-------
eii.es
The Office of Children's Health Protection (OCHP) at the U.S. Environmental Protection Agency
(EPA) has created the Paper Series on Children's Health and the Environment to share scientific, reg-
ulatory, and policy information about children's health and the environment with a broad audi-
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All papers in the Series are distributed for purposes of information sharing and discussion only.
The opinions and findings expressed in these papers are those of the authors and do not neces-
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CRmCAi. PERIODS :N DEVELOPMENT
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(Critical Periods m Development
OCHP Paper Series on Children's
Health and the Environment
Paper 2OO3-2
Prepared by Kara Altshuler,* Michael Berg,* Linda M Frazier,**
Jim Laurenson,* Janice Longstreth,* William Mendez,* and Craig A. Molgaard*
February 2QQ3
* ICF Consulting, Inc.
** University of Kansas School of Medicine-Wichita
Disclaimer
This paper is being distributed for purposed of information sharing and discussion only. The
opinions and findings expressed in this paper are those of the authors and do not necessarily
represent those of the U S. Environmental Protection Agency or of the Office of Children's
Health Protection. No official Agency endorsement should be inferred from the paper.
CR:TICA!. f»ER:OD8 iN OEVEi.OPMF.NT
-------
Ac 1m ow 1 cclg'mcTi is
This paper, the second in the Office of Children's Health Protection's Paper Series on Children's
Health and the Environment, reviews crucial stages in human development from conception
through adolescence and the implications of environmental insults or exposures at these differ-
ent stages.
Many individuals and organizations assisted in preparing this paper The authors at ICF
Consulting and the colleagues who helped them relied largely on the results of a scientific litera-
ture review for OCHP by the University of Kansas, School of Medicine at Wichita, which was
completed in early 2001. OCHP appreciates the invaluable suggestions of the following internal
EPA peer reviewers: David Chen, Brenda Foos, Gary Kimmel, Amal Mahfouz, Gregory Miller,
and Onyemaechi Nweke, and the following external peer reviewers Cynthia F Bearer of the
Department of Pediatrics and Neurosciences at Case Western Reserve University School of
Medicine, Ruth Etzel of the School of Public Health and Health Services at George Washington
University, Daniel Goldstein of Monsanto, and Philip ) Landrigan of the Department of
Community and Prevents live Medicine at the Mount Sinai School of Medicine.
CfimCAi. PERIODS Ht DEVELOPMENT
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lame or Contents
1. Introduction 1
2. What Are Critical Periods of Development and Why Are They Critical? 2
2.1 Major Stages of Development from Conception to Adulthood 2
2.1.1 Germ Cell Development 2
212 Embryonic and Fetal Development During Pregnancy .. .... 2
2.1.3 Ongoing Development During Childhood 5
2.2 Why Certain Developmental Stages May Be Especially
Vulnerable to Environmental Exposures 5
221 Control of Cell Division 6
222 Apoptosis (Programmed Cell Death) 7
223 Gene Expression 7
224 Cellular Metabolism and Biotransformation of
Environmental Agents .... 8
2 3 How Are Effects During Critical Periods Identified? 8
3 Adverse Effects of Parental Exposures Before or Around the Time of Conception . .10
31 Environmental Agents That May Damage Germ Cells ... .10
3.2 Environmental Agents That May Cause Damage At or Just
After Conception 13
4. Adverse Effects of Environmental Exposures During Pregnancy 15
41 Genera] Pattern of Fetal Development and Environmental
Toxicity During Pregnancy 15
4 2 Adverse Effects During Pregnancy 16
4.21 Early Fetal Death 16
4.2 2 Congenital Malformations 16
4.2.3 Growth Deficits During Pregnancy and Pre-Term Birth 18
4.2.4 Pregnancy Complications and Late Fetal Death . .18
5 Adverse Effects of Exposures During Childhood . .19
5.1 Neonatal Mortality 19
5 2 Growth Deficits During Early Childhood 20
5.3 Functional Deficits and Delayed or Impaired Functional Maturation ... 20
5 4 Effects on Puberty and Sexual Maturation 21
5 5 Cancer In Children 22
6. Adverse Effects of Early Exposures That May Be Delayed Until Adulthood 27
61 Cancers That Develop Later in Life .. ... . 27
