemicals26; however, the most common
translocation in ALL, ETV6-RUNX1, appears to be
strongly and specifically associated with parental smoking27 and home paint use,28,29 which provides some
credence to viability of this pathway.
Epigenetic modifications are a normal part of a blood
cell’s development from a stem cell to a mature cell.
Changes to the usual epigenetic programming can occur,
however, as cells adapt to new environments. This type of
adaptation is the essence of the “developmental
origins of health and disease” initiatives that seek
to understand when such adaptations early in life can
lead to later disease risk, such as the demonstration
that starvation in utero can lead to obesity and
cardiac disease risk later in life.30 Adaptations can
occur as the result of exposures to specific environmental factors—for instance the specific demethylation of CpG loci in the gene AHRR has been
exquisitely related to cigarette smoke.31 Likewise,
methylation changes have also been observed in
response to folic acid exposures.32 Our understanding of the specific effects of environmental exposures
on epigenetic features is just in its infancy, and it is
unknown whether these perturbations could impact
leukemogenesis.

The Role of Immune Factors in a Cancer of the
Immune System
Infection is a direct cause of viral-induced cancers,
such as human papillomavirus-induced cervical cancer

Curr Probl PediatrAdolesc Health Care, October 2016

and Merkel cell virus-induced skin cancer. Inflammation from infection is also a risk factor for many
cancers, resulting from the collateral damage of tissue
disorganization, tissue remodeling, and chronic exposure to reactive oxygen species following inflammatory processes. Childhood ALL is also a disease of the
immune system, which begs the question can infection
directly stimulate leukemia or stimulate leukemia via
inflammatory processes?
Viruses that directly integrate into the genome have
not been reported in childhood ALL. Epidemiological
studies have, however, demonstrated clear effects of
immune factors on leukemogenesis, most overtly in the
form of a consistently observed reduced risk of childhood ALL associated with more childhood contacts in
daycare [odds ratio (OR) ¼ 0.77; 95% confidence
interval (95% CI): 0.71─0.84; N ¼ 7399 cases] and
other markers of early exposure to immune stimulus
such as breastfeeding for at least 6 months (OR ¼ 0.86,
95% CI: 0.79─0.94), having an older sibling (OR ¼
0.94, 95% CI: 0.88─1.00), or a history of four or more
common infections in the first year of life (OR ¼ 0.88,
95% CI: 0.79─0.98).33 Just as regular immune stimulation appears to reduce risk for allergies and asthma,
the same immune exercise can reduce the risk of
leukemia. In the absence of these priming exposures,
children may respond too strongly to the myriad of
infections subsequently encountered in school, resulting in a cytokine “storm” and excess cell stimulation,
secondary mutations, and in some cases, leukemia.
This putative pathology is referred to as the “Greaves
hypotheses” after its first proponent.34 Other ancillary
data on immune education seem to fit this pattern as
well—normal childhood vaccines, the presence of
older siblings, and breastfeeding were all associated
with reduced risks of childhood leukemia. Population
mixing, in which large numbers of a “new” population
are mixed into a standing community, seems to
transiently increase the risk of leukemia and also fit
with the notion of an infectious stimulation for childhood ALL.35 A corollary hypothesis to Greaves' was
suggested by Kinlen who noticed that leukemia space–
time clusters often followed recent population mixing
events, such as the creation of new towns or population
movements during warfare. He proposed that such
mixing facilitated the transmission of a specific
leukemia-initiating virus which, while plausible, was
not followed up with biological validation as noted
above. More likely, population mixing permits the
transmission of common viruses to populations

321

 without herd immunity rather than spreading specific
leukemia-initiating viruses.
Recent studies have noted that the child’s medical
records confuse the infection issue somewhat—ALL
patients visit their general practitioner for infections
in the first year of life much more commonly than
children who do not grow up to get leukemia.36,37
This suggests that the damage wrought by fulminant
infections may occur much earlier than previously
thought, and also that children who get leukemia may
respond to infection differently, that is, more strongly
to typical childhood infections. Part of this sensitivity
may be a lack of immunomodulation from suppressive cytokines like IL-10 that tend to be present at
lower levels in newborns who go on to develop
leukemia.38

Chemicals as Leukemogens
The ability of a chemical to act as carcinogen was
originally thought to hinge on its capacity as mutagen,
but it is likely that many other more biologically
relevant activities are important in leukemogenesis as
well. Some chemicals exhibit properties that allow
them to target the bone marrow specifically, due to its
metabolic activity (benzene for an example). Other
chemicals may impact the immune system indirectly,
setting up the individual for aberrant responses to
infection. The role of exogenous factors such as
chemicals, many of which are immunosuppressive, in
this process is unknown and likely to be a major
research field in the future. Other activities of chemicals are summarized in a recent review of chemicals as
carcinogens.39 Below, we discuss chemical exposures
that may cause leukemia and weigh the evidence for
causal relationships.

Environmental Risk Factors for
Childhood Leukemia
Exposure Science in Studies of Childhood
Leukemia Risk
As mentioned earlier, childhood leukemia is the
most common form of pediatric cancer; but, for the
purposes of epidemiological study, it is a rare disease.
As such, the vast majority of epidemiological investigations into the causes of childhood leukemia are
forced to employ a case–control study design. In

322

many instances, case–control studies of childhood
leukemia are designed to assess children’s exposure to
disease risk factors retrospectively. That is, a child is
first diagnosed with leukemia, then s/he is enrolled in
the case–control study, and only afterwards can investigators begin to assess the agents to which s/he
has been exposed. This design imposes limitations on
the epidemiologist, as etiologically relevant specimens—biological and environmental—are not necessarily available for collection by the time the child is
under study. As discussed above, childhood leukemia
can be initiated during the prenatal period, but most
cases are not diagnosed until the child is between 2
and 4 years old. This leaves a long time interval
between the first windows of susceptibility to leukemogenic agents and the time period when investigators can start measuring a child’s exposure to those
agents. To overcome these challenges, childhood
leukemia investigators have employed a variety of
strategies to assess children’s exposures to potentially
carcinogenic agents.

Using Parent Interviews to Assess Children’s
Exposures to Chemicals
One simple way to circumvent the need for the
collection of biological or environmental samples
during etiologically relevant time periods is to interview participating parents to obtain information about
their child’s history of exposure to specific agents.
Such interviews can be used to pinpoint historical
exposures during critical windows of a child’s development (e.g., the second trimester of pregnancy), they
can be wide-ranging in scope, and they can be
especially effective in assessing parents' conscious
behaviors (e.g., smoking habits, residential pesticide
use, occupational histories). On the other hand,
interview-based exposure assessments have inherent
limitations; they are imprecise measures of chemical
exposure, they provide little information about any of a
child’s exposures that go unrecognized by the parents,
and they are potentially subject to recall and reporting
biases if parents of case and control children remember
or report their children’s exposures in different ways.
In practice, though, reproducibility studies have suggested that, for some of the environmental exposures
that are of interest in childhood leukemia research—
ionizing radiation,40–42 pesticides,43 and smoking27—
there is minimal evidence of differential recall between
cases and controls.

Curr Probl PediatrAdolesc Health Care, October 2016

 Measuring Chemicals in Settled Dust

research from the Center for Integrative Research on
Another strategy to obtain information about a
Childhood Leukemia and the Environment also indicates
child’s exposure to chemicals during etiologically
a relationship between levels of persistent chemicals in
relevant time periods is to measure levels of chemicals
matched samples of settled dust and biospecimens.53,54
in stable environmental matrices. For example, persisTaken together, the observation that chemical levels can be
tent chemicals accumulate on settled dust particles,
correlated in matched samples of settled dust and human
which can become trapped deep within a carpet, and
serum as well as the observation that chemical levels in
this settled dust acts as a long-term reservoir for these
settled dust are relatively stable over time support the use
chemicals.44 With limited exposure to direct sunlight
of chemical levels measured in dust collected after
diagnosis as surrogates for chemical exposures that
and microbial action, persistent chemicals, like polychildren received during etiologically relevant time periods
chlorinated biphenyls (PCBs), are extremely slow to
(before diagnosis).
degrade on dust particles that settle indoors. As a
result, collecting samples of settled dust from carpets
or other household surfaces and measuring levels of
persistent chemicals in these samples provides an
Estimating Ambient Environmental Exposures
integrated measure of chemical contamination over a
Using Geographic Information Systems
long period of time.
An alternative strategy for assessing a child’s history of
As part of the California Childhood Leukemia Study, we
environmental
exposures is to estimate ambient pollution
have collected multiple dust samples from a large group of
using Geographic Information Systems (GIS) and geohomes at time intervals of several years between sampling
spatial modeling and to use these estimates of ambient
rounds. We found that while there was substantial
conditions as surrogates for the child’s total exposure to
variability in chemical levels between sampling rounds,
chemicals. Many governing bodies record a child’s home
there was also moderate correlation in the relative ranking
address on the birth certificate and this information can be
of exposures (i.e., rankings from highest to lowest
obtained for research purposes contingent on appropriate
exposures) among homes over time.45–47 These findings
ethical review and approval. Exposure models based on
support the hypothesis that chemical levels in dust samples
GIS data and geocoded birth addresses could provide
collected after diagnosis may be informative surrogates for
useful information about childchemical contamination that was
ren’s exposure to chemicals at
present in the home during important developmental periods of a Chemicals measured in samples the time of birth and, potentially,
child’s life.
of settled dust collected from a throughout the prenatal period as
well (if participating mothers did
Accidental ingestion of settled
child’s home after diagnosis are not change residence during
dust is an important route of
human exposure to chemicals useful surrogates for the chemical pregnancy). Moreover, complete
along with the consumption of exposures s/he received during residential histories can be
obtained from parents via intercontaminated food and the inhalaetiologically-relevant periods
view, which allows for a more
tion of contaminated air. For exambefore and after birth.
comprehensive model of a
ple, it has been suggested that dust
child’s historic exposures to
ingestion is the major route of
ambient chemicals. Agricultural pesticide applicaexposure to the flame retardant chemicals, polybrominated
tion,55,56 traffic-related air pollution,57 and electromagdiphenyl ethers (PBDEs) in North America48 and positive
netic fields58 have been estimated using GIS in the
relationships have been observed between PBDE levels in
context of epidemiological studies of childhood leukematched samples of dust and serum among U.S.
49,50
mia. One limitation of using estimates of ambient
adults.
Due to their tendency to make hand-to-mouth
pollution as surrogates for total exposures is the inability
contact and their proximity to the floor, young children are
to account for chemical exposures that occur indoors.
expected to receive a relatively large proportion of their
51
This is a substantial drawback, because children tend to
total chemical intake via settled dust compared to adults,
spend the vast majority of their time indoors, there are
and a positive relationship has been observed between
distinct chemical sources indoors, and chemical expoPBDE levels in matched samples of dust and serum in one
sures tend to be higher indoors than outdoors.59,60
investigation of toddlers from North Carolina.52 Likewise,

Curr Probl PediatrAdolesc Health Care, October 2016

323

 Measuring Chemicals in Archived
Pre-diagnostic Biospecimens

Using these strategies for assessing children’s exposure
to environmental agents, epidemiologists have identified
several suspected environmental risk factors for childhood
leukemia, including pesticides, parental smoking, paint,
petroleum solvents, traffic emissions, persistent organic
pollutants, and radiation, as summarized in Table 1.

Perhaps the most straightforward way to obtain prediagnostic biospecimens would be to establish a
prospective birth cohort and follow leukemia incidence
in the participating children into adulthood. However,
as discussed above, this study design is generally
not feasible for childhood leukemia and will generally
Pesticides
be limited by a small number of available cases.
Several studies have suggested that home pesticide
The International Childhood Cancer Cohort Consorexposure
before birth and during a child’s early years
tium seeks to combine a number of large infant/
may increase the risk of childhood leukemia. Indeed,
child prospective studies (on the order of 100,000
exposure to pesticides is one of the
participants per study)—
most frequently investigated chemiwhich were originally
cal risk factors for childhood leukedesigned to examine enviEpidemiological studies have
mia. A causal link between exposure
ronmental and genetic
identified several environmental to pesticides and childhood leukemia
determinants of common
risk factors for childhood
is supported by many studies, includchildhood
diseases—for
ing the California Childhood Leukepooled analyses of childleukemia and those findings
hood leukemia and other have been confirmed with large mia Study, which demonstrated a
relationship between exposure to
childhood cancers.61
meta-analyses
and
pooled
insecticides—as a general class—
Alternatively, it may be
analyses
that
combined
data
and childhood leukemia.67 Existing
possible to utilize archived
from thousands of children with studies have generally used interbiospecimens—collected
before diagnosis as part of leukemia and healthy controls. views with parents to assess children’s exposure to pesticides; as such,
routine medical testing—to
62
no
specific
pesticide,
or class of pesticides, has been
measure prenatal chemical exposures. For example, in
implicated as the causal agent underlying these
many countries, blood spots are collected from each
observations.
newborn infant by heel-stick for the purposes of genetic
screening. In the State of California, blood spots left over
Pooled Analyses of Home Pesticide Use and
from genetic screening are archived in a State laboratory
Childhood Leukemia
and made available for research contingent upon approInvestigators from the Childhood Leukemia Internapriate ethical review and approval. These archived
tional
Consortium pooled individual parents' responses
neonatal blood spots provide a useful resource for
to interview questions about children’s exposure to
childhood leukemia research, offering insight into the
pesticides from 12 case–control studies.29 Each conchemicals to which the developing fetus was exposed
tributing study used a unique set of questions, often
during the prenatal period, including folate,63 cotinine,64
65
written in different languages, so exposure data were
and PBDEs. Using current technology for exposure
harmonized into compatible formats before pooled
biology, investigators can characterize prenatal exposure
analyses could be conducted using multivariable logisto thousands of different chemicals with as little as a few
tic regression. ALL was associated with any pesticide
drops of archived neonatal blood. Some important
exposure shortly before conception (OR ¼ 1.39; 95%
technical considerations include the potential instability
CI: 1.25–1.55; N ¼ 2785 cases and 3635 controls),
of chemical analytes during long-term storage, the
during pregnancy (OR ¼ 1.43; 95% CI: 1.32–1.54;
possibility of chemical contamination during storage,
N ¼ 5055 cases and 7370 controls), and after birth (OR
and the complex dynamics of newborn metabolite levels
66
¼ 1.36; 95% CI: 1.23–1.51; N ¼ 4162 cases and 5179
immediately after birth. Despite these limitations, the
controls). Corresponding odds ratios for risk of AML
use of archived pre-diagnostic biospecimens for expowere 1.49 (95% CI: 1.02─2.16, N ¼ 173 cases and
sure assessment in epidemiological studies of childhood
1789 controls), 1.55 (95% CI: 1.21–1.99; N ¼ 344
leukemia is very promising.

324

Curr Probl PediatrAdolesc Health Care, October 2016

 TABLE 1. Environmental risk factors for childhood leukemia

Childhood leukemia
risk factor

Exposure measure

Level of consensus

Subtype
specificity

Exposure details

Odds ratio (95% CI)

Home pesticide use

Parental interview

Pooled analysis of 12 studies
from CLIC.29

ALL
ALL
ALL
AML
AML
AML

Before conception
During pregnancy
After birth
Before conception
During pregnancy
After birth

1.39
1.43
1.36
1.49
1.55
1.08

Parental occupational
exposure to
pesticides

Parental interview

Pooled analysis of 13 studies
from CLIC & meta-analysis
of CLIC þ non-CLIC studies.74

ALL

Maternal during
pregnancy
Paternal at conception
Paternal at conception
Paternal at conception
Maternal during
pregnancy
Paternal at conception

1.01 (0.78, 1.30)

ALL
T-cell ALL
ALL after 5y
AML
AML

Proximity to agricultural GIS Model
pesticide application

Novel finding.55

ALL
ALL
ALL
ALL
ALL

Chlorthal, an herbicide

Settled dust levels

Novel finding.80

ALL
ALL
ALL

Parental smoking

Parental interview

Pooled analysis of 14 studies
from CLIC & meta-analysis
of CLIC þ non-CLIC studies.83

AML
AML
AMMoL

Home paint use

Parental interview

Pooled analysis of 8 studies
from CLIC.86

ALL
ALL
ALL
ALL
ALL—t(12;21)

Parental occupational
exposure to paint

Parental interview

Pooled analysis of 13 studies
from CLIC.89

ALL
ALL
AML
AML

Parental occupational
exposure to solvents

Parental interview

Meta-analysis.88

ALL

Meta-analysis.88,90

ALL
ALL
ALL

Curr Probl PediatrAdolesc Health Care, October 2016

Insecticides, moderate,
lifetime
Fumigants, moderate,
lifetime
Organophosphates,
moderate, lifetime
Chlorinated phenols,
moderate, lifetime
Triazines, moderate,
lifetime

1.20
1.42
1.38
1.94

(1.25,
(1.32,
(1.23,
(1.02,
(1.21,
(0.76,

(1.06,
(1.04,
(1.13,
(1.19,

1.55)
1.54)
1.51)
2.16)
1.99)
1.53)

1.38)
1.94)
1.67)
3.18)

0.91 (0.66, 1.24)
1.5 (0.9, 2.4)
1.7 (1.0, 3.1)
1.6 (1.0, 2.7)
2.0 (1.0, 3.8)
1.9 (1.0, 3.7)

Detected, 1st Tertile vs. 1.49 (0.82, 2.72)
Not Detected
Detected, 2nd Tertile vs. 1.49 (0.83, 2.67)
Not Detected
Detected, 3rd Tertile vs. 1.57 (0.90, 2.73)
Not Detected
Paternal at any time
Maternal during
pregnancy, Latinas
Paternal at any time