6 2 Other Effects Later in Life 28
7 Summary 30
References . .. 31
,V CRsTIGAl. Pf-R-008 IN QEVE1.OPMF.NT
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Introduction
The course of human development from con-
ception to adulthood is extremely complex. A
huge number of biochemical, physical, and
organizational processes must be precisely
coordinated to assure orderly development,
maintain health, and avoid disease Because
of the complexity, there are numerous oppor-
tunities for "things to go wrong." Children at
particular developmental stages may be
uniquely vulnerable to influences that have
little impact at other points in their develop-
ment or on adults
This paper reviews crucial stages in human
development from conception through ado-
lescence and the implications of environmen-
tal insults or exposures at those different
stages It focuses on the developmental stages
during which children may be particularly
sensitive to exposures to environmental
agents or may be at risk of adverse effects that
would not occur if exposures occurred during
adulthood. Identifying these "critical" periods
is essential to developing strategies that pro-
tect children from adverse health effects asso-
ciated with environmental exposures
The remainder of this paper is divided into six
chapters. Chapter 2 defines the important
stages of early human development. The sub-
sequent chapters review the evidence of
adverse impacts of environmental exposures
on key periods of germ cell development
(Chapter 3), pregnancy (Chapter 4); and infan-
cy, early childhood, and adolescence (Chapter
5) Chapter 6 briefly discusses potential
adverse effects of environmental exposures
during development that may not become
manifest until adulthood. Chapter 7 summa-
rizes the major findings and data gaps con-
cerning the impacts of environmental factors
during key periods of development
Following Chapter 7 is a list of references used
in this paper.
This paper discusses a broad range of chil-
dren's environmental health issues, but avoids
the technical details of specific studies or
methods, and does not present EPA policies
or positions on these issues. Interested read-
ers can find additional information in the pri-
mary literature and the more detailed review
articles and textbooks cited throughout the
paper and ksted at the end of the document.
Further, this paper discusses potential
adverse effects from exposure to many toxi-
cants and physical agents, some of which are
not environmental in origin. While EPA gen-
erally does not have the authority to address
non-environmental exposures (e.g, drugs or
medical x-rays), information regarding poten-
tial adverse effects from these exposures is
included because many of these adverse
effects are similar to the adverse effects caused
by exposure to environmental contaminants
CRITICAL PERIODS :N
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What Are Critical Periods 01
Development ami Why Are 1 oey
Critical?
The first section of Chapter 2 briefly reviews
the major stages of early human develop-
ment. The next section discusses the biologi-
cal basis for suspecting that particular stages
of tissue and organ development are espe-
cially susceptible to environmental insult
The third and final section describes how the
effects of environmental exposures are
detected and why identifying specific causes
of developmental impacts often is difficult
2.1 Major Stages of
Development from
Conception to
Adulthood
Individual development proceeds from the
formation of germ cells (sperm and egg)
through fertilization, embryonic and fetal
development (both of which take place during
pregnancy), infancy, early childhood, and
adolescence Sped he events during each of
these broad developmental stages may create
sensitivity to environmental influences
Damage from environmental exposures may
occur and manifest itself immediately or may
not appear until subsequent stages of devel-
opment or after development is complete.
2.1.1 Germ Celt Development
Germ cells are the sperm and egg cells. They
carry the genetic information —DNA —from
each parent. The combination of genetic
material from sperm and egg cells provide the
unique genetic blueprint for each child
Environmental toxicants that harm germ cells
can affect an adult's own fertility as well as the
health of the offspring.