1.34 (1.11, 1.62)
2.08 (1.20, 3.61)

1–3 months before
conception
During pregnancy
After birth
Professional painter,
during pregnancy
During pregnancy

1.54 (1.28, 1.85)

1.87 (1.08, 3.25)

1.14 (1.04, 1.25)
1.22 (1.07, 1.39)
1.66 (1.21, 2.28)
1.51 (1.08, 2.11)

Paternal at conception
Maternal during
pregnancy
Paternal at conception
Maternal during
pregnancy
Maternal during
pregnancy

0.93 (0.76, 1.14)
0.81 (0.39, 1.68)

All solvents, maternal
during pregnancy
Petroleum, maternal
during pregnancy

1.25 (1.09, 1.45)

0.96 (0.65, 1.41)
1.31 (0.38, 4.47)
1.23 (1.02, 1.47)

1.42 (1.10, 1.84)
1.71 (0.91, 3.24)a

325

 TABLE 1. (Continued )
Childhood leukemia
risk factor

Exposure measure

Level of consensus

Replicated.91

Subtype
specificity

ALL
ALL

Traffic-related air
pollution

GIS model

Two independent metaanalyses.92,93

ALL
Any
ALL

Exposure details

Odds ratio (95% CI)

Benzene, maternal
during pregnancy
Org. solvents, paternal 1.48 (1.01, 2.16)
at conception
Cl-hydrocarbon, paternal 2.28 (0.97, 5.37)
at conception
1.25 (0.92, 1.69)
1.53 (1.12, 2.10)
1.21 (1.04, 1.41)

AML

Traffic density
Traffic density
Nitrogen dioxide
estimates
Benzene estimates

2.28 (1.09, 4.75)

PAHs

Settled dust levels,
vacuum cleaners

Novel finding.94

ALL
ALL
ALL
ALL
ALL

Benzo[a]pyrene
Dibenzo[a,h]anthracene
Benzo[k]fluoranthene
Indeno[1,2,3-c,d]pyrene
PAH toxic equivalence

1.42
1.98
1.71
1.81
2.35

PCBs

Settled dust levels

Novel finding.81

ALL

Any PCB detected vs.
none detected
Top quartile Σ6PCB vs.
bottom quartile

1.97 (1.22, 3.17)

ALL

PBDEs

Settled dust levels

Novel finding.95

ALL
ALL
ALL
ALL
ALL
ALL
ALL

Top quartile ΣPentaBDEs vs. bottom
Top quartile ΣOcta-BDEs
vs. bottom
Top quartile ΣDecaBDEs vs. bottom
BDE-196 concentrations
BDE-203 concentrations
BDE-206 concentrations
BDE-207 concentrations

(0.95,
(1.11,
(0.91,
(1.04,
(1.18,

2.12)
3.55)
3.22)
3.16)
4.69)

2.78 (1.41, 5.48)

0.7 (0.4, 1.3)
1.3 (0.7, 2.3)
1.0 (0.6, 1.8)
2.1
2.0
2.1
2.0

(1.1, 3.8)
(1.1, 3.6)
(1.1, 3.9)
(1.03, 3.8)

ALL ¼ acute lymphoblastic leukemia; AML ¼ acute myeloblastic leukemia; AMMoL ¼ acute myelomonocytic leukemia; CI ¼ confidence
interval; CLIC ¼ Childhood Leukemia International Consortium; GIS ¼ geographic information systems; PAHs ¼ polycyclic aromatic
hydrocarbons; PCBs ¼ polychlorinated biphenyls; PBDEs ¼ polybrominated diphenyl ethers.
a
Relative risk reported.

cases and 4666 controls) and 1.08 (95% CI: 0.76–1.53,
N ¼ 198 cases and 2655 controls), respectively.
The Childhood Leukemia International Consortium
investigators29 confirmed the observed association
between home pesticide exposure during pregnancy
and childhood leukemia using meta-analyses as
well. Other investigators have reported similar findings
in independent meta-analyses,68–70 generally observing the strongest associations for indoor insecticide use.

Pooled Analyses of Parental Occupational
Exposure to Pesticides and Childhood
Leukemia
Given the consistently observed association between
home pesticide use during early childhood and

326

leukemia risk, a logical extension of this line of
research has been to examine the effect of parental
occupational exposure to pesticides on childhood
leukemia risk. There is evidence that adults exposed
to pesticides at work can track these chemicals back to
their homes on their shoes, clothing, and skin, potentially exposing their families.71,72 Moreover, paternal
exposure to pesticides before conception could result
in germ cell damage, whereas maternal exposure to
pesticides during pregnancy could also expose the
fetus to these chemicals.73 The Childhood Leukemia
International Consortium investigators pooled individual parents' responses to interview questions about job
histories and the data were harmonized to a compatible
format that characterized parents' pesticide exposures
at work.74 ALL was associated with paternal exposure

Curr Probl PediatrAdolesc Health Care, October 2016

 to pesticides at work around the time of conception
(OR ¼ 1.20; 95% CI: 1.06─1.38; N ¼ 8169 fathers of
cases and 14,201 fathers of controls), but was not
associated with maternal exposure during pregnancy
(OR ¼ 1.01; 95% CI: 0.78─1.30; N ¼ 8236 case and
14,850 control mothers). In contrast, AML was associated with maternal exposure to pesticides at work
during pregnancy (OR ¼ 1.94; 95% CI: 1.19─3.18;
N ¼ 1329 case and 12,141 control mothers), but was
not associated with paternal exposure around the time of
conception (OR ¼ 0.91; 95% CI: 0.66─1.24; N ¼ 1231
case and 11,383 control fathers). The modest association between paternal exposure to pesticides around the
time of conception and ALL risk in the offspring was
more evident in children diagnosed at an older age
(5þ years old) and in children with the T-cell ALL
subtype. The Childhood Leukemia International Consortium’s findings of a significant association between
maternal exposure to pesticides during pregnancy and
AML risk in the offspring is consistent with previous
reports.75–77
In a meta-analysis that accompanied the abovereferenced pooled analysis, the Childhood Leukemia
International Consortium investigators74 found a
positive association between maternal occupational
exposures to pesticides during pregnancy and
AML as well as between paternal occupational exposures around conception and T-cell ALL. This
meta-analysis followed a systematic review and it
included studies participating in the Childhood
Leukemia International Consortium as well as nonparticipating, independent studies. Other investigators78,79 have reported similar findings in independent
meta-analyses, observing an association between prenatal maternal exposure to pesticides at work and
childhood leukemia.

GIS-Estimated Ambient Pesticide Levels and
Childhood Leukemia
Investigators from the California Childhood Leukemia Study have also evaluated the association between
residential proximity to agricultural pesticide applications and childhood ALL.55 For the families of 213
ALL cases and 268 matched controls, the authors
linked residential histories together with agricultural
pesticide use reports from the California Department of
Pesticide Regulation, to assess whether living within a
half-mile (0.8 km) of pesticide applications was associated with childhood leukemia risk. Elevated ALL

Curr Probl PediatrAdolesc Health Care, October 2016

risk was associated with lifetime moderate exposure,
but not high exposure, to certain physicochemical
categories of pesticides, including organophosphates,
chlorinated phenols, and triazines, and with pesticides
classified as insecticides or fumigants.

Exposure to Herbicides and Childhood
Leukemia
Epidemiological studies of childhood leukemia that
use environmental or biological samples are relatively
scarce. In one such study, investigators from the
California Childhood Leukemia Study evaluated the
relationship between childhood ALL and herbicide
concentrations in settled dust as surrogates of herbicide
exposures.80 The herbicide analysis included 269 ALL
cases 0–7 years of age and 333 healthy controls
matched on date of birth, sex, and race/ethnicity.
Dust samples were collected from carpets using a
high-volume small-surface sampler or from participant vacuum cleaners. Concentrations of agricultural
or professional herbicides (alachlor, metolachlor,
bromoxynil, bromoxynil octanoate, pebulate, butylate, prometryn, simazine, ethalfluralin, and pendimethalin) and residential herbicides (cyanazine,
trifluralin, 2-methyl-4-chlorophenoxyacetic acid,
mecoprop, 2,4-dichlorophenoxyacetic acid, chlorthal, and dicamba) were used in logistic regression
adjusting for age, sex, race/ethnicity, household
income, year and season of dust sampling, neighborhood type, and residence type. The risk of childhood
ALL was associated with dust levels of chlorthal;
compared to homes with a measurement below the
analytical limit of detection, odds ratios for the first,
second, and third tertiles were 1.49 (95% CI:
0.82─2.72), 1.49 (95% CI: 0.83─2.67), and 1.57
(95% CI: 0.90─2.73), respectively (p value for linear
trend ¼ 0.05). No other herbicides were identified as
risk factors of childhood ALL. Metayer et al.80
postulated that 2,3,7,8-tetrachlorodibenzo-p-dioxin
—a potent carcinogen and an impurity found in
chlorthal—might be the causal agent underlying the
observed association.

Limitations of Existing Research on Pesticides
and Childhood Leukemia
Previous studies of the relationship between pesticide
exposure and childhood leukemia, including pooled
analyses conducted by the Childhood Leukemia International Consortium have utilized interviews to assess
pesticide exposures to children and their parents.

327

 Unfortunately, this study design has precluded investigators from identifying specific chemicals that may
be causal agents underlying the observed associations.
Findings from the California Childhood Leukemia
Study seem to rule out organochlorine pesticides, such
as DDT and chlordane, as the culpable pesticides
underlying the observed association with childhood
leukemia.81

Summary of Existing Research on Pesticides
and Childhood Leukemia
Pooled analyses of data from studies around the
world show a relationship between home pesticide
use—especially of insecticides indoors—and the risk
of childhood leukemia, which is confirmed by independent systematic reviews and meta-analyses.
Pooled analyses of data from the Childhood Leukemia
International Consortium demonstrate a relationship
between prenatal maternal exposure to pesticides at
work and the risk of childhood AML. Likewise, these
findings were supported by independent systematic
reviews and meta-analyses. Future studies will continue to exam relationships between pesticide exposures and the risk of specific leukemia subtypes and
will also identify the specific pesticides which act as
causal agents.

Parental Smoking
Parental tobacco use is another suspected risk factor for
childhood leukemia that has received a lot of attention
from researchers. Cigarettes contain numerous harmful
constituents and tobacco use is well known to cause a
variety of cancers in adults, including leukemia, via both
direct and secondhand means of exposure. Likewise,
there is evidence that parental cigarette smoking may also
be associated with childhood cancer risk.
Investigators from the California Childhood Leukemia
Study, for example, examined the association between
parental smoking and childhood leukemia among 281
ALL cases, 46 AML cases, and 416 controls matched on
age, sex, maternal race, and Latino ethnicity.82 Maternal
smoking was not associated with an increased risk of
either ALL or AML. Paternal preconception smoking
was significantly associated with an increased risk of
AML (OR ¼ 3.84, 95% CI: 1.04─14.17) and marginally
associated with an increased risk of ALL (OR ¼ 1.32,
95% CI: 0.86─2.04).

328

Pooled Analyses of Parental Cigarette Smoking
and Childhood AML
The Childhood Leukemia International Consortium
pooled individual parents' responses to interview
questions about tobacco use from 14 case–control
studies, representing 1300 AML and 15,000 controls.83
Individual studies ascertained information about parental cigarette smoking at a number of stages of the
child’s development with varying degrees of specificity, including maternal smoking during pregnancy and
paternal smoking during the three months before
conception. The findings from the pooled analyses
strengthened the existing evidence of modest associations between paternal cigarette smoking at any time
and childhood AML, with dose–response relationships
(p o 0.05). Maternal smoking during pregnancy was
associated with an increased risk of AML for Latino
children only.

Meta-analyses of Parental Cigarette Smoking
and Childhood ALL
In 2009, a review of studies which evaluated the
association between parental smoking and childhood
leukemia revealed that 6 of 13 studies which had
examined the relationship between paternal smoking
and childhood leukemia reported significant positive
associations.84 Subsequently, Liu et al.85 conducted a
meta-analysis, which suggested that childhood ALL
was associated with paternal smoking during preconception (OR ¼ 1.25, 95% CI: 1.08─1.46) during
pregnancy (OR ¼ 1.24, 95% CI: 1.07─1.43), and after
birth (OR ¼ 1.24, 95% CI: 0.96─1.60), with a dose–
response relationships observed between childhood
ALL and paternal smoking before conception or
after birth.

Parental Cigarette Smoking and Childhood
Leukemia Subtypes
There is some evidence that the strength of the
association between parental cigarette smoking and
childhood leukemia varies by the cytogenetic subtype
of the tumor. For example, Metayer and colleagues27
reported that children with a history of paternal prenatal
smoking combined with postnatal passive smoking had
a 1.5-fold increased risk of ALL (95% CI: 1.01─2.23),
compared to those without smoking history; but this
joint effect was seen for B-cell precursor ALL with t
(12;21) only (OR ¼ 2.08, 95% CI: 1.04─4.16), not for
high hyperdiploid B-cell ALL. Similarly, the

Curr Probl PediatrAdolesc Health Care, October 2016

 aforementioned pooled AML analysis conducted by the
Childhood Leukemia International Consortium found
that the highest smoking-related risk was seen for the
myelomonocytic leukemia, a subtype common in
treatment-related AML. Childhood leukemia comprises
many subtypes and these findings demonstrate that each
subtype may have a distinct set of characteristic risk
factors corresponding to its unique etiology. As such,
studies that evaluate subtype-specific chemical risk
factors are the most likely to identify true relationships.
Tellingly, when risk factors for each leukemia subtype
are considered separately, higher odds ratios tend to be
revealed.

Limitations of Existing Research on Tobacco
Use and Childhood Leukemia
As was the case for pesticides above, previous
studies of the relationship between parental tobacco
use and childhood leukemia, including pooled analyses
conducted by the Childhood Leukemia International
Consortium, have utilized interviews to characterize
parental smoking histories. This method of exposure
assessment is useful, because it allows investigators to
examine the effect of parental smoking at critical
windows of a child’s development and because it
enables investigators to untangle the separate effects
of cigarette smoking done by the mother, father, or
other family members. Moreover, in contrast to other
environmental exposures that are of interest to leukemia researchers, parents are conscious of the number of
cigarettes they tend to smoke each day and they can
help quantify their own exposures to tobacco. However, recall and reporting biases are still concerns, as
parents (especially parents of children with leukemia)
may not accurately remember or may not feel comfortable discussing their past tobacco use history during
the interview. The lack of an observed association
between maternal smoking during pregnancy and
childhood leukemia may be related to this potential
for bias when using interview data to assess exposure.
Alternatively, the lack of an observed association may
also be the result of smoking-induced adverse birth
outcomes (e.g., fetal loss, still birth) that preclude the
subsequent development of childhood leukemia,
thereby biasing epidemiological findings.

Summary of Existing Research on Tobacco Use
and Childhood Leukemia
Pooled analyses of data from studies around the
world show a relationship between paternal smoking

Curr Probl PediatrAdolesc Health Care, October 2016

before conception and AML risk. Likewise, these
findings were supported by an independent systematic
review and meta-analysis. Future studies will provide
an increased focus on the role of prenatal maternal
smoking on leukemia risk in Latino children and will
pool data from the Childhood Leukemia International
Consortium for an analysis of smoking-related ALL
risk.

Chemicals Found in Paints, Petroleum Solvents,
and Traffic Emissions
A collection of studies have investigated the associations between childhood leukemia and a looselyrelated group of environmental exposures including
paint, petroleum solvents, and vehicle traffic. These
general exposure categories share characteristic chemical signatures, including the leukemogenic agent,
benzene.
Investigators from the California Childhood Leukemia Study examined the association between childhood leukemia and the use of paint or petroleum
solvents in the home before birth and in early childhood. The analysis included 550 ALL cases, 100 AML
cases, and one or two controls per case individually
matched for sex, age, Latino ethnicity, and race.
Conditional logistic regression techniques were used
to adjust for income. Home paint exposure was
associated with ALL risk (OR¼1.65; 95% CI:
1.26─2.15). The association was restricted to ALL
with t(12;21) (OR ¼ 4.16, 95% CI: 1.66─10.4). Home
use of petroleum solvents was associated with an
increased risk for AML (OR ¼ 2.54, 95% CI:
1.19─5.42) but not ALL.

Pooled Analyses of Home Exposure to Paint
and Childhood Leukemia
The Childhood Leukemia International Consortium
pooled individual responses to questions about home
paint exposures from eight case–control studies.86 Data
were harmonized to account for inter-study differences
in reported paint types, time periods of exposure, and
leukemia subtypes and a compatible format was used
in logistic regression. ALL risk was associated with
home paint exposure in the 1–3 months before
conception (OR ¼ 1.54; 95% CI: 1.28─1.85; N ¼
3002 cases and 3836 controls), during pregnancy (OR
¼ 1.14; 95% CI: 1.04─1.25; N ¼ 4382 cases and 5747
controls), and after birth (OR ¼ 1.22; 95% CI:
1.07─1.39; N ¼ 1962 cases and 2973 controls). The
329

 risk was greater if someone other than the parents did
the painting, for example, a professional painter, which
is indirect evidence of a dose–response relationship.
The paint–leukemia association was stronger for ALL
with t(12;21) than for other cytogenetic subtypes of
leukemia.

Meta-analyses of Parental Occupational
Exposures to Paint, Solvents, Vehicle Exhaust,
and Childhood Leukemia
As an extension of the research that has identified
an association between exposure to paint in the home
and childhood leukemia, meta-analyses have demonstrated associations between childhood leukemia
risk and parental exposures in related occupational
settings.
For example, a meta-analysis summarizing the existing literature on parental occupational exposures and
childhood cancer found that relationships between
childhood leukemia and paternal exposure to paints,
solvents (e.g., benzene and trichloroethylene), and
employment in motor vehicle-related occupations were
among the strongest of the more than 1000 occupation–childhood cancer combinations that were evaluated.87 The studies that comprised this meta-analysis
had several limitations related to the quality of the
exposure assessment including the small numbers of
exposed cases studied, the likelihood of false positives
due to multiple comparisons, and possibility of publication bias. Despite these limitations, this metaanalysis provides evidence that when parents are
exposed to certain chemicals at work, the effects are
harmful to their offspring.
Another meta-analysis summarized findings from 28
case–control studies and one cohort study that investigated the relationship between maternal occupational
exposures and childhood leukemia in the offspring
using 16,695 participating cases and 1,472,786 controls.88 ALL risk was associated with maternal paint
exposures at work during pregnancy (OR ¼ 1.23, 95%
CI: 1.02─1.47), with maternal solvent exposures at
work during pregnancy (OR ¼ 1.25, 95% CI:
1.09─1.45), and with maternal petroleum exposure at
work during pregnancy (OR ¼ 1.42, 95% CI:
1.10─1.84). No publication bias was found in this
meta-analysis and consistent results were observed for
subgroup and sensitivity analyses. However, an analysis of parental occupational paint exposures pooled
from 13 case–controls studies revealed no increased
risk for childhood ALL or AML.89

330

Carlos-Wallace et al.90 conducted meta-analyses to
evaluate the risk of childhood leukemia associated with
parental occupational exposure to benzene and solvents,
as well as household use of products containing benzene
and solvents. Maternal occupational exposure to benzene was associated with increased risk of childhood
leukemia, yielding a summary relative risk of 1.71 (95%
CI: 0.91─3.24). Use of household products containing
benzene, aromatic hydrocarbons, solvents, or petroleum, was also associated with childhood leukemia
risk, with a summary relative risk of 1.67 (95% CI:
1.01─2.78). The above associations were stronger for
AML than for ALL and strongest for women who were
exposed during pregnancy.
The California Childhood Leukemia Study examined
the relationship between occupational exposure to
organic solvents and the risk of childhood leukemia.91
Occupational histories were obtained via interview
using 19 task-based job modules from parents of
children with ALL (N ¼ 670), children with AML
(N ¼ 104), and healthy control children (N ¼ 1021).
Logistic regressions were used to estimate odds ratios
adjusted for socio-demographic factors. Among children with non-Latino fathers, none of the exposures
evaluated were associated with risks of ALL and AML.
In contrast, exposure to any organic solvents in Latino
fathers was associated with an increased risk of childhood ALL (OR ¼ 1.48, 95% CI: 1.01─2.16); in
multivariable analyses and the odds ratio for exposure
to chlorinated hydrocarbons, in particular, was elevated
(OR ¼ 2.28, 95% CI: 0.97─5.37), whereas risk
estimates for other exposures—aromatic hydrocarbons,
glycol ethers, and other hydrocarbon mixtures—were
close to one. One common industrial chlorinated hydrocarbon, which might be the causal agent underlying the
observed association, is trichloroethylene (TCE). As
with other analyses that rely on interview-derived
exposure data, the specific chlorinated hydrocarbon or
mixture of chlorinated hydrocarbons responsible for the
associations observed in these studies is not known. A
large majority of mothers were not exposed to chemicals at work, and no associations were reported for risk
of childhood ALL and AML.

Traffic-Related Air Pollution and Childhood
Leukemia
Three recent meta-analyses independently demonstrated an association between childhood leukemia and
postnatal traffic exposure.90,92,93 Boothe et al.92

Curr Probl PediatrAdolesc Health Care, October 2016

 combined findings from seven studies to estimate that
childhood leukemia was positively associated with
postnatal traffic density near the residence (OR ¼
1.53, 95% CI: 1.12─2.10). There was no association
between childhood leukemia and prenatal traffic
exposures.
Filippini et al.93 combined 6 ecologic and 20 case–
control studies that had assessed home exposure to
traffic-related pollution by estimating traffic density in
the neighboring roads, by estimating the vicinity to gas
stations, or by modeling ambient nitrogen dioxide and
benzene concentrations with GIS. Among high-quality
studies that used traffic density to assign exposure, no
significant increase in childhood leukemia risk was
observed, even in the highest exposure category (OR ¼
1.07, 95% CI: 0.93─1.24). Among studies that used
NO2 estimates as the measure of exposure, there was a
marginally significant association with childhood leukemia (OR ¼ 1.21, 95% CI: 0.97─1.52), which was
stronger for ALL (OR ¼ 1.21, 95% CI: 1.04─1.41)
than for AML (OR ¼ 1.06, 95% CI: 0.51─2.21).
Among studies that used benzene estimates as the
measure of exposure, there was a stronger association
with AML (OR ¼ 2.28, 95% CI: 1.09─4.75) than ALL
(OR ¼ 1.09, 95% CI: 0.67─1.77). Observed associations between childhood leukemia and exposure to
traffic pollution were generally stronger for exposures
in the postnatal period compared to the prenatal period.
Carlos-Wallace et al.90 conducted meta-analyses to
evaluate the risk of childhood leukemia associated with
traffic density and traffic-related air pollution. Both
measures of traffic were associated with childhood
leukemia; the summary relative risk was 1.48 (95% CI:
1.10─1.99). The relationship was stronger for AML
than for ALL and stronger in studies that involved
detailed models of traffic pollution than in those that
estimated traffic density.
The findings from these three meta-analyses support
a link between ambient exposure to traffic pollution
and childhood leukemia risk, particularly due to
benzene.

Benzene as the Potential Causal Agent
Once again, most of the studies that have evaluated
the risk of childhood leukemia associated with paint,
petroleum solvents, or traffic density are based on
parent interviews. As such, it is challenging to identify
the specific causal agent underlying the observed
associations in these existing studies. Benzene is one
potential culprit as it is a well-known leukemogen that

Curr Probl PediatrAdolesc Health Care, October 2016

is present in oil-based paints, petroleum solvents used
in occupational and residential settings (e.g., in paint
thinner), and vehicle exhaust. However, given that
childhood leukemia subtype analyses have yielded
disparate results depending on the specific exposure
measure that was used in the meta/pooled analysis, it is
also possible that this loose grouping of chemical
exposures actually comprises several distinct chemical
risk factors for leukemia. For example, in addition to
benzene, other chemicals, such as 1,3-butadiane,
styrene, xylene, and polycyclic aromatic hydrocarbons
(PAHs) might also play a role in some of these
observed relationships. The recent development of a
mouse model for childhood leukemia will enable
investigators to evaluate the role of specific chemical
risk factors in the etiology of childhood leukemia.

Summary of Existing Research on Paint,
Solvents, Traffic and Childhood Leukemia
Pooled analyses of data from studies around the
world show a relationship between home exposure to
paint and ALL risk. These findings were indirectly
supported by a variety of systematic reviews and metaanalyses, which showed evidence of relationships
between childhood leukemia and exposure to petroleum solvents (at home and at the mother’s work) and
traffic (as measured by surrounding traffic density and
modeled concentrations of traffic-related air pollutants). Several possible chemical risk factors may
explain the observed association, including the wellknown leukemogen, benzene.

Persistent Organic Pollutants
Epidemiological studies of childhood leukemia that
use environmental or biological samples are relatively
scarce. A series of analyses conducted as part of the
California Childhood Leukemia Study have evaluated
the relationship between childhood ALL and chemical
concentrations in settled dust collected from participating homes as surrogates for chemical exposures.

Polycyclic Aromatic Hydrocarbons (PAHs) and
Childhood Leukemia
The California Childhood Leukemia Study evaluated
the relationship between childhood ALL and PAH
concentrations in settled dust.94 As part of this
population-based case–control study, dust samples
were collected from 251 ALL cases and 306 birthcertificate controls using a high-volume small-surface

331

 sampler (N ¼ 185 cases, 212 controls) or directly from
participants' household vacuum cleaner bags (N ¼ 66
cases, 94 controls). Logistic regression was used to
evaluate the relationship between ALL risk and logtransformed concentrations of 9 individual PAHs, the
summed PAHs, and the summed PAHs weighted by
their carcinogenic potency (the toxic equivalence)
while adjusting for demographic characteristics and
duration between diagnosis/reference date and dust
collection. Among participants with dust samples
collected by high-volume small-surface sampler, risk
of ALL was not associated with increasing concentration of any PAHs. However, among participants
with dust samples collected by participants' vacuum
cleaners, a positive association was observed between
ALL risk and increasing concentrations of benzo[a]
pyrene (OR ¼ 1.42, 95% CI: 0.95─2.12), dibenzo[a,h]
anthracene (OR ¼ 1.98, 95% CI: 1.11─3.55), benzo[k]
fluoranthene (OR ¼ 1.71, 95% CI: 0.91─3.22), indeno
[1,2,3-cd]pyrene (OR ¼ 1.81, 95% CI: 1.04─3.16),
and the toxic equivalents (OR ¼ 2.35, 95% CI:
1.18─4.69). The observed association between ALL
risk and PAH concentrations among participants with
dust collected by vacuum suggests that PAH exposure
may increase the risk of childhood ALL; however,
understanding the reasons for the different results by
sample type requires further scrutiny.
PAHs are byproducts of incomplete combustion that
are found at high concentrations in cigarette smoke and
vehicle exhaust. PAHs, especially dibenzo[a,h]anthracene, are potent human carcinogens. As such, it is
possible that one PAH or a combination of PAHs may
be the causal agent(s) responsible for the observed
associations between parental smoking and childhood
leukemia or between traffic density and childhood
leukemia.

Polychlorinated Biphenyls (PCBs) and
Childhood Leukemia
The California Childhood Leukemia Study has also
evaluated the relationship between childhood ALL and
levels of six PCBs—industrial chemicals that are
probable human carcinogens and immune system
disruptors—in settled dust.81 The PCB analysis
included 184 ALL cases 0–7 years of age and 212
birth certificate controls matched to cases by birth date,
sex, race, and Latino ethnicity. Dust samples were
collected from the room where the child spent the most
time using the high-volume small-surface sampler. In

332

homes where any PCB was detected in the dust, there
was a 2-fold increased risk of ALL (OR ¼ 1.97, 95%
CI: 1.22─3.17). When considering the sum of the six
PCBs analytes, compared to those in the lowest
quartile of Σ6PCBs, the highest quartile was associated
with about a 3-fold risk of ALL (OR ¼ 2.78, 95% CI:
1.41─5.48). The risk of ALL was positively associated
with increasing concentrations of PCB congeners 118,
138, and 153 in dust. The associations with PCBs were
stronger among non-Latino whites than among Latinos
despite the presence of a similar distribution of PCB
levels among controls in each racial/ethnic groups.

Polybrominated Diphenyl Ethers (PBDEs) and
Childhood Leukemia
Along the same lines, the California Childhood
Leukemia Study evaluated the relationship between
childhood ALL and levels of PBDEs—chemical flame
retardants—in settled dust.95 PBDEs are structural
analogs to PCBs that also cause immune system
perturbations. The PBDE analysis included 167 ALL
cases 0–7 years of age and 214 birth certificate controls
matched on date of birth, sex, and race/ethnicity. Dust
samples were collected from carpets in the room where
the child spent the most time while awake using a highvolume small-surface sampler or by sampling from
participants' household vacuum cleaners. Concentrations of 14 PBDE congeners were measured including
constituents of the Penta- (28, 47, 99, 100, 153, 154),
Octa- (183, 196, 197, 203), and Deca-BDEs commercial mixtures (206–209). Odds ratios were calculated
using logistic regression, adjusting for demographics,
income, year of dust collection, and sampling method.
Comparing the highest to lowest quartile showed no
association with ALL for summed Penta- (OR ¼ 0.7,
95% CI: 0.4─1.3), Octa- (OR ¼ 1.3, 95% CI: 0.7─2.3),
or Deca-BDEs (OR ¼ 1.0, 95% CI: 0.6─1.8). Comparing homes in the highest tertile to those below the
analytical limit of detection, revealed a significant
positive association with ALL risk for BDE-196 (OR
¼ 2.1, 95% CI: 1.1─3.8), BDE-203 (OR ¼ 2.0, 95%
CI: 1.1─3.6), BDE-206 (OR ¼ 2.1; 95% CI: 1.1─3.9),
and BDE-207 (OR ¼ 2.0, 95% CI: 1.03─3.8).
Interestingly, the significant associations with ALL
risk observed in this analysis were for minor PBDE
congeners that are found in dust at relatively low
concentrations; whereas the most abundant PBDE
congeners (e.g., BDEs 47, 99, and 209) were not
associated with ALL risk. These low-concentration

Curr Probl PediatrAdolesc Health Care, October 2016

 PBDE congeners were measured with less analytical
precision than their more common analogs, because the
measured values were relatively close to the analytical
limit of detection. In other words, the low-level PBDE
congeners that were associated with ALL risk in this
analysis were the ones measured with the least
precision and, therefore, the ones with the greatest
potential for a spurious finding. Still, there may be a
plausible biological mechanism to explain the inconsistency of the risk estimates between PBDE congeners, as toxic and carcinogenic effects are expected to
differ by congener.48,96 The fact that PCBs and PBDEs
have a similar chemical structure lends credence to the
hypothesis that these chemicals may be acting via the
same mechanism of action, for example, immune
dysregulation.

Strengths of Existing Research on Persistent
Organic Pollutants and Childhood Leukemia
Unlike much of the research described in this section,
one strength of the existing research on persistent
organic pollutants and childhood leukemia is the use of
objective environmental measurements to assess chemical exposures, rather than interviews. Not only does
this reduce the likelihood of recall bias, but it also
allows investigators to identify specific chemicals as
causal agents in the etiology of leukemia. Recognizing
causal agents can be the first step in planning a
successful intervention that will reduce future incidence of leukemia.

Limitations of Existing Research on Persistent
Organic Pollutants and Childhood Leukemia
The relative stability of persistent organic pollutants
in settled dust allows for exposure measurements that
have limited temporal variability. This stability is a
benefit of the sampling technique, because the resulting measurements represent long-term average levels
of chemical contamination, which can be useful
when trying to estimate past chemical exposures.
However, this stability also obscures short-term
fluctuations in chemical levels that might be important
to investigators who want to identify critical windows
of a child’s development when chemical exposures
are especially harmful. That is, measuring chemical
levels in settled dust will not enable a researcher
to distinguish the leukemogenic effect of prenatal vs.
postnatal chemical exposures, for example.

Curr Probl PediatrAdolesc Health Care, October 2016

Moreover, children are exposed to chemicals through
several other pathways in addition to the ingestion of
contaminated settled dust. In particular, the ingestion
of settled dust plays a relatively minor role in children’s exposure to PCBs compared to the ingestion of
PCB-contaminated food. This is owing to the bioaccumulative nature of PCBs and the fact that they have
been banned from production in the U.S. for several
decades. Indeed, it is a testament to the persistence of
these hazardous chemicals that they can still be so
readily measured inside homes. In these analyses, the
design of the California Childhood Leukemia Study
did not account for chemical exposures received via
the inhalation of contaminated air, the ingestion of
contaminated food, or any other pathways. As such,
the dust measurements are limited surrogates for total
chemical exposure.
To date, the California Childhood Leukemia Study has
only utilized dust samples to identify risk factors for
ALL, the most common leukemia subtype. There is an
insufficient number participants with dust samples available to analyze the risk of AML or to stratify by
cytogenetic subtype.
Also of some concern is the fact that the subset of
California Childhood Leukemia Study participants
who were eligible for and consented to dust sampling
had higher socioeconomic status than the full California Childhood Leukemia Study population and its
underlying source population, the State of California.
As such, the findings from these studies may not be
representative of the general population. Fortunately,
data from the California Childhood Leukemia Study
indicates that both the case families and the control
families participating in dust sampling had elevated
socioeconomic status, which limits the risk of differential selection bias.
Perhaps the most important limitation of these
studies is that they have not been substantiated by
independent investigators. Whereas many members of
Childhood Leukemia International Consortium and
other studies have collected interview data about
pesticides, smoking, and paint; very few have measured chemicals in environmental samples. As such,
there are no meta-analyses or pooled analyses published showing the risk of ALL associated with
exposure to persistent organic pollutants, as there
have been previously for the other, more well-studied,
ALL risk factors that were discussed above.

333

 Summary of Existing Research on Persistent
Organic Pollutants and Childhood Leukemia

Three novel findings from the California Childhood
Leukemia Study suggest that home exposures to
persistent organic pollutants, such as PAHs, PCBs,
and PBDEs, are associated with an increased risk of
ALL. Future studies should attempt to interrogate these
associations to replicate or refute their veracity.