Germ cells begin development in fetal life,
even though they do not mature until puber-
ty. In the male fetus, primordial germ cells
develop in utero From puberty throughout
adulthood, these cells undergo cell division,
mitosis and meiosis, to produce mature
sperm In females, primordial germ cells
undergo mitosis and the first phase of meiosis
during fetal life Most of these primary
oocytes-mitially numbering in the
millions-degenerate naturally until, by puber-
ty, only about 400,000 remain as primary folli-
cles During each menstrual cycle, a group of
these follicles ripen, with typically only one
resuming meiosis to form the egg released
during ovulation. During each stage, the pri-
mordial germ cells in both sexes as well as pri-
mary oocytes in females can be damaged by
environmental exposures (Anderson, 2000,
Lemasters, 1993) Results of such damage
may include reduced fertility later in life or
offspring with congenital health problems
(Loeffler, 1999, Silbergeld, 1999)
2.1,2 Embryonic and Fetal
Development During
Pregnancy
Between conception (the union of sperm and
egg) and birth, human life advances from a
single-cell zygote to an infant capable of living
outside the womb Because of the complexity
and speed of development and the high rate
of growth through the prenatal period, this
stage of development has a special set of vul-
nerabilities to environmental exposures that
are not seen at any other time
CRiTICAI. PER-QQ8 IN QeVEI.OPMENT
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Figure 1. Sensitive or Critic*! St*s«« of Human Development
Reprinted with permission of W.B SaundersCo. (Moore, 1998)
As shown in Figure \, prenatal development
is often divided into three stages: periconcep-
tual (generally the 2 weeks following fertiliza-
tion), embryonic (3 to 7 weeks), and fetal (8 to
38 weeks). During the periconceptual period,
the zygote undergoes rapid cell division,
implants into the wall of the uterus, and forms
a simple embryo. During this period, haz-
ardous environmental exposures usually
cause fetal death rather than injury (Sadler,
2000). Lethal effects during this period would
result in a spontaneous abortion only
detectable biochemically, for instance via a
transiently positive serum pregnancy test
(Hakim, 1995; Rowland, 1995; Wilcox, 1988).
Most major organs begin to form during the
embryonic period, with growth and develop-
ment continuing through the remainder of
pregnancy and into infancy for some systems.
During the early period of organ development,
which varies by organ system from 3-8 weeks
to 12-16 weeks, the basic structures of the
organs are established, as shown in the second
column of Table 1. Disruption of development
during this period can result in major disrup-
tions in the large-scale structure of organs or
other structures (Bertollini, 1985; Omtzigt,
1992; Rodriguez-Pinilla, 2000). This type of
damage may result in fetal death, but is more
likely to take the form of major physical mal-
formations (congenital anomalies). Note that
Table 1 refers predominantly to structural
development and does not provide a compre-
hensive list of all systems. "Ear," for example,
refers to the major physical structures of the
auditory system, whereas auditory function is
not manifest before about 28 weeks gestational
age. Also, Table 1 presents only a brief sum-
mary of the most important developmental
events. More detailed discussions of specific
developmental milestones and potential envi-
ronmental effects on those milestones are pro-
vided in the following sections.
Both the organ affected by exposure during
this period and the resulting type of anomaly
are highly dependent on both the agent and the
gestational age at which the exposure occurs.