Radiation
In utero exposure to low-dose radiation delivered
from medical x-rays is one of the few widelyrecognized risk factors for childhood leukemia.97
While the prevalence of fetal exposure to x-rays in
utero has decreased markedly following radiation
protection standards, the use of medical imaging
procedures, including computerized tomography (CT)
scans,98 has increased drastically during the past 30
years. In fact, CT scans are now the largest medical
sources of radiation in economically developed countries.99 In addition, CT scans deliver an effective dose
of radiation that is up to several hundred times stronger
than conventional x-rays (depending on the target
organ), which has led to major increases in the per
capita radiation dose from medical sources (up 600%
in the US since 1980).99 The carcinogenic effects of
CT scans have not been established, but exposures to
children are especially concerning because they are
more sensitive to radiation-induced cell damage.97
Findings on children’s postnatal exposure to lowdose medical radiation and the risk of childhood
leukemia are inconsistent, with modest positive associations reported in some studies, but not all.97,99 Risk
prediction models have anticipated increased risks of
childhood leukemia following CT scans, but these
models were criticized for extrapolating from the
effects of much higher levels of radiation that were
observed in the Life Span Study of atomic-bomb
survivors.100–102 Only one case–control study to date
has published results on self-reported history of CT
scans showing no increased risk of childhood ALL,
based on small numbers of exposed children.103
Recent cohort studies with access to medical data in
Europe,101,104–106 Australia,107 and the US,102 have
reported small to moderate increases in the risk of
leukemia in children exposed to CT scans; findings,
however, were based on small number of excess cases
ranging from 6 to 74. Pearce et al.106 conducted a
retrospective cohort study of 178,604 UK children

334

and young adults with CT scans from 1985 to 2002.
Patients were followed up through 2008 and linked
with 74 leukemia diagnoses and 135 brain cancer
diagnoses. A cumulative dose of 50 milligray was
estimated to triple the risk of childhood leukemia
within 10 years of the first CT scan; likewise, a
cumulative dose of 60 milligray tripled the risk of
brain cancer.106 The main criticism of the study was
the lack of an unexposed control group. Other cohort
studies are underway108 including a pooled European
study (EPI-CT)104 of about one million subjects (age
0–21 years). Although the number of excess childhood leukemia cases is still likely to be low (estimated
to be approximately 60–100), this study will obtain
more precise exposure information than previously
possible, including individual doses of radiation for
each organ.
Confounding by indication (reverse causation) is also
a concern in studies of the relationship between medical
radiation and childhood leukemia. In a French cohort
study, the analyses accounting for child’s cancerpredisposing factors (mostly rare genetic conditions in
less than 2% of children) showed a modest impact on
the risk of childhood leukemia associated with CT
scans.109 This was consistent with a case–control study
of prenatal x-rays showing an overall 13% reduction in
relative risk of childhood cancers, after adjusting for
maternal illnesses during pregnancy.110 Others have
argued that cancer-predisposing conditions may instead
act as effect modifiers.111–113 Overall, despite methodological challenges, epidemiologic studies so far mostly
support an association between postnatal exposure to
CT scans and childhood leukemia, while results for
lower dose x-rays are less consistent.
Pooled analyses reported that exposure to high levels
of extremely low-frequency-electromagnetic fields
over 0.3 or 0.4 mT is associated with an increased risk
of childhood leukemia,114,115 which was the basis to
classify extremely low-frequency-electromagnetic
fields as possibly carcinogenic to humans (Group
2B).116 Methodological issues including possible confounding, selection bias, and measurement errors have
been put forward as an alternate explanation for the
observed association, and animal studies are ongoing
to identify possible biological mechanisms.117,118 If
the association between extremely low-frequencyelectromagnetic fields and childhood leukemia is
causal, the overall population attributable risk has
been estimated to be 1.9% (1–4% depending on the
countries).117,118

Curr Probl PediatrAdolesc Health Care, October 2016

 Future Steps in Identifying Environmental
Causes of Childhood Leukemia

examining relationships between exposure and disease
that have not been considered, to date.

A multitude of studies on the environmental causes of
childhood leukemia, including those conducted by our
Dietary Risk Factors for Childhood
research team and others that are described above, have
Leukemia
led to progress in identifying the etiological roles of
environmental exposures in childhood leukemia. HowIntroduction
ever, much work remains to be done. As discussed,
Diet has been linked to several cancers in adults and
several of the observed associations between chemical
children.119 These observations may be explained by
exposures and childhood leukemia are derived from
various biological mechanisms such as exposure to
interview data, an approach which can limit an invesdietary mutagens, mutagenesis due to nutrient defitigator’s ability to identify specific chemical risk factors
ciencies, and intake of micronutrients and other dietary
for childhood leukemia. As such one goal of future
components that may protect against the development
research will be to understand which specific causal
of cancer by supporting cellular integrity, reducing
agents underlie previously observed associations. For
inflammation and improving immune response.120–122
example, in collaboration with the National Cancer
A growing body of research also suggests that the
Institute, the California Childhood Leukemia Study is
influence of particular nutrients on epigenetic procconducting a study to measure glyophosate in particesses may contribute to carcinogenesis.123
ipating homes. This study will follow-up on a previThe role of the intrauterine environment is crucial in
ously observed association between reported residential
determining risk of disease later in life, and the
herbicide use and childhood ALL. The California
“developmental origins of health and disease” hypothChildhood Leukemia Study has observed associations
esis posits that nutritional and
between childhood leukemia risk
environmental exposures in
and levels of certain PCBs,
PBDEs, PAHs, and herbicides Diet quality is a comprehensive utero permanently alter gene
in settled dust. These unique
measure of nutritional status, expression and the physical
development of the fetus
findings need to be confirmed
and healthy maternal diet at the through a process called “proin independent studies, preferatime of conception and during gramming.”124,125 This hypothbly in ones that use a distinct
method for assessing children’s pregnancy is linked to a reduced esis is likely central to the
exposure to chemicals.
risk of leukemia in the offspring. development of childhood leukemia, as well. Indeed, materAs an alternative approach for
nal nutrition during pregnancy
identifying the causal agents in
may be related to both the occurrence of primary and
childhood leukemia, the Center for Integrative Research
secondary oncogenic events that lead to leukemia in
on Childhood Leukemia and the Environment will
the offspring. Subsequently, a child’s diet during the
employ a mouse model of ALL with t(12;21) to test
early years of life is likely to also play an important
the carcinogenic potential of a variety of chemicals,
role in leukemogenesis. Breastfeeding has been conincluding, for example, compounds that comprise the
sistently found to reduce leukemia risk in children, via
broadly-defined groups of pesticides, solvents, or traffic
intake of essential nutrients not readily available in
pollutants. The mouse model will also be helpful in
newborns and due to the resulting beneficial effects of
identifying mechanisms of action for the chemical risk
immune system priming. In contrast, the impact of diet
factors of childhood leukemia. In fact, this is a central
—both the mother’s and the child’s—on childhood
goal of the Center, as immunological factors and
leukemia has been less studied.
epigenetics will both be interrogated as possible cancer
Here we provide an overview of the current knowlmechanisms. Moreover, state-of-the-science untargeted
edge about the associations between diet and childhood
analytical approaches will allow investigators to identify
leukemia.
novel chemical risk factors for childhood leukemia, by

Curr Probl PediatrAdolesc Health Care, October 2016

335

 Maternal Diet

demonstrated to influence DNA
methylation in children.131
Reduced risks of childhood
Epidemiologic studies examfolic acid supplemenleukemia are associated with Maternal
ining the relationship between
tation also protects against some
adequate folate before
maternal diet during pregnancy
childhood diseases, such as neuconception and early in
and the risk of childhood leural tube defects.132 High folate
kemia, have been mostly conintake has been associated with
pregnancy, breastfeeding,
ducted in developed countries.
of breast133 and
and early exposure to routine reduced risk
134
Exposures of interest varied to
colorectal
cancer
and
childhood infections.
include food groups (e.g., fruits,
increased risk of prostate canvegetables, proteins), micronucer135 among adults, whereas
trients from dietary and supplement sources (e.g.,
meta-analyses have indicated no effect of folic acid
folate and vitamins), food sources of topoisomerase
supplementation on adult cancer incidence.135–137
II inhibitors (known risk factors for treatment-related
Maternal intake of folate and other nutrients involved
leukemia), consumption of coffee, tea, and alcohol,
in one-carbon metabolism may influence childhood
and holistic measures of a healthy diet.
leukemia risk due to the importance of these nutrients
for DNA synthesis and repair, chromosomal integrity,
and epigenetic processes that determine gene expresFood Groups
sion and influence cancer risk, including histone
Fruits and vegetables contain a variety of vitamins and
modification, levels of non-coding RNAs, and DNA
minerals that have anti-cancer, anti-proliferative, and antimethylation.123,130
123
inflammatory effects,
and the consumption of fruits
Practices of prenatal folic acid supplementation have
and vegetables has been associated with a reduced risk of
varied substantially across countries and over time, and
various types of cancer.119 Some food groups, in
individual epidemiologic studies that have evaluated
particular fruits and vegetables, have been associated
the relationship between maternal folate intake through
with childhood leukemia risk in several studies. Research
supplements and the risk of childhood ALL have
has found statistically significant negative associations
yielded mixed findings. However, a recent Childhood
between maternal consumption of fruits and vegetables
Leukemia International Consortium analysis, the larg126–128
and risk of childhood ALL,
and one study found
est to date, pooled original interview data from 12
significant or near-significant inverse linear trends
studies (representing 6963 ALL, 585 AML, and
between the risk of infant leukemia and maternal con11,635 healthy controls) to observe that folic acid
sumption of fresh fruits and vegetables, especially for
supplementation was protective against childhood
129
specific ALL subtypes.
Negative associations have
leukemia.138 Folic acid taken before conception or
also been observed for childhood leukemia and maternal
during pregnancy—with or without intake of other
consumption of other food groups, specifically protein
vitamins—was associated with a reduced risk of
sources such as fish and seafood128 as well as beans and
childhood ALL (OR ¼ 0.80, 95% CI: 0.71─0.89)
126,127
One study demonstrated an increased risk of
beef.
and AML (OR ¼ 0.68, 95% CI: 0.48─0.96), after
ALL with increased maternal consumption of meat or
adjustment for study center.138 Interestingly, the
meat products and sugars or sirups.128
reduced risks were seen only among women with
low and medium education levels—a surrogate marker
Folate and Other One-Carbon Metabolism
for low socio-demographic status and possibly for a
low-quality (low-folate) diets—suggesting that women
Nutrients
who enter the peri-conception period with inadequate
The one-carbon metabolism cycle is critical for the
folate/vitamin levels would benefit the most from
synthesis of DNA and RNA, the conversion of
prenatal folate and vitamin supplementation.
homocysteine to methionine, and the formation of
Only a small number of studies, however, have
s-adenosylmethionine (SAM), the primary methyl
130
examined the role of folate intake from food or the
donor for DNA, RNA, proteins, and lipids.
Folate
role of any other nutrients involved in the one-carbon
and other B vitamins are important cofactors in the
metabolism cycle in the development of childhood
one-carbon metabolism cycle,130 and maternal folic
leukemia. In addition, there has been only limited
acid supplementation during pregnancy has been

336

Curr Probl PediatrAdolesc Health Care, October 2016

 consideration of the role of maternal diet on risk of
AML. A case–control study in Australia found some
evidence that higher dietary intakes of folate and B12
from food in the last 6 months of pregnancy were
associated with a decreased risk of ALL, whereas
higher dietary intakes of vitamin B6 were unexpectedly
associated with an increased risk of ALL.139 Previous
analyses from a subset of the California Childhood
Leukemia Study population examined the total intake
of folate, vitamin B6 or vitamin B12 from both diet and
supplements, and found no associations with
ALL.126,127,140 However, in a recent and expanded
California Childhood Leukemia Study analysis (681
ALL cases, 103 AML cases, and 1076 controls) that
employed principal components analysis to account for
the high correlations between nutrients, higher maternal intake of one-carbon metabolism nutrients from
food and supplements was associated with a reduced
risk of ALL (OR ¼ 0.91, 95% CI: 0.84─0.99) and
possibly AML (OR ¼ 0.83, 95% CI: 0.66─1.04).141
The association of ALL with nutrient intake exclusively from food (excluding supplements) was similar
to the association of total nutrient intake from food and
supplements, both in the study population overall and
within racial/ethnic groups. However, high intake of B
vitamins from supplements (versus none) was associated with a statistically significant reduced risk of ALL
in children of Latinas (OR ¼ 0.36 95% CI: 0.17─0.74),
but not in children of non-Latina white women (OR ¼
0.76, 95% CI: 0.50─1.16) or Asian women (OR ¼
1.51, 95% CI: 0.47─4.89).141 Racial/ethnic differences
in nutrient intake and in genetic polymorphisms in the
one-carbon (folate) pathway may partly explain the
observed difference in leukemia risk.
In a biomarker analysis conducted as part of the
California Childhood Leukemia Study, folate concentration measured in neonatal blood samples were
similar between children with leukemia (313 ALL
cases and 44 AML cases) and 405 controls, suggesting
that folate levels at the end of pregnancy did not affect
leukemia risk.63 The study was conducted in California
where most pregnant women used prenatal vitamin
supplementation, therefore limiting the ability to detect
an association. Moreover, late pregnancy may not be
the period of a child’s development during which a
beneficial effect of folic acid and multivitamins, is
critical to leukemia risk. However, this explanation
would not be consistent with observations from the
large pooled analyses of the Childhood Leukemia
International Consortium that showed reduced risks

Curr Probl PediatrAdolesc Health Care, October 2016

of ALL and AML associated with self-reported supplementation during each trimester of the
pregnancy.138
Newborn and child serum-nutrient levels are influenced by many factors, including maternal and child
genetic polymorphisms.142 Many studies have found
significant associations between single nucleotide
polymorphisms (SNPs) in folate-related genes, such
as MTHFR variants, and childhood leukemia; but,
there are inconsistencies in the specific SNPs that have
been identified across studies.140,143–147 A study examining the largest number of genes and SNPs in the
folate pathway found statistically significant associations between SNPs in genes CBS, MTRR, and TYMS/
ENOFS (but not MTHFR) and childhood ALL.140
Levels of maternal folate intake during pregnancy,
and child’s Latino ethnicity were found to modify
some of these associations.140 Other studies, however,
did not report such interactions.144,148,149 Key findings
regarding folate intake and other vitamins are summarized in Table 2.

Topoisomerase II Inhibitors
The use of topoisomerase II inhibitors (a nuclear
enzyme involved in DNA replication) in cancer
chemotherapy has long been known to be associated
with common MLL gene translocations that are characteristic of therapy-related AML.150 Consequently, it
was hypothesized that topoisomerase inhibitors may be
involved in the etiology of infant leukemia, because
this subtype commonly involves the same MLL gene
translocation that has been identified in these therapyrelated leukemias.151 Aside from chemotherapeutic
agents, topoisomerase inhibitors are found in diverse
sources, including herbal medicines, quinolone antibiotics, certain types of laxatives, and pesticides.152
Certain dietary sources also contain topoisomerase
inhibitors including, but not limited to, tea, coffee,
wine, and certain fruits and vegetables.152 Recent
laboratory studies, however, suggest that tea, wine,
and cocoa do not inhibit topoisomerase activity in vitro
and thus are unlikely to increase the risk of MLL
translocations.153
A small exploratory study examining maternal exposure to topoisomerase inhibitors during pregnancy and
the risk of childhood leukemia found an increased risk
of AML with increasing topoisomerase II inhibitor
exposure (OR ¼ 10.2; 95% CI: 1.1─96.4; N ¼ 29 cases
for high exposure), but no increased risk for ALL

337

 TABLE 2. Association between folate and other vitamins and risk of childhood leukemia: selected case–control studies

Population

No. of cases Source of vitamins

Period of interest OR (95% CI)

Childhood Leukemia
6963 ALL
International Consortium.138 585 AML

Maternal supplement

Prenatal

Folate only
ALL: OR ¼ 0.80 (0.78, 0.92)
AML: OR ¼ 0.68 (0.48–0.96)
Any vitamins
ALL: OR ¼ 0.85 (0.80, 0.94)
AML: OR ¼ 0.92 (0.75–1.14)

Australia.139

Maternal diet

Pregnancy

Folate
ORQ2 ¼ 0.68 (0.44,
ORQ3 ¼ 0.58 (0.37,
ORQ4 ¼ 0.44 (0.27,
ORQ5 ¼ 0.70 (0.44,
p-trend ¼ 0.05
B12 vitamin
ORQ2 ¼ 0.72 (0.47,
ORQ3 ¼ 0.79 (0.71,
ORQ4 ¼ 0.85 (0.71,
ORQ5 ¼ 0.49 (0.71,
p-trend ¼ 0.02
B6 vitamin
ORQ2 ¼ 1.04 (0.67,
ORQ3 ¼ 1.15 (0.74,
ORQ4 ¼ 1.28 (0.82,
ORQ5 ¼ 1.60 (1.02,
p-trend ¼ 0.03

333 ALL

1.06)
0.91)
0.71)
1.12)

1.10)
1.21)
1.31)
0.77)

1.62)
1.81)
2.00)
2.51)

California.141

681 ALL
103 AML

Maternal diet & supplements Peri-conception

One-carbon metabolism
nutrients (i.e., folate, B vitamins)
ALL: ORPC ¼ 0.91 (0.84, 0.99)
AML: ORPC ¼ 0.91 (0.66, 1.04)

California.63

317ALL
44 AML

Blood levels

Hemoglobin concentration of folate at birth
No difference in between ALL, AML, and controls

Neonatal

ALL ¼ acute lymphoblastic leukemia; AML ¼ acute myeloblastic leukemia; Q ¼ quintile; PC ¼ principal component for one-carbon metabolism
nutrients.

(OR ¼ 1.1; 95% CI: 0.5─2.3; N ¼ 82).151 Subsequent
studies confirmed a positive relationship between
maternal dietary intake of topoisomerase II inhibitors
and risk of infant AML with a MLL gene translocation,
but have found no association between dietary intake
of topoisomerase II inhibitors and risk of other
subtypes of infant AML or any type of ALL.126,129

Coffee, Cola, and Tea
An early case–control study of 280 cases and 288
hospitalized controls found an increased risk of ALL
among children of mothers reporting coffee consumption more than four cups a day during pregnancy
(OR ¼ 2.4; 95% CI: 1.3─4.7 for 4–8 cups; and
OR ¼ 3.1, 95% CI: 1.0─9.5 for 48 cups), with
similar ORs observed for acute non-lymphoblastic
leukemia that did not reach statistical significance.154
Subsequent case–control studies have found maternal

338

consumption of coffee during pregnancy to be associated with an increased risk of ALL, AML, and
possibly infant leukemia, while others have failed to
find an association, as summarized in a recent metaanalysis.155 There is some evidence from these studies
that the increased risk of leukemia with maternal
coffee consumption may be more pronounced among
children born to non-smoking mothers.156,157 Similarly, cola-based drinks have been associated with
increased risk of childhood ALL (summary OR ¼
1.31, 95% CI: 1.09─2.47), while reduced risks have
been reported with maternal tea consumption during
pregnancy (summary OR ¼ 0.85, 95% CI:
0.75─0.97).155 A general limitation of those studies
is the lack of information on the type of drinks (e.g.,
caffeinated or not, green or black tea), which contain
different nutrients and other compounds with either
anti- or pro-carcinogenetic properties.

Curr Probl PediatrAdolesc Health Care, October 2016

 Alcohol

also been associated with birth outcomes, such as
Maternal alcohol intake before or during pregnancy
neural tube and congenital heart defects.168
In a recent study169 overall maternal diet quality, as
has been hypothesized to influence childhood leukemia
summarized by a diet quality index using a modified
risk by altering immune function or by teratogenic
version of the 2010 Healthy Eating Index, was
effects on cell differentiation.158 Alcohol is also an
associated with a reduced risk of childhood ALL
antagonist to folate metabolism and methionine syn(OR for each five point increase on the index ¼
thase and may modify DNA methylation status in
0.88, 95% CI: 0.78─0.98). A more pronounced reducinteraction with folate levels.159 A systematic review
tion in risk was observed among younger children and
and meta-analysis of 21 case–control studies found that
children of women who did not use vitamin supplealcohol intake during pregnancy was associated with
ments before pregnancy. There was a similar reduced
AML (summary OR ¼ 1.56, 95% CI: 1.13─2.15
risk of AML with increasing
produced from 9 studies
maternal diet quality score,
comprising 731 cases) but
not with ALL (summary OR Breastfeeding for six months or although this assosciation was not
statistically significant (OR ¼
¼ 1.10, 95% CI: 0.93─1.29
longer, is associated with a
0.76, 95% CI: 0.52─1.11). No
produced from 11 studies
reduced risk of childhood
single diet quality index compocomprising 5108 cases).159
leukemia, whereas early
nent (i.e., food group or nutrient)
Heterogeneity between studintroduction to milk formula
appeared to account for the results,
ies was explained in part by
suggesting that the quality of the
some studies160,161 that demmay increase leukemia risk.
whole diet and the cumulative
onstrated a negative associaeffects of many dietary components may be important
tion of childhood leukemia with maternal alcohol
in influencing childhood leukemia risk.169
consumption during pregnancy. Repeating the metaanalysis by subgroup of alcohol indicated an increased
risk of AML associated with reported consumption of
Paternal Diet
wine but not beer or spirits, providing some additional
159
support for the topoisomerase II hypothesis.
For
In contrast to maternal diet, very few studies have
ALL, there was an association between maternal
examined the relationship between paternal diet before
consumption of spirits during pregnancy, but not beer
conception and childhood leukemia. One study sugor wine.159 One subsequent study supported the findgested that the risk of childhood leukemia increased
with increasing paternal consumption of hot dogs
ing of an increased risk of AML with maternal alcohol
consumption during pregnancy162 while another did
(sources of carcinogenic compounds from N-nitroso
precursors).170 Also, there is no strong indication that
not find an association156; neither found a relationship
between maternal alcohol consumption and ALL. In
paternal intake of folate and other vitamins from diet
contrast, two other recent studies found that maternal
and supplements before the child’s conception reduced
consumption of alcohol during pregnancy was assothe risk of leukemia in the offspring.171,172
163
ciated with a decreased risk of ALL
and of infant
leukemia.164

Child’s Diet

Healthy Diet Index
In contrast to studies that have evaluated the role of a
limited number of specific nutrients or food components, measures of overall diet quality may better
represent nutritional status and the complex biological
interaction of multiple nutrients.165 Diet quality indices
are often positively correlated with biological markers
of micronutrient intake and have been associated with
reduced risk of all-cause mortality, including cancer
risk.166,167 Maternal dietary patterns and quality have

Curr Probl PediatrAdolesc Health Care, October 2016

As mentioned earlier, breastfeeding and duration of
breastfeeding (6 months of more) have been associated
with the risk of childhood ALL, as summarized in
recent pooled173 and meta-analyses174 conducted by
the Childhood Leukemia International Consortium.
Besides breastfeeding, little is known about the influence of child’s early diet. Feeding with formula as
early as 14 days after birth,175 alone or in combination
with breast milk, was associated with an increased
risk of childhood ALL and dose–response relationships were reported for the duration of formula

339

 feeding.175,176 These studies contrasted previous null
recognized that health care providers should act as
findings.177 Infants and children fed with milk formula
resources for information on environmental health for
have been found to have higher serum levels of IGF-1
their patients; unfortunately, U.S. medical education is
than those breastfed, and fetal growth pathway has
largely void of training in Environmental Medicine.181
176
been hypothesized to play a role in leukemogenesis.
Pediatricians and other providers report low selfAssociations between a child’s consumption of various
efficacy in basic skills of Environmental Medicine
food groups and the risk for childhood ALL or for all
such as taking a history of environmental expoleukemias combined are inconsistent, especially
sures.10,182,183 A survey of members of the American
regarding the consumption of fruits and fruit juice, as
College of Obstetrics and Gynecology reported that
well as the consumption of meat.170,175,177–179 Older
although three quarters of those surveyed agreed that
counseling patients could reduce
age at introduction to solid food
exposure to environmental hazin general,176 and possibly
ards, fewer than 20% routinely
older age at introduction to
Increased risks of childhood
vegetables in particular,175 was leukemia have been consistently discussed environmental exposures—even known developassociated with an increased
associated with exposures to mental toxicants—with their
risk of childhood ALL, while
pesticides, tobacco smoke,
patients. Despite a lack of traina reduced risk was reported for
ing in environmental health,
late introduction to eggs.175
solvents, and traffic-related
clinicians report a high interest
Child’s consumption of colapollution.
in learning more about current
based drinks does not appear
environmental health research as it may apply to their
to be associated with leukemia, in contrast to maternal
practice.10,182
consumption during pregnancy.155
Environmental Health Literacy is an evolving discipline that “combines key principles and procedural
Conclusions
elements from the fields of risk communication, health
literacy, environmental health sciences, communicaMost of the evidence to date supports the role of
tions' research and safety culture.”184 A basic level of
prenatal folate supplementation, alone or with other
environmental health literacy will help clinicians to
vitamins, in reducing childhood leukemia risk. Apart
have a sense of self-efficacy about environmental
from the possible beneficial intake of fruits and
health
and to fulfill roles as alert clinicians, educators,
vegetables both during pregnancy and in the early
and advocates for children’s health.
years of life, studies have led to mixed or isolated
The key studies on environmental risk factors for
findings regarding the potential leukemogenic effect of
childhood
leukemia are rarely published in clinical
other food groups, likely due to small sample sizes and
journals
and
presentations on new environmental
challenges of collecting accurate descriptions of parepidemiologic research are rare at clinical meetings.
ticipants' diets. In addition, there has been relatively
These circumstances require clinicians to make a
limited consideration of the role of maternal diet on
special effort to stay informed about the impact of
risk of AML, a less common subtype than ALL.
the environment on health. Fortunately, many online
Finally, measures of overall diet quality may represent
resources are becoming available to make this easier
nutritional status and the complex biological interac(Text Box 1).
tion of multiple nutrients better than single-nutrient
assessment, and should be used in future studies.

A Clinical Perspective on
Environmental Health Literacy
Nurses, doctors, and other health care providers are
highly respected as sources for health information; as
such they play an important role in translating new
scientific findings to the public.180 It has long been
340

Childhood Leukemia: Is it Time for Primary
Prevention?
As presented in the preceding sections of this article,
there is a large and growing body of literature that
demonstrates the role of environmental agents in
determining the risk for childhood leukemias. This is
in contrast to other pediatric cancers that are more rare
and for which there have been far fewer environmental

Curr Probl PediatrAdolesc Health Care, October 2016

 TEXT BOX 1–Online resources on environmental health literacy
for clinicians
1) Pediatric Environmental Health Toolkit online training. An introduction to the basics of children's
environmental health and approaches to anticipatory guidance. Free continuing medical education
credits (http://www.atsdr.cdc.gov/emes/health_pro
fessionals/pediatrics.html).
2) A Story of Health. Multimedia e-book explores how
environments interact with genes to influence health
across the lifespan; includes a chapter on childhood
leukemia. Free continuing medical education credits
available from the CDC (http://wspehsu.ucsf.edu/forclinical-professionals/training/a-story-of-health-a-multimedia-ebook/).
3) Little Things Matter. Video illustrates key concepts in
children’s environmental health (in multiple languages)
(https://www.youtube.com/channel/UCbl
p9EePwfR8doGm9JbJOjA/videos).
4) Webinars, fact sheets, and other resources are
available from the Pediatric Environmental Health
Specialty Units, a network of experts in reproductive
and children's environmental health (http://www.
pehsu.net/health_professionals.html).

epidemiologic studies conducted. The evidence implicating environmental causes of childhood leukemia
comes from a variety of individual studies worldwide
and includes meta- and pooled analyses from the
Childhood Leukemia International Consortium, as
discussed in the Environmental Risk Factors for
Childhood Leukemia section. Exposures to agents such
as pesticides, tobacco smoke, solvents, and trafficrelated pollution have been consistently linked to an
increased risk of developing childhood leukemia. On
the other hand, intake of vitamins and folate supplementation during the preconception period or pregnancy has been associated with a reduced risk of
childhood leukemia as have breastfeeding and early
exposure to infection, as characterized by attendance at
large daycare and pre-school settings. Despite the fact
that many studies have identified modifiable risk
factors (increased or decreased risk) for childhood
leukemia we are aware of no current prevention
program that specifically addresses childhood leukemia, anywhere in the world. The American Cancer
Society does support programs that discourage tobacco
use and promote healthy nutrition and exercise for
children, with the understanding that addressing these
factors early in life will reduce future cancer burden.1
Why is it that activities to reduce childhood leukemia
have not been incorporated into cancer prevention
programs when potentially modifiable risk factors have

Curr Probl PediatrAdolesc Health Care, October 2016

been identified? Recently, our research group has
suggested that the time is right to develop activities
focused on primary prevention of childhood
leukemia.185,186

What Evidence Is Needed Before We Take
Action?
Historically, there have been many chemicals for
which early warning signs of serious health impacts
have been ignored due to a lack of scientific consensus.
In some cases, protective efforts and corrective actions
were not undertaken until many years or even decades
after the first trouble was spotted.187 For example, long
after initial concerns were raised about DDT, PCBs,
and lead, these chemicals continued to be used in large
quantities. While these chemicals were eventually
banned or restricted in use, in the interim they
continued accumulating in the environment, and left
a long-term legacy of detrimental exposures that were
unnecessary and avoidable.
The European Community recognizes the precautionary principle, which provides justification for
public policy actions in situations of scientific uncertainly in order to reduce health threats. In contrast, in
the U.S., the regulatory framework generally requires
scientific consensus of proof of harm before policy
actions are carried out. The lack of public health
campaigns specifically focused on primary prevention
of childhood leukemia may, in part, result from this
tendency to avoid taking precautionary actions. In
clinical medicine, our mandate to “do no harm” often
dictates that we are wary of false positives, for
example, when interpreting results from a clinical trial.
However, in the context of environmental epidemiology, it is also important to avoid making interpretations
that will yield false negatives, because a failure to
identify a hazard and take preventive actions poses a
threat to the public health.
At this time, despite steadily accumulating evidence
that environmental exposures increase the risk of
childhood leukemia, authoritative bodies, including
the International Agency for Research on Cancer
(IARC), consider only radiation and parents' active
smoking as “causative” factors in the development of
childhood leukemia. The Agency reviews individual
chemicals only periodically and many of the suspected
environmental risk factors for childhood leukemia
have not been reviewed in the last decade; a period

341

 TEXT BOX 2–The range of evidence suggested* as necessary to
validate public health action
1.
2.
3.
4.
5.
6.
7.

Animal studies and toxicologic profiles
Human studies
Systematic structured reviews and meta-analyses
Prevalence of exposure to risk factor
Severe/dreaded outcomes
Risk benefit or cost benefit analysis
Likelihood of unintended consequences of potential
actions
8. Difficulty of sustaining intervention
9. Co-morbidities also associated with exposure
10. Mechanistic basis for health impact
*Adapted with permission from Holman and Buchanan.185

of time during which the environmental epidemiology
of childhood leukemia has developed substantially.
Clinical medicine has embraced an evidence-based
approach and uses systematic reviews (e.g., Cochrane,
GRADE) as the gold standard for determining the
quality of evidence. The highest quality of evidence
(within the evidence-based paradigm) is obtained from
double blinded, randomized trials, but this study design
would be impossible and unethical in the context of
childhood leukemia research on environmental exposures. Prospective cohort studies, which generally are
thought to provide high quality of evidence, are
prohibitively expensive for a disease like childhood
leukemia with an incidence of less than 100 per million
population. Even an international effort to combine
existing mother–child cohorts leads to small numbers
of children diagnosed with leukemia and other cancers.
Studies assessing the role of environmental exposures
in childhood leukemia would almost exclusively be
given a lower quality of evidence rating, given that
they are usually, by necessity, observational studies
with case–control-designs. Adaptations of the systematic review methodology have been developed to
respond to the needs of environmental health and
may allow for more precautionary assessments in the
future.188,189
Primary prevention of cancer includes reducing
exposures to risk factors or changing the underlying
conditions which result in disease. While the CDC has
been exploring opportunities for early life prevention
of child and adult cancers, there are diverse opinions
about whether there is an adequate evidence base for
primary prevention of cancer.185 In a summary of
expert opinion on what evidence should be necessary

342

to support taking action, suggestions range from
animal studies and toxicologic profiles to highquality systematic reviews (Text Box 2).185

Addressing Specific Evidence Needs for
Action
Many of the requirements suggested as a rationale for
undertaking primary prevention programs listed in
Text Box 2 have already been satisfied in the context
of childhood leukemia research. For example, many of
the risk factors identified in recent research are
common, resulting in widespread exposure to the
general population. Moreover, childhood leukemia
could certainly be considered “a severe and dreaded
outcome.” Though childhood leukemia treatment
results in an 80–90% cure rate, the treatment has
long-term health implications for those treated, as well
as profound impacts on the families and the communities who endure it. While most items on the checklist
for taking preventive action (Text Box 2) have been
completed, one notable exception is that, to date,
animal studies of leukemia have been limited, since it
is only recently that animal models of human childhood leukemia have been developed.190
Structured systematic reviews and meta-analyses are
viewed as key elements that support the validity of
findings from individual studies. Multiple metaanalyses have been conducted on the most highlystudied risk factors for childhood leukemia: pesticide
use, tobacco smoke, and traffic-related air pollution. As
noted in the Environmental Risk Factors for Childhood
Leukemia section, the Childhood Leukemia International Consortium has investigated many of these key
risk factors for childhood leukemia using metaanalyses and pooled analysis of original data from
case–control studies. These studies have been carefully
conducted and can be considered systematic reviews of
the epidemiologic literature.
Each factor in this issue that has been associated with
altered risk of childhood leukemia is also associated
with altering the risk of other health outcomes in
children as well as adults. In fact, these same exposures
that are implicated in the risk for childhood leukemia
have substantial documentation of their non-cancer
health impacts, including neurobehavioral deficits and
respiratory disorders. Thus, acting to prevent childhood
leukemia would also reduce the incidence of other
diseases, and vice versa. These potential co-benefits
should lessen any concerns that an error in attribution

Curr Probl PediatrAdolesc Health Care, October 2016

 TABLE 3. Examples of exposures associated with altered risk (increased or decreased) for developing childhood leukemia and. co-benefits of improved
health outcomes by clinical and public health actions

Exposure

Health impacts other than childhood
leukemia

Clinical recommendations

Public health activities

Integrated Pest Management
American Academy of Pediatrics
recommended by U.S. EPA and
recommends Integrated Pest
cooperative extension services
Management, exposure reductions.
Advocates clinicians become familiar
with acute and chronic/subclinical
effects and provide anticipatory guidance
Tobacco
Respiratory disease and asthma, adverse Smoking cessation, avoidance of
National and local tobacco control
birth outcomes, cardiovascular disease, secondhand smoke universally
programs, cessation hotlines
adult cancers, neurocognitive disorders, recommended
sudden infant death syndrome
Many programs for air pollution reduction.
Includes preterm birth, decreased birth Less amenable to individual action.
Air Pollution
Local programs to encourage walking
Recommendations to restrict outdoor
wt., asthma and respiratory
(including
and biking. No idle zones, replacement
activities during high air pollution days
development, cardiovascular dis.,
traffic related)
of old diesel vehicles. School siting
(AirNow.gov). Avoid wood fires.
neurobehavioral disorders
regulations.
Fortification of supplementation
Inadequate folate early in pregnancy
Preconception or prenatal folate
Folate (risk
recommended by U.S. Preventive
associated with neural tube defects,
supplementation recommended by
reduction)
Services Task Force
increase in autism risk, other birth
American College of Obstetrics and
supplementadefects
Gynecology and American Academy of
tion/healthy
Family Physicians and others
diet
Breastfeeding
Sudden infant death syndrome, diarrhea, Promote breastfeeding as the norm,
2011 Surgeon General's Call to Action to
(risk reduction) bacteremia, otitis media, childhood
develop skills to assess and collaborate Support Breastfeeding: Actions for nonobesity, respiratory infection.204
with obstetrical community and certified governmental organizations,
counselors, serve as advocates for
government, employers, etc.
breastfeeding
All states have breastfeeding coalitions,
programs to promote and support
breastfeeding in minority
communities.205

Pesticides

Neurobehavioral disorders, asthma,
adverse birth outcomes, adult cancer,
reproductive toxicity

would result in unwarranted actions with potential
negative impacts on health or increased financial
burdens without benefit to society. Moreover, some
high-risk behaviors—such as parental smoking—
already have clinical and/or public health recommendations that attempt to alter exposure patterns.
Although these efforts are to be applauded, including
an additional focus on the potential of reducing childhood leukemia in these existing public health campaigns may improve effectiveness. With the exception
of tobacco control and lead poisoning prevention,
efforts at wide-scale promotion of children’s
environmental health activities have received limited
funding and attention. When evaluating the costs and
benefits of reducing exposure to an environmental
hazard, one must consider the total social and economic
impacts for risk reduction associated with all relevant
health outcomes (such as cancer, neurobehavioral
deficits, and respiratory disorders). Examples of risk
factors and protective factors associated with childhood
leukemia, other co-morbidities associated with these
exposures, and current clinical or public health recommendations relevant to these exposures are presented in
Table 3.