For example, rubella infection before the
CRITiCAi. PERIODS iN DEVE1.QPMF.NT
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Table 1, Stages of Prenatal and Postnatal Organ Structural Development
s' 3er.es., «0?: Dl»t«:t. 2000; Johntsn. 7000; Moor*. 1977;
Htealeman, 2000; Rice. 2000; WortSOHhc, 2002
Organ System Early Prenatal
Central nervous system 3-16 weeks
Ear 4-16 weeks
Heart 3-8 weeks
Immune system 8-16 weeks
Kidneys
Limbs
Lungs
Palate
Reproductive system
Skeleton
Teeth
4-16 weeks
4-8 weeks
3-16 weeks
6-10 weeks
7-9 weeks
1-12 weeks
12-16 weeks
Mid-Late
Prenatal
17-40 weeks
17-20 weeks
17-40 weeks
17-40 weeks
17-40 weeks
10-40 weeks
17-24+weeks
week of gestation may cause congenital heart
defects and deafness (Miller, 1982). If infection
occurs at 13 to 16 weeks, deafness usually
occurs without heart defects. If infection
occurs after 16 weeks, no structural anomalies
usually occur Another example of age-specif-
ic gestational damage occurs with maternal
exposure to diethylshlbestrol (DES). This
exposure was found to cause genital anomalies
twice as often among male children of women
who took the medication before the 11th week
of gestation as compared to those male chil-
dren exposed later in gestation (Wilcox, 1995).
Other effects of DES exposure are discussed in
subsequent chapters
During later stages of prenatal development,
environmental exposures can result in
impaired growth, physiological defects, or
functional deficiencies, as shown in the third
PostRataj
Continues into adulthood
Immunocompetence
0-1 + years Immune memory
1-18 years
Nephrons mature in outer cortical
region, providing ability to
concentrate unne
> 80% of alveoli are formed after
birth to age 8-10
Sexual maturation, breast, and cervix
development 9-16 years
Ossification continues for -25 years
Primary dentation 4 months after
conception to 3 years postnatal
Permanent dentition 3 months after
birth to 25 years
column of Table 1. As discussed in the follow-
ing secbons, these effects may be manifested as
low birth weight, prematurity, pregnancy com-
plications, or late fetal death (Bogden, 1995;
Hewitt, 1998, Rabinowitz, 1987; Wergeland,
1997).
The patterns of susceptibility summarized
above are broad generalizations derived from
an extensive body of medical and clinical liter-
ature There are many exceptions to these pat-
terns and many unresolved issues regarding
the relationship of adverse health effects in
children and environmental exposures during
specific periods of development Some of the
difficulties in relating exposures during specif-
ic critical developmental periods to observed
health impacts are discussed in Section 2 3
•4 CRITICAL PE-RiOQS IN OEVSI.OPMP.NT
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2.1,3 Ongoing Development
During Childhood
Important development processes continue
after birth. As shown in the last column of
Table 1, major cellular structures of the brain
and other systems continue to develop through
childhood For example, in the brain and nerv-
ous system, neuron migration, cell prolifera-
tion, and synapse formation are all very acbve
from birth through three years of age, and
myelmation, the development of cellular insu-
lation around nerve fibers, continues for at
least 10 years (Rice, 2000) and possibly well
into adulthood (Benes, 1998)
The immune system also develops extensively
during early childhood as immune memory is
established (Dietert, 2000). Improper develop-
ment of the immune system can cause allergies
or autoimmune diseases Exposure to environ-
mental agents during early childhood may
affect immune system development and may
contribute to the development of asthma later
in life (Peden, 2000; Weiss, 1998).
Physical growth and maturation of organ sys-
tems continues through adolescence Puberty
and sexual maturation are primary develop-
mental milestones of adolescent development
Physiologic and hormonal changes related to
puberty begin well before adolescence, at ages
six to eight years In girls, the cells of the cervix
begin to mature and develop into a form and
structure that will be consistent through adult-
hood (Moscicki, 19%). The appearance of sec-
ondary sexual characteristics is marked by the
development of breast buds (thelarche) and is
followed by the onset of menses (menarche)
about two years later. Boys typically show
signs of puberty two to three years later than
girls. For both genders, puberty is accompa-
nied by a rapid increase in height (Needleman,
2000). The process of sexual maturation is
accompanied by complex interactions between
the central nervous system and hormone-
secreting organs, which can be affected by
environmental factors.