Curr Probl PediatrAdolesc Health Care, October 2016

Moving Toward Prevention
There have been rare instances when the conventional American wisdom—that a determination of
causation is required before any action can be taken
to protect the public health—has been bypassed to
great benefit. For example, in 1964, the U.S. Surgeon
General supported action to reduce tobacco use stating
Although the causative role of cigarette smoking in deaths from
coronary disease is not proven, the Committee considers it more prudent
from the public health viewpoint to assume that the established
association has causative meaning than to suspend judgment until no
uncertainty remains.191

Similarly, the “Back to Sleep” campaign sponsored
by the U.S. National Institute of Child Health and
Human Development to reduce sudden infant death
syndrome (SIDS) is another example of a highly
successful public health measure that has saved many
lives despite being adopted with less-than-uniform
agreement on causation.192 In 1992, the American
Academy of Pediatrics issued its policy statement
suggesting that infants be placed to sleep on their
backs or sides rather than prone.193 At that time there
were several case–control studies, but no prospective

343

 randomized clinical trials, to support the American
Academy of Pediatrics recommendation. Indeed, the
American Academy of Pediatrics statement acknowledged many limitations in the epidemiological literature that was available for SIDS at that time. As
highlighted in the policy statement abstract
This recommendation is made with the full recognition that the existing
studies have methodologic limitations and were conducted in countries
with infant care practices and other SIDS risk factors that differ from
those in the United States (eg, maternal smoking, types of bedding,
central heating, etc).

taking public health action to reduce human exposure
should be considered substantial. Under the American
Academy of Pediatrics rubric noted above many of the
risk factors in Table 3 should receive the highest rating
for evidence quality.

Examples of Primary Prevention in Clinical and
Public Health Practice
Folate

As noted in the Dietary Risk Factors for Childhood
In fact, the recommendation was in part informed by
Leukemia section, adequate folate during the preconception and very early pregnancy periods is not only
ecologic studies, which is the study design that
associated with reductions in the incidence of childgenerally provides the least convincing support for
hood leukemia but it also protects
causality. These ecologic studagainst neural tube and other birth
ies reported on SIDS inciand
possibly
dence following large-scale
Risk factors for childhood leu- defects
autism.195,196 In 1992, the U.S.
changes in regional sleep positioning practice; observing kemia are also associated with Public Health Service recomthe risk of developing other
that when parents started putmended that all women capable
ting children to sleep in a cancers, neurobehavioral defi- of becoming pregnant take
prone position the incidence
cits, and respiratory disorders. 400 μg of folic acid daily. In
194
of SIDS increased.
1998, the United States introSubseduced fortification of enriched
quently, in 1994, the “Back to
Sleep” campaign was launched to discourage prone
cereal grain products with folate. It has been estimated
that folate fortification has resulted in approximately
sleeping for infants. By 2000, the U.S. mortality rate
1300 fewer children being born with neural tube
for SIDS had dropped to one-half of the rate in 1990. A
defects, annually.197 Despite these dramatic results,
set of additional recommendations aimed at decreasing
SIDS was included in the 2011 American Academy of
nearly one quarter of women of childbearing age in the
Pediatrics policy statement based on findings of varyNational Health and Nutrition Examination Survey
192
ing scientific rigor.
(2007–2012) were found to have suboptimal folateblood levels.198 In addition, Latinas were noted to have
In making these policy statements, American Academy of Pediatrics adapted a strength of evidence
significantly lower blood folate levels than white
scheme from the U.S. Preventive Services Task Force
women. Given that Latino children—those living in
with a highest level of recommendation that requires
Central or South American as well as those living in
California—are recognized to be at greater risk of
…good and consistent scientific evidence (i.e., there are consistent
childhood leukemia than white children, a public
findings from at least 2 well-designed, well-conducted case–control
studies, a systematic review, or a meta-analysis). There is high certainty
health campaign targeting folate supplementation in
that the net benefit is substantial, and the conclusion is unlikely to be
Latinas of childbearing age could be a particularly
strongly affected by the results of future studies.
important opportunity for childhood leukemia
prevention.
Many of the childhood leukemia risk factors listed in
A caution would be a concern about the possibility of
Table 1 have multiple studies demonstrating their
some women exceeding the tolerable upper intake
effect and at least one meta-analysis if not a systematic
level for folic acid. The National Health and Nutrition
review. Moreover, at least for the environmental agents
Examination Survey estimated that 2.7% of particithat have been assessed via the comprehensive, pooled
pants (primarily women) exceed these recommended
analyses conducted by the Childhood Leukemia Interfolate values.199 Nonetheless, a careful emphasis on
national Consortium, it is unlikely that future studies
will contradict the current findings. Finally, when one
improving nutritional status by ensuring fresh foods
takes into account the multiple other diseases that are
and folic acid supplementation for women of pregalso associated with these exposures, the benefit of
nancy age seems warranted.

344

Curr Probl PediatrAdolesc Health Care, October 2016

 Tobacco
Although tobacco control programs and policies have
significantly reduced smoking, there are still between
15% and 23% of young adult men and women who
smoke in the U.S.200 It is likely that most are not aware
of the link between paternal smoking around the time
of conception and a child’s subsequent risk of developing leukemia. To prevent soon-to-be-dads from
smoking before conception, fuller implementation of
proven tobacco control strategies aimed at preventing
smoking initiation and reducing smoking in teenagers
and young adults is needed.

Pesticides
Pesticide exposure, both prenatal and postnatal, has
been associated with leukemia risk. This supports
introduction of programs focused on the use of safe
pesticide practices during the preconception period. An
example of materials that target an audience of people
who are considering becoming, or currently are, pregnant is available from the Program for Reproductive
Health and the Environment at the University of
California, San Francisco. These include Pesticides
Matter: Steps to Reduce Exposure and Protect Your
Health (http://prhe.ucsf.edu/prhe/pesticidesmatter.html).

Preconception Care
Recently,
reproductive
health
professionals
involved in the care and support of women of
childbearing age have begun to emphasize preconception care. These professionals are interested in
including environmental factors as part of their
message to their patients about health promotion
before conception and during pregnancy.201 Including
both men and women in health promotion provides
an ideal opportunity to address environmental exposures prior to early critical windows of development,
even before conception. Initial studies on the effectiveness of strategies to promote behavior change to
reduce chemical hazard exposures preconception and
during pregnancy indicate that perceived normative
pressure (perception of what is common among peers
and important to family, friends and doctors) is a key
element.202 The U.S. Centers for Disease Control and
Prevention and the American College of Obstetrics
and Gynecology have begun programs to address
preconception health (http://www.cdc.gov/preconcep
tion/index.html, see Preconception Health and Health
Care). An effort should be made to ensure that

Curr Probl PediatrAdolesc Health Care, October 2016

environmental health literacy and childhood cancer
prevention activities are addressed within the context
of these evolving programs and included in a new
standard of care.
The cancer prevention activities suggested by our
research on childhood leukemia and others203 largely
reinforce programs already in existence by different
public health entities (e.g., tobacco cessation, healthy
diet during pregnancy and folate supplementation,
avoidance of exposure to volatile organic compounds, pesticides, and paint). Public health agencies
and health care systems can partner to extend
current programs with similar goals. Innovative
cross-agency, multidisciplinary program opportunities
include

 
 
 
 
 

 

Enhance the use of news media and add risk
reduction for childhood leukemia to environmental health literacy education activities for the
general public, as appropriate.
Include environmental health messaging in preconception, prenatal, and child preventive health
care and as part of programs such as “Text
4 Baby” and “Bright Futures.”
Assure that preconception health programs
include environmental health components and
additional emphasis on healthy diet.
Use emerging systematic review methodologies
to evaluate environmental health risks with the
goal of having environmental health programs
recognized as evidence-based medicine.
Improve health care provider counseling for
women and couples to integrate concepts of
environmental health—specifically the risk factors associated with childhood leukemia—into
medical education at all levels (during schooling
and post-graduate education) for nurses, physicians, and allied health professionals.
Develop policy initiatives to reduce exposures to
chemicals associated with childhood leukemia
(and other negative health outcomes) during prepregnancy, pregnancy, and early childhood.

The currently available toxicologic and observational
epidemiologic studies (including meta and pooled
analyses) provide a strong evidentiary basis for the
presence of casual associations (of small to moderate
sizes) between several environmental exposures and
childhood leukemia. Awaiting a more complete evidentiary basis for decision-making, though ideal, will

345

 result in significant delays in safeguarding children’s
health. Education of clinicians and the public on
primary prevention—actions that an individual can
take to reduce their own family’s exposures to chemical risk factors for childhood leukemia as well as other
disorders—is something that can occur now. Ultimately, regulatory actions based on the evolving
science are needed to shift the burden from the
individual to producers.

References
1. American Cancer Society. Cancer Facts & Figures 2016.
http://www.cancer.org/acs/groups/content/@research/docu
ments/document/acspc-047079.pdf. 2016 Accessed 17.06.16.
2. Madhusoodhan PP, Carroll WL, Bhatla T. Progress and
prospects in pediatric leukemia. Curr Probl Pediatr Adolesc
Health Care 2016;46(7):229–41.
3. Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term
outcomes in survivors of childhood acute lymphoblastic
leukemia. Hematol Oncol Clin North Am 2009;23(5):
1065–82:vi-vii.
4. Iyer NS, Balsamo LM, Bracken MB, Kadan-Lottick NS.
Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review
and meta-analysis. Blood 2015;126(3):346–53.
5. Curtin K, Smith KR, Fraser A, Pimentel R, Kohlmann W,
Schiffman JD. Familial risk of childhood cancer and
tumors in the Li-Fraumeni spectrum in the Utah
Population Database: implications for genetic evaluation in
pediatric practice. Int J Cancer 2013;133(10):2444–53.
6. Wiemels J. Perspectives on the causes of childhood leukemia.
Chem Biol Interact 2012;196(3):59–67.
7. Giddings B, Whitehead TP, Metayer C, Miller MD. Childhood leukemia incidence in California: high and rising in the
Hispanic population. Cancer 2016:(In press).
8. Vlaanderen J, Portengen L, Rothman N, Lan Q, Kromhout H,
Vermeulen R. Flexible meta-regression to assess the shape of
the benzene-leukemia exposure–response curve. Environ
Health Perspect 2010;118(4):526–32.
9. Lanphear BP, Hornung R, Khoury J, et al. Low-level
environmental lead exposure and children’s intellectual
function: an international pooled analysis. Environ Health
Perspect 2005;113(7):894–9.
10. Zachek CM, Miller MD, Hsu C, et al. Children’s Cancer and
Environmental Exposures: Professional Attitudes and Practices. J Pediatr Hematol Oncol 2015;37(7):491–7.
11. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell
2000;100(1):57–70.
12. Wiemels JL. Chromosomal translocations in childhood leukemia: natural history, mechanisms, and epidemiology. J Natl
Cancer Inst Monogr 2016:(In press).
13. McHale CM, Wiemels JL, Zhang L, et al. Prenatal origin of
childhood acute myeloid leukemias harboring chromosomal
rearrangements t(15;17) and inv(16). Blood 2003;101(11):
4640–1.

346

14. McHale CM, Wiemels JL, Zhang L, et al. Prenatal origin of
TEL-AML1-positive acute lymphoblastic leukemia in children born in California. Genes Chromosomes Cancer 2003;
37(1):36–43.
15. Wiemels JL, Cazzaniga G, Daniotti M, et al. Prenatal origin
of acute lymphoblastic leukaemia in children. Lancet
1999;354(9189):1499–503.
16. Wiemels JL, Xiao Z, Buffler PA, et al. In utero origin of
t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood 2002;99(10):3801–5.
17. Chang P, Kang M, Xiao A, et al. FLT3 mutation incidence
and timing of origin in a population case series of pediatric
leukemia. BMC Cancer 2010;10:513.
18. Wiemels JL, Kang M, Chang JS, et al. Backtracking RAS
mutations in high hyperdiploid childhood acute lymphoblastic leukemia. Blood Cells Mol Dis. 2010;45(3):186–91.
19. Wiemels JL, Leonard BC, Wang Y, et al. Site-specific
translocation and evidence of postnatal origin of the t(1;19)
E2A-PBX1 fusion in childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2002;99(23):15101–6.
20. Mori H, Colman SM, Xiao Z, et al. Chromosome translocations and covert leukemic clones are generated during
normal fetal development. Proc Natl Acad Sci U S A 2002;
99(12):8242–7.
21. Zuna J, Ford AM, Peham M, et al. TEL deletion analysis
supports a novel view of relapse in childhood acute lymphoblastic leukemia. Clin Cancer Res 2004;10(16):5355–60.
22. Tsai AG, Lieber MR. Mechanisms of chromosomal rearrangement in the human genome. BMC Genomics 2010;
11(suppl 1):S1.
23. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al. Loci on
7p12.2, 10q21.2 and 14q11.2 are associated with risk of
childhood acute lymphoblastic leukemia. Nat Genet 2009;41(9):
1006–1010.
24. Pluth JM, Nicklas JA, O’Neill JP, Albertini RJ. Increased
frequency of specific genomic deletions resulting from in vitro
malathion exposure. Cancer Res 1996;56(10):2393–9.
25. Smith MT, Skibola CF, Allan JM, Morgan GJ. Causal models
of leukaemia and lymphoma. IARC Sci Publ 2004;157:
373–92.
26. Kaur M, de Smith AJ, Selvin S, et al. Tobacco smoke and Ras
mutations among Latino and non-Latino children with acute
lymphoblastic leukemia. Arch Med Res 2016:(Invited submission, in preparation).
27. Metayer C, Zhang L, Wiemels JL, et al. Tobacco smoke
exposure and the risk of childhood acute lymphoblastic and
myeloid leukemias by cytogenetic subtype. Cancer Epidemiol Biomarkers Prev 2013;22(9):1600–11.
28. Scelo G, Metayer C, Zhang L, et al. Household exposure to
paint and petroleum solvents, chromosomal translocations,
and the risk of childhood leukemia. Environ Health Perspect
2009;117(1):133–9.
29. Bailey HD, Infante-Rivard C, Metayer C, et al. Home
pesticide exposures and risk of childhood leukemia: findings
from the childhood leukemia international consortium. Int J
Cancer 2015;137(11):2644–63.
30. Barker DJ. The origins of the developmental origins theory.
J Intern Med 2007;261(5):412–7.

Curr Probl PediatrAdolesc Health Care, October 2016

 31. Joubert BR, Felix JF, Yousefi P, et al. DNA methylation in
newborns and maternal smoking in pregnancy: genome-wide
consortium meta-analysis. Am J Hum Genet 2016;98(4):
680–96.
32. Gonseth S, Roy R, Houseman EA, et al. Periconceptional
folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer
development genes. Epigenetics 2015;10(12):1166–76.
33. Rudant J, Lightfoot T, Urayama K, et al. Childhood
acute lymphoblastic leukemia and indicators of early
immune stimulation: a Childhood Leukemia International
Consortium (CLIC) Study. Am J Epidemiol 2016:
(In press).
34. Greaves MF, Alexander FE. An infectious etiology for
common acute lymphoblastic leukemia in childhood? Leukemia 1993;7(3):349–60.
35. Kinlen LJ. Epidemiological evidence for an infective basis in
childhood leukaemia [editorial]. Br J Cancer 1995;71(1):1–5.
36. Crouch S, Lightfoot T, Simpson J, Smith A, Ansell P, Roman
E. Infectious illness in children subsequently diagnosed with
acute lymphoblastic leukemia: modeling the trends from birth
to diagnosis. Am J Epidemiol 2012;176(5):402–8.
37. Chang JS, Tsai CR, Tsai YW, Wiemels JL. Medically
diagnosed infections and risk of childhood leukaemia: a
population-based case–control study. Int J Epidemiol
2012;41(4):1050–9.
38. Chang JS, Zhou M, Buffler PA, Chokkalingam AP, Metayer
C, Wiemels JL. Profound deficit of IL10 at birth in children
who develop childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev 2011;20(8):1736–40.
39. Smith MT, Guyton KZ, Gibbons CF, et al. Key Characteristics of Carcinogens as a Basis for Organizing Data on
Mechanisms of Carcinogenesis. Environ Health Perspect
2016;124(6):713–21.
40. Infante-Rivard C, Jacques L. Empirical study of parental
recall bias. Am J Epidemiol 2000;152(5):480–6.
41. Preston-Martin S, Bernstein L, Maldonado AA, Henderson
BE, White SC. A dental x-ray validation study. Comparison
of information from patient interviews and dental charts. Am J
Epidemiol 1985;121(3):430–9.
42. Berrington de Gonzalez A, Ekbom A, Glass AG, et al.
Comparison of documented and recalled histories of exposure
to diagnostic x-rays in case–control studies of thyroid cancer.
Am J Epidemiol 2003;157(7):652–63.
43. Slusky DA, Metayer C, Aldrich MC, et al. Reliability of
maternal-reports regarding the use of household pesticides:
experience from a case–control study of childhood leukemia.
Cancer Epidemiol 2012;36(4):375–80.
44. Roberts JW, Wallace LA, Camann DE, et al. Monitoring and
reducing exposure of infants to pollutants in house dust. Rev
Environ Contam Toxicol 2009;201:1–39.
45. Whitehead TP, Brown FR, Metayer C, et al. Polychlorinated
biphenyls in residential dust: sources of variability. Environ
Sci Technol 2014;48(1):157–64.
46. Whitehead TP, Brown FR, Metayer C, et al. Polybrominated
diphenyl ethers in residential dust: sources of variability.
Environ Int 2013;57–58:11–24.

Curr Probl PediatrAdolesc Health Care, October 2016

47. Whitehead TP, Metayer C, Petreas M, Does M, Buffler PA,
Rappaport SM. Polycyclic aromatic hydrocarbons in residential dust: sources of variability. Environ Health Perspect
2013;121(5):543–50.
48. Lorber M. Exposure of Americans to polybrominated diphenyl
ethers. J Expo Sci Environ Epidemiol 2008;18(1):2–19.
49. Johnson PI, Stapleton HM, Sjodin A, Meeker JD. Relationships between polybrominated diphenyl ether concentrations
in house dust and serum. Environ Sci Technol 2010;44(14):
5627–5632.
50. Watkins DJ, McClean MD, Fraser AJ, et al. Impact of dust
from multiple microenvironments and diet on PentaBDE
body burden. Environ Sci Techol 2012;46(2):1192–200.
51. Johnson-Restrepo B, Kannan K. An assessment of sources
and pathways of human exposure to polybrominated diphenyl
ethers in the United States. Chemosphere 2009;76(4):542–8.
52. Stapleton HM, Eagle S, Sjodin A, Webster TF. Serum PBDEs
in a North Carolina toddler cohort: associations with handwipes, house dust, and socioeconomic variables. Environ
Health Perspect 2012;120(7):1049–54.
53. Whitehead TP, Crispo-Smith SM, Park JS, Petreas M,
Rappaport SM, Metayer C. Concentrations of persistent
organic pollutants in California women’s serum and vacuum
dust. Environ Res 2014;136:57–66.
54. Whitehead T, Crispo Smith SM, Park JS, Petreas M,
Rappaport S, Metayer C. Concentrations of persistent organic
pollutants in California children’s whole blood and residential
dust. Chemosphere 2016:(Submitted for publication).
55. Rull RP, Gunier R, Von Behren J, et al. Residential proximity
to agricultural pesticide applications and childhood
acute lymphoblastic leukemia. Environ Res 2009;109(7)
891–9.
56. Gunier RB, Ward MH, Airola M, et al. Determinants of
agricultural pesticide concentrations in carpet dust. Environ
Health Perspect 2011;119(7):970–6.
57. Von Behren J, Reynolds P, Gunier RB, et al. Residential
traffic density and childhood leukemia risk. Cancer Epidemiol Biomarkers Prev 2008;17(9):2298–301.
58. Slusky DA, Does M, Metayer C, Mezei G, Selvin S, Buffler
PA. Potential role of selection bias in the association between
childhood leukemia and residential magnetic fields exposure:
a population-based assessment. Cancer Epidemiol 2014
307–13.
59. Wallace LA, Pellizzari ED, Hartwell TD, et al. The TEAM
(Total Exposure Assessment Methodology) Study: personal
exposures to toxic substances in air, drinking water, and
breath of 400 residents of New Jersey, North Carolina, and
North Dakota. Environ Res 1987;43(2):290–307.
60. Adgate JL, Eberly LE, Stroebel C, Pellizzari ED, Sexton K.
Personal, indoor, and outdoor VOC exposures in a probability
sample of children. J Expo Anal Environ Epidemiol 2004;
14(suppl 1):S4–13.
61. Brown RC, Dwyer T, Kasten C, et al. Cohort profile: the
International Childhood Cancer Cohort Consortium (I4C). Int
J Epidemiol 2007;36(4):724–30.
62. Funk WE, Waidyanatha S, Chaing SH, Rappaport SM.
Hemoglobin adducts of benzene oxide in neonatal and adult

347

 63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

348

dried blood spots. Cancer Epidemiol Biomarkers Prev
2008;17(8):1896–901.
Chokkalingam AP, Chun DS, Noonan EJ, et al. Blood levels
of folate at birth and risk of childhood leukemia. Cancer
Epidemiol Biomarkers Prev 2013;22(6):1088–94.
Spector LG, Murphy SE, Wickham KM, Lindgren B, Joseph
AM. Prenatal tobacco exposure and cotinine in newborn dried
blood spots. Pediatrics 2014;133(6):e1632–8.
Ma WL, Yun S, Bell EM, et al. Temporal trends of
polybrominated diphenyl ethers (PBDEs) in the blood of
newborns from New York State during 1997 through 2011:
analysis of dried blood spots from the newborn screening
program. Environ Sci Technol 2013;47(14):8015–21.
Wagner M, Tonoli D, Varesio E, Hopfgartner G. The use of
mass spectrometry to analyze dried blood spots. Mass
Spectrom Rev 2016;35(3):361–438.
Ma X, Buffler PA, Gunier RB, et al. Critical windows of
exposure to household pesticides and risk of childhood
leukemia. Environ Health Perspect 2002;110(9):955–60.
Turner MC, Wigle DT, Krewski D. Residential pesticides and
childhood leukemia: a systematic review and meta-analysis.
Environ Health Perspect 2010;118(1):33–41.
Van Maele-Fabry G, Lantin AC, Hoet P, Lison D. Residential
exposure to pesticides and childhood leukaemia: a systematic
review and meta-analysis. Environ Int 2011;37(1):280–91.
Chen M, Chang CH, Tao L, Lu C. Residential exposure to
pesticide during childhood and childhood cancers: a metaanalysis. Pediatrics 2015;136(4):719–29.
Curl CL, Fenske RA, Kissel JC, et al. Evaluation of takehome organophosphorus pesticide exposure among agricultural workers and their children. Environ Health Perspect
2002;110(12):A787–92.
Coronado GD, Vigoren EM, Thompson B, Griffith WC,
Faustman EM. Organophosphate pesticide exposure and
work in pome fruit: evidence for the take-home pesticide
pathway. Environ Health Perspect 2006;114(7):999–1006.
Ostrea EM Jr, Bielawski DM, Posecion NC Jr, et al.
Combined analysis of prenatal (maternal hair and blood)
and neonatal (infant hair, cord blood and meconium) matrices
to detect fetal exposure to environmental pesticides. Environ
Res 2009;109(1):116–22.
Bailey HD, Fritschi L, Infante-Rivard C, et al. Parental
occupational pesticide exposure and the risk of childhood
leukemia in the offspring: findings from the childhood
leukemia international consortium. Int J Cancer 2014;135(9):
2157–72.
Alexander FE, Patheal SL, Biondi A, et al. Transplacental
chemical exposure and risk of infant leukemia with MLL
gene fusion. Cancer Res 2001;61(6):2542–6.
Buckley JD, Robison LL, Swotinsky R, et al. Occupational
exposures of parents of children with acute nonlymphocytic
leukemia: a report from the Childrens Cancer Study Group.
Cancer Res 1989;49(14):4030–7.
Ferreira JD, Couto AC, Pombo-de-Oliveira MS, Koifman S,
Brazilian Collaborative Study Group of Infant Acute Leukemia. . In utero pesticide exposure and leukemia in Brazilian
children o 2 years of age. Environ Health Perspect 2013;
121(2):269–75.

78. Wigle DT, Turner MC, Krewski D. A systematic review and
meta-analysis of childhood leukemia and parental occupational pesticide exposure. Environ Health Perspect 2009;117
(10):1505–13.
79. Van Maele-Fabry G, Lantin AC, Hoet P, Lison D. Childhood
leukaemia and parental occupational exposure to pesticides: a
systematic review and meta-analysis. Cancer Causes Control
2010;21(6):787–809.
80. Metayer C, Colt JS, Buffler PA, et al. Exposure to herbicides
in house dust and risk of childhood acute lymphoblastic
leukemia. J Expo Sci Environ Epidemiol 2013;23(4):
363–70.
81. Ward MH, Colt JS, Metayer C, et al. Residential exposure to
polychlorinated biphenyls and organochlorine pesticides and
risk of childhood leukemia. Environ Health Perspect
2009;117(6):1007–13.
82. Chang JS, Selvin S, Metayer C, Crouse V, Golembesky A,
Buffler PA. Parental smoking and the risk of childhood
leukemia. Am J Epidemiol 2006;163(12):1091–100.
83. Metayer C, Petridou E, Mejia Arangure JM, et al. Parental
Tobacco Smoking and Acute Myeloid Leukemia in Children:
Pooled and Meta-analyses from the Childhood Leukemia
International Consortium. Am J Epidemiol 2016:(In press).
84. Chang JS. Parental smoking and childhood leukemia. Methods Mol Biol 2009;472:103–37.
85. Liu R, Zhang L, McHale CM, Hammond SK. Paternal smoking
and risk of childhood acute lymphoblastic leukemia: systematic
review and meta-analysis. J Oncol 2011;2011:854584.
86. Bailey H, Metayer C, Milne E, et al. Home paint exposures
and risk of childhood acute lymphoblastic leukemia: findings
from the Childhood Leukemia International Consortium.
Cancer Causes Control 2015;26(9):1257–70.
87. Colt JS, Blair A. Parental occupational exposures and risk of
childhood cancer. Environ Health Perspect 1998;106(suppl
3):909–25.
88. Zhou Y, Zhang S, Li Z, et al. Maternal benzene exposure
during pregnancy and risk of childhood acute lymphoblastic
leukemia: a meta-analysis of epidemiologic studies. PloS One
2014;9(10):e110466.
89. Bailey HD, Fritschi L, Metayer C, et al. Parental occupational
paint exposure and risk of childhood leukemia in the offspring: findings from the Childhood Leukemia International
Consortium. Cancer Causes Control 2014;25(10):1351–67.
90. Carlos-Wallace FM, Zhang L, Smith MT, Rader G, Steinmaus C. Parental, in utero, and early-life exposure to benzene
and the risk of childhood leukemia: a meta-analysis. Am J
Epidemiol 2016;183(1):1–14.
91. Metayer C, Scelo G, Kang A, et al. A task-based assessment
of parental occupational exposure to organic solvents and
other compounds and the risk of childhood leukemias in
California. Environ Res 2016:(In press).
92. Boothe VL, Boehmer TK, Wendel AM, Yip FY. Residential
traffic exposure and childhood leukemia: a systematic review
and meta-analysis. Am J Prev Med 2014;46(4):413–22.
93. Filippini T, Heck JE, Malagoli C, Del Giovane C, Vinceti M.
A review and meta-analysis of outdoor air pollution and risk
of childhood leukemia. J Environ Sci Health C Environ
Carcinog Ecotoxicol Rev 2015;33(1):36–66.

Curr Probl PediatrAdolesc Health Care, October 2016

 94. Deziel NC, Rull RP, Colt JS, et al. Polycyclic aromatic
hydrocarbons in residential dust and risk of childhood acute
lymphoblastic leukemia. Environ Res 2014;133:388–95.
95. Ward MH, Colt JS, Deziel NC, et al. Residential levels of
polybrominated diphenyl ethers and risk of childhood acute
lymphoblastic leukemia in california. Environ Health Perspect 2014;122(10):1110–6.
96. Birnbaum LS, Staskal DF. Brominated flame retardants:
cause for concern? Environ Health Perspect 2004;112(1):
9–17.
97. Linet MS, Kim KP, Rajaraman P. Children’s exposure to
diagnostic medical radiation and cancer risk: epidemiologic
and dosimetric considerations. Pediatric Radiol 2009;39
(suppl 1):S4–26.
98. Smith-Bindman R, Miglioretti DL, Johnson E, et al.
Use of diagnostic imaging studies and associated radiation
exposure for patients enrolled in large integrated health care
systems, 1996–2010. J Am Med Assoc 2012;307(22):
2400–2409.
99. Linet MS, Slovis TL, Miller DL, et al. Cancer risks associated
with external radiation from diagnostic imaging procedures.
CA Cancer J Clin 2012.
100. Brenner DJ, Hall EJ. Computed tomography—an increasing
source of radiation exposure. N Engl J Med 2007;357(22):
2277–84.
101. Journy N, Ancelet S, Rehel JL, et al. Predicted cancer risks
induced by computed tomography examinations during childhood, by a quantitative risk assessment approach. Radiat
Environ Biophys 2014;53(1):39–54.
102. Miglioretti DL, Johnson E, Williams A, et al. The use of
computed tomography in pediatrics and the associated
radiation exposure and estimated cancer risk. JAMA Pediatr
2013;167(8):700–7.
103. Bailey HD, Armstrong BK, de Klerk NH, et al. Exposure to
diagnostic radiological procedures and the risk of childhood
acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers
Prev 2010;19(11):2897–909.
104. Krille L, Jahnen A, Mildenberger P, et al. Computed
tomography in children: multicenter cohort study design for
the evaluation of cancer risk. Eur J Epidemiol 2011;26
(3):249–50.
105. Meulepas JM, Ronckers CM, Smets AM, et al. Leukemia and
brain tumors among children after radiation exposure from
CT scans: design and methodological opportunities of the
Dutch Pediatric CT Study. Eur J Epidemiol 2014;29(4):
293–301.
106. Pearce MS, Salotti JA, Little MP, et al. Radiation exposure
from CT scans in childhood and subsequent risk of leukaemia
and brain tumours: a retrospective cohort study. Lancet
2012;380(9840):499–505.
107. Mathews JD, Forsythe AV, Brady Z, et al. Cancer risk in
680,000 people exposed to computed tomography scans in
childhood or adolescence: data linkage study of 11 million
Australians. Br Med J 2013;346:f2360.
108. Einstein AJ. Beyond the bombs: cancer risks of
low-dose medical radiation. Lancet 2012;380(9840):455–7.
109. Journy N, Rehel JL, Ducou Le Pointe H, et al. Are the studies
on cancer risk from CT scans biased by indication? Elements

Curr Probl PediatrAdolesc Health Care, October 2016

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.
121.

122.

123.

124.
125.

126.

of answer from a large-scale cohort study in France Br J
Cancer 2015;112(1):185–93.
Knox EG, Stewart AM, Kneale GW, Gilman EA. Prenatal
irradiation and childhood cancer. J Soc Radiol 1987;7(4):
177–87.
Cardis E, de Basea MB. Comment on ‘Are the studies on
cancer risk from CT scans biased by indication? Elements of
answer from a large-scale cohort study in France’—evidence
of confounding by predisposing factors unclear Br J Cancer
2015;112(11):1842–3.
Journy N, Laurier D, Bernier MO. Comment on: are the
studies on cancer risk from CT scans biased by indication?
Elements of answer from a large-scale cohort study in France
Br J Cancer 2015;112(11):1843–4.
Muirhead CR. Response to ‘Are the studies on cancer risk
from CT scans biased by indication? Elements of answer
from a large-scale cohort study in France’ Br J Cancer.
2015;112(11):1841–2.
Ahlbom A, Day N, Feychting M, et al. A pooled analysis of
magnetic fields and childhood leukaemia. Br J Cancer
2000;83(5):692–8.
Greenland S, Sheppard AR, Kaune WT, Poole C, Kelsh MA.
A pooled analysis of magnetic fields, wire codes, and childhood leukemia. Childhood Leukemia-EMF Study Group.
Epidemiology 2000;11(6):624–34.
IARC. Non-Ionizing Radiation: I, Static and Extremely LowFrequency (ELF) Elctric and Magnetic Fields. Lyon, France:
International Agency for Research on Cancer, 2002.
Schuz J, Lagorio S, Bersani F. Electromagnetic fields and
epidemiology: an overview inspired by the fourth course at
the International School of Bioelectromagnetics. Bioelectromagnetics 2009;30(7):511–24.
Teepen JC, van Dijck JA. Impact of high electromagnetic
field levels on childhood leukemia incidence. Int J Cancer
2012;131(4):769–78.
Mosby TT, Cosgrove M, Sarkardei S, Platt KL, Kaina B.
Nutrition in adult and childhood cancer: role of carcinogens
and anti-carcinogens. Anticancer Res 2012;32(10):4171–92.
Ferguson LR, Philpott M. Nutrition and mutagenesis. Annu
Rev Nutr 2008;28:313–29.
Forster SE, Powers HJ, Foulds GA, et al. Improvement in
nutritional status reduces the clinical impact of infections in
older adults. J Am Geriatr Soc 2012;60(9):1645–54.
Gibson A, Edgar JD, Neville CE, et al. Effect of fruit and
vegetable consumption on immune function in older people: a
randomized controlled trial. Am J Clinl Nutr 2012;96(6):
1429–36.
Stefanska B, Karlic H, Varga F, Fabianowska-Majewska K,
Haslberger A. Epigenetic mechanisms in anti-cancer actions
of bioactive food components—the implications in cancer
prevention. Br J Pharmacol 2012;167(2):279–97.
Barker DJ. Sir Richard Doll Lecture. Developmental origins
of chronic disease. Public Health 2012;126(3):185–9.
Waterland RA, Michels KB. Epigenetic epidemiology of the
developmental origins hypothesis. Annual Rev Nutr 2007;
27:363–88.
Jensen CD, Block G, Buffler P, Ma X, Selvin S, Month S.
Maternal dietary risk factors in childhood acute

349

 127.

128.

129.

130.

131.
132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

350

lymphoblastic leukemia (United States). Cancer Causes
Control 2004;15(6):559–70.
Kwan ML, Jensen CD, Block G, Hudes ML, Chu LW,
Buffler PA. Maternal diet and risk of childhood acute
lymphoblastic leukemia. Public Health Rep 2009;124(4):
503–14.
Petridou E, Ntouvelis E, Dessypris N, Terzidis A,
Trichopoulos D, Childhood Hematology-Oncology Group.
Maternal diet and acute lymphoblastic leukemia in young
children. Cancer Epidemiol Biomarkers Prev 2005;14(8):1935–9.
Spector LG, Xie Y, Robison LL, et al. Maternal diet and
infant leukemia: the DNA topoisomerase II inhibitor hypothesis: a report from the children’s oncology group. Cancer
Epidemiol Biomarkers Prev 2005;14(3):651–5.
Locasale JW. Serine, glycine and one-carbon units: cancer
metabolism in full circle. Nat Rev Cancer 2013;13(8):
572–83.
Lim U, Song MA. Dietary and lifestyle factors of DNA
methylation. Methods Mol Biol 2012;863:359–76.
Blom HJ, Shaw GM, den Heijer M, Finnell RH. Neural tube
defects and folate: case far from closed. Nat Rev Neurosci
2006;7(9):724–31.
Chen P, Li C, Li X, Li J, Chu R, Wang H. Higher dietary
folate intake reduces the breast cancer risk: a systematic
review and meta-analysis. Br J Cancer 2014;110(9):2327–38.
Kennedy DA, Stern SJ, Moretti M, et al. Folate intake and the
risk of colorectal cancer: a systematic review and metaanalysis. Cancer Epidemiol 2011;35(1):2–10.
Wien TN, Pike E, Wisloff T, Staff A, Smeland S, Klemp M.
Cancer risk with folic acid supplements: a systematic review
and meta-analysis. BMJ Open 2012;2(1):e000653.
Clarke R, Halsey J, Lewington S, et al. Effects of lowering
homocysteine levels with B vitamins on cardiovascular
disease, cancer, and cause-specific mortality: meta-analysis
of 8 randomized trials involving 37 485 individuals. Arch
Intern Med 2010;170(18):1622–31.
Vollset SE, Clarke R, Lewington S, et al. Effects of folic acid
supplementation on overall and site-specific cancer incidence
during the randomised trials: meta-analyses of data on 50,000
individuals. Lancet 2013;381(9871):1029–36.
Metayer C, Milne E, Dockerty JD, et al. Maternal supplementation with folic acid and other vitamins and risk of
leukemia in offspring: a childhood leukemia international
consortium study. Epidemiology 2014;25(6):811–22.
Bailey HD, Miller M, Langridge A, et al. Maternal dietary
intake of folate and vitamins b6 and B12 during pregnancy
and the risk of childhood acute lymphoblastic leukemia. Nutr
Cancer 2012;64(7):1122–30.
Metayer C, Scelo G, Chokkalingam AP, et al. Genetic variants
in the folate pathway and risk of childhood acute lymphoblastic
leukemia. Cancer Causes Control 2011;22(9):1243–58.
Singer AW, Selvin S, Block G, Golden C, Carmichael SL,
Metayer C. Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia. Cancer Causes
Control 2016;27(7):929–40.
Hay G, Clausen T, Whitelaw A, et al. Maternal folate and
cobalamin status predicts vitamin status in newborns and
6-month-old infants. J Nutr 2010;140(3):557–64.

143. Ajrouche R, Rudant J, Orsi L, et al. Childhood acute
lymphoblastic leukaemia and indicators of early immune
stimulation: the Estelle study (SFCE). Br J Cancer 2015;
112(6):1017–106.
144. Amigou A, Rudant J, Orsi L, et al. Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of
childhood leukemia: the ESCALE study (SFCE). Cancer
Causes Control 2012;23(8):1265–77.
145. Koppen IJ, Hermans FJ, Kaspers GJ. Folate related gene
polymorphisms and susceptibility to develop childhood acute
lymphoblastic leukaemia. Br J Haematol 2010;148(1):3–14.
146. Lightfoot TJ, Johnston WT, Painter D, et al. Genetic variation
in the folate metabolic pathway and risk of childhood
leukemia. Blood 2010;115(19):3923–9.
147. Wong NC, Ashley D, Chatterton Z, et al. A distinct DNA
methylation signature defines pediatric pre-B cell acute
lymphoblastic leukemia. Epigenetics 2012;7(6):535–41.
148. Lupo PJ, Dietz DJ, Kamdar KY, Scheurer ME. Geneenvironment interactions and the risk of childhood acute
lymphoblastic leukemia: exploring the role of maternal folate
genes and folic Acid fortification. Pediatr Hematol Oncol
2014;31(2):160–8.
149. Milne E, Greenop KR, Scott RJ, et al. Folate pathway gene
polymorphisms, maternal folic acid use, and risk of childhood
acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers
Prev 2015;24(1):48–56.
150. Mosad E, Abdou M, Zaky AH. Rearrangement of the
myeloid/lymphoid leukemia gene in therapy-related myelodysplastic syndrome in patients previously treated with agents
targeting DNA topoisomerase II. Oncology 2012;83(3):
128–34.
151. Ross JA, Potter JD, Reaman GH, Pendergrass TW, Robison
LL. Maternal exposure to potential inhibitors of DNA
topoisomerase II and infant leukemia (United States): a report
from the Children’s Cancer Group. Cancer Causes Control
1996;7(6):581–90.
152. Lightfoot TJ, Roman E. Causes of childhood leukaemia and
lymphoma. Toxicol Appl Pharmacol 2004;199(2):104–17.
153. Lanoue L, Green KK, Kwik-Uribe C, Keen CL. Dietary
factors and the risk for acute infant leukemia: evaluating the
effects of cocoa-derived flavanols on DNA topoisomerase
activity. Exp Biol Med 2010;235(1):77–89.
154. Menegaux F, Steffen C, Bellec S, et al. Maternal coffee and
alcohol consumption during pregnancy, parental smoking and
risk of childhood acute leukaemia. Cancer Detect Prev 2005;
29(6):487–93.
155. Thomopoulos TP, Ntouvelis E, Diamantaras AA, et al.
Maternal and childhood consumption of coffee, tea and cola
beverages in association with childhood leukemia: a metaanalysis. Cancer Epidemiol 2015;39(6):1047–59.
156. Bonaventure A, Rudant J, Goujon-Bellec S, et al. Childhood
acute leukemia, maternal beverage intake during pregnancy,
and metabolic polymorphisms. Cancer Causes Control 2013;
24(4):783–93.
157. Milne E, Royle JA, Bennett LC, et al. Maternal consumption
of coffee and tea during pregnancy and risk of childhood
ALL: results from an Australian case–control study. Cancer
Causes Control 2011;22(2)207–18.

Curr Probl PediatrAdolesc Health Care, October 2016

 158. Shu XO, Ross JA, Pendergrass TW, Reaman GH, Lampkin
B, Robison LL. Parental alcohol consumption, cigarette
smoking, and risk of infant leukemia: a Childrens Cancer
Group study. J Natl Cancer Inst 1996;88(1):24–31.
159. Latino-Martel P, Chan DS, Druesne-Pecollo N, Barrandon E,
Hercberg S, Norat T. Maternal alcohol consumption during
pregnancy and risk of childhood leukemia: systematic review
and meta-analysis. Cancer Epidemiol Biomarkers Prev
2010;19(5):1238–60.
160. Infante-Rivard C, Krajinovic M, Labuda D, Sinnett D.
Childhood acute lymphoblastic leukemia associated with
parental alcohol consumption and polymorphisms of
carcinogen-metabolizing genes. Epidemiology 2002;13(3):
277–81.
161. Petridou E, Trichopoulos D, Kalapothaki V, et al. The risk
profile of childhood leukaemia in Greece: a nationwide case–
control study. Br J Cancer 1997;76(9):1241–7.
162. Orsi L, Rudant J, Ajrouche R, et al. Parental smoking,
maternal alcohol, coffee and tea consumption during pregnancy, and childhood acute leukemia: the ESTELLE study.
Cancer Causes Control 2015;26(7):1003–17.
163. Milne E, Greenop KR, Scott RJ, et al. Parental alcohol
consumption and risk of childhood acute lymphoblastic
leukemia and brain tumors. Cancer Causes Control 2013;
24(2):391–402.
164. Slater ME, Linabery AM, Blair CK, et al. Maternal prenatal
cigarette, alcohol and illicit drug use and risk of infant
leukaemia: a report from the Children’s Oncology Group.
Paediatr Perinat Epidemiol 2011;25(6):559–65.
165. Hu FB. Dietary pattern analysis: a new direction in nutritional
epidemiology. Curr Opin Lipidol 2002;13(1):3–9.
166. Harnack L, Nicodemus K, Jacobs D.R. Jr., Folsom AR. An
evaluation of the dietary guidelines for Americans in relation
to cancer occurrence. Am J Clin Nutr 2002;76(4):889–96.
167. Kant AK. Dietary patterns and health outcomes. J Am Diet
Assoc 2004;104(4):615–35.
168. Carmichael SL, Yang W, Feldkamp ML, et al. Reduced
risks of neural tube defects and orofacial clefts with higher
diet quality. Arch Pediatr Adolesc Med 2012;166(2):
121–126.
169. Singer AW, Carmichael SL, Selvin S, Fu C, Block G,
Metayer C. Maternal diet quality before pregnancy and risk
of childhood leukemia. Br J Nutr (In press).
170. Peters JM, Preston-Martin S, London SJ, Bowman JD,
Buckley JD, Thomas DC. Processed meats and risk of
childhood leukemia (California, USA). Cancer Causes Control 1994;5(2):195–202.
171. Bailey HD, Miller M, Greenop KR, et al. Paternal intake of
folate and vitamins B6 and B12 before conception and risk of
childhood acute lymphoblastic leukemia. Cancer Causes
Control 2014;25(12):1615–25.
172. Wen W, Shu XO, Potter JD, et al. Parental medication use
and risk of childhood acute lymphoblastic leukemia. Cancer
2002;95(8):1786–94.
173. Rudant J, Amigou A, Orsi L, et al. Fertility treatments, congenital
malformations, fetal loss, and childhood acute leukemia: The
ESCALE study (SFCE). Pediatr Blood Cancer 2013;60(2):301–8.

Curr Probl PediatrAdolesc Health Care, October 2016

174. Amitay EL, Keinan-Boker L. Breastfeeding and Childhood
Leukemia Incidence: A Meta-analysis and Systematic
Review. JAMA Pediatr 2015;169(6):e151025.
175. Greenop KR, Bailey HD, Miller M, et al. Breastfeeding and
nutrition to 2 years of age and risk of childhood acute
lymphoblastic leukemia and brain tumors. Nutr Cancer
2015;67(3):431–41.
176. Schraw JM, Dong YQ, Okcu MF, Scheurer ME, Forman MR.
Do longer formula feeding and later introduction of solids
increase risk for pediatric acute lymphoblastic leukemia?
Cancer Causes Control 2014;25(1):73–80.
177. Kwan ML, Block G, Selvin S, Month S, Buffler PA. Food
consumption by children and the risk of childhood acute
leukemia. Am J Epidemiol 2004;160(11):1098–107.
178. Diamantaras AA, Dessypris N, Sergentanis TN, et al. Nutrition in early life and risk of childhood leukemia: a case–
control study in Greece. Cancer Causes Control, 24; 2013.
p. 117–24.
179. Sarasua S, Savitz DA. Cured and broiled meat consumption
in relation to childhood cancer: Denver, Colorado (United
States). Cancer Causes Control 1994;5(2):141–8.
180. Rifkin R. American rate nurses highest on honesty, ethical
standards. Gallup Poll, Social Issues 2014; http://www.gallup.
com/poll/180260/americansrate-nurses-highest-honesty-ethicalstandards.aspx; 2016 Accessed 09.06.16.
181. Institute of Medicine. Role of the Primary Care Physicians in
Occupational and Environmental Medicine. National Academies
Press, Washington, DC; 1988.
182. Kilpatrick N, Frumkin H, Trowbridge J, et al. The environmental history in pediatric practice: a study of pediatricians'
attitudes, beliefs, and practices. Environ Health Perspect
2002;110(8):823–7.
183. Trasande L, Boscarino J, Graber N, et al. The environment in
pediatric practice: a study of New York pediatricians'
attitudes, beliefs, and practices towards children’s environmental health. J Urban Health 2006;83(4):760–72.
184. Finn S, O’Fallon L. The Emergence of Environmental Health
Literacy-From Its Roots to Its Future Potential. Environ Health
Perspect 2015; http://dx.doi.org/10.1289/ehp.1409337.
185. Holman DM, Buchanan N, Cancer Prevention During Early
Life Expert Group. Opportunities during early life for cancer
prevention: 2016. Highlights from a series of virtual meetings
with experts. Pediatrics 2016:(In press).
186. Metayer C, Dahl G, Wiemels J, Miller M. Childhood
leukemia: a preventable disease. Pediatrics 2016:(In press).
187. Gee D. Late lessons from early warnings: toward realism and
precaution with endocrine-disrupting substances. Environ
Health Perspect 2006;114(suppl 1):152–60.
188. Rooney AA, Boyles AL, Wolfe MS, Bucher JR, Thayer KA.
Systematic review and evidence integration for literaturebased environmental health science assessments. Environ
Health Perspect 2014;122(7):711–8.
189. Woodruff TJ, Sutton P. The navigation guide systematic
review methodology: a rigorous and transparent method
for translating environmental health science into better
health outcomes. Environ Health Perspect 2014;122(10):
1007–14.

351

 190. Bergerson RJ, Collier LS, Sarver AL, et al. An insertional
mutagenesis screen identifies genes that cooperate with MllAF9 in a murine leukemogenesis model. Blood 2012;119(19)
4512–23.
191. US Department of Health E, and Welfare. Report of the
Advisory Committee to the Surgeon General of the Public
Health Service. Washington, DC: US Department of Health,
Education, and Welfare, Public Health Service, 1964.
192. Task Force on Sudden Infant Death Syndrome, Moon RY.
SIDS and other sleep-related infant deaths: expansion of
recommendations for a safe infant sleeping environment.
Pediatrics 2011;128(5):e1341–67.
193. American Academy of Pediatrics AAP Task Force on Infant
Positioning and SIDS: positioning and SIDS. Pediatrics
1992;89(6 Pt 1):1120–6.
194. Engelberts AC, de Jonge GA. Choice of sleeping position for
infants: possible association with cot death. Arch Dis Child
1990;65(4):462–7.
195. Schmidt RJ, Tancredi DJ, Ozonoff S, et al. Maternal
periconceptional folic acid intake and risk of autism spectrum
disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case–
control study. Am J Clin Nutr 2012;96(1):80–9.
196. Suren P, Roth C, Bresnahan M, et al. Association between
maternal use of folic acid supplements and risk of autism
spectrum disorders in children. J Am Med Assoc 2013;309(6):
570–577.
197. Williams J, Mai CT, Mulinare J, et al. Updated estimates of
neural tube defects prevented by mandatory folic Acid
fortification—United States, 1995–2011. MMWR Morb Mortal Wkly Rep 2015;64(1):1–5.
198. Tinker SC, Hamner HC, Qi YP, Crider KS. U.S. women of
childbearing age who are at possible increased risk of a neural

352

199.

200.

201.

202.

203.

204.

205.

tube defect-affected pregnancy due to suboptimal red blood
cell folate concentrations, National Health and Nutrition
Examination Survey 2007 to 2012. Birth Defects Res A Clin
Mol Teratol 2015;103(6):517–26.
Orozco AM, Yeung LF, Guo J, Carriquiry A, Berry RJ.
Characteristics of U.S. adults with usual daily folic acid
intake above the tolerable upper intake level: National Health
and Nutrition Examination Survey, 2003–2010. Nutrients
2016;8(4).
Jamal A, Homa DM, O'Connor E, et al. Current cigarette
smoking among adults—United States, 2005–2014. MMWR
Morb Mortal Wkly Rep 2015;64(44):1233–40.
Sutton P, Woodruff TJ, Perron J, et al. Toxic environmental
chemicals: the role of reproductive health professionals in
preventing harmful exposures. Am J Obstet Gynecol
2012;207(3):164–73.
Mello S, Hovick SR. Predicting behaviors to reduce toxic
chemical exposures among new and expectant mothers: the
role of distal variables within the integrative model of
behavioral prediction. Health Educ Behav 2016; http://dx.
doi.org/10.1177/1090198116637600.
Grason HA, Misra DP. Reducing exposure to environmental
toxicants before birth: moving from risk perception to risk
reduction. Public Health Rep 2009;124(5):629–41.
Gartner LM, Morton J, Lawrence RA, et al. Breastfeeding and the use of human milk. Pediatrics 2005;115(2):
496–506.
Office of the Surgeon General (US), Centers for Disease
Control and Prevention (US), Office on Women’s Health
(US). The Surgeon General’s Call to Action to Support
Breastfeeding. Office of the Surgeon General, Rockville, MD,
2011.

Curr Probl PediatrAdolesc Health Care, October 2016