2.2 Why Certain Developments!
Stages May && Especially
Vulnerable to Environmental
Exposures
This section briefly reviews some of the under-
lying biological reasons for the sensitivity of
specific developmental stages to environmen-
tal exposures Concepts introduced in this sec-
tion will be helpful in understanding the exam-
ples presented in later chapters
The rapid and diverse nature of processes that
occur in critical developmental periods give
rise to concerns about special vulnerability
during early life stages Some processes, such
as sexual maturation, occur only during cer-
tain periods of development. Other processes
such as apoptosis, or programmed cell death,
occur more widely during development and
are less prominent during adulthood Cell
division in most organs occurs much faster
during development than in adulthood
Finally, many complex processes need to be
effectively coordinated during development,
which requires the cellular and intercellular
signaling systems to work correctly.
The following sections of this chapter briefly
discuss four important processes and instances
where environmental exposures have dis-
turbed these processes, resulting in adverse
developmental impacts
• Control of cell division,
• Apoptosis,
• Gene expression, and
• Cellular metabolism and biotransfbrma-
tion of environmental agents
As will be seen in the following sections, cell
division and apoptosis are more active in cer-
tain developmental stages, resulting in vulner-
abilities to environmental influences that are
unique to early development. Gene expression
is ubiquitous throughout development and
strongly modulates responses to environmen-
CRITICAi. PERIODS :* DEVELOPMENT
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Table 2. Checkpoints in the Ceil Cycie
Source: Alberts, 1SS4a
Phase
GI
Key Checkpoint
Conditions Needed to
f3ss_Chec_kgpjnt ______
Growth
G, cyclin-dependent
protein kinases
Adequate cell growth,
favorable environment
Synthesis of DMA Re-replication blocking factors One copy of DMA made
M
Growth
Mitosis,
Cytokinesis
G2 cyclin-dependent
protein kinases
M-phase promoting factor
All DNA replicated, adequate cell
growth, favorable environment
All chromosomes aligned on
protein spindle
The cell cycle consists of tour distinct phases, each regulated by specific control molecules end characterized by
specific conditions required to advance to the next phase If the conditions are not met. the cycle will not enter the next
phase However, if the checkpoint molecules have been inhibited by a toxicant, the cell cycle might advance before all
conditions are met, leading to unfavorable results such as cell death
tal stimuli The metabolism of pollutants
strongly affects the nature and magnitude of
responses to environmental exposures, and
patterns of metabolism and biotransformation
change in important ways throughout devel-
opment.
Other complex processes in the development
of the central nervous system include cell
migration, axon development (the "wiring" of
the nervous system), synaptogenesis (develop-
ment of connections between nerve cells), and
synaptic plasticity (changes in the pattern of
neurological connections associated with learn-
ing and other developmental processes) Less
is known about potential environmental influ-
ences on these processes, and therefore they are
not covered in this paper. The reader is urged
to review other literature concerning neurolog-
ical development including a review article
regarding critical periods of vulnerability for
the developing nervous system (Rice, 2000).
2.2.1 Control of CeH Division
Rapid cell division is a primary driver of devel-
opment The cell cycle, the process of cell divi-
sion and growth, involves the interaction of
many metabolic and control pathways
(Alberts, 1994a; latropoulos, 1996; Lodish,
1999) In most mammalian tissues, the cell
cycle consists of four distinct phases, as shown
in Table 2 The cell cycle involves continuous
DNA transcription and synthesis of a wide
variety of proteins
All DNA must be successfully replicated
before cell division can occur. Cell growth is
regulated by at least nine growth factor pro-
teins (Alberts, 1994a); normal cell growth
requires that these proteins work properly.
As indicated in Table 2, checkpoints through-
out the cell cycle prevent entry into the next
phase of the cycle if previous stages are not
complete (Alberts, 1994a). Each of the more
than 210 cell types in the human body has its
own usual cell cycle length, ranging from a few
hours to several months or longer A shorter
cycle, implying more rapid metabolic activity,
generally makes cells more vulnerable to toxi-
cant effects. Embryonic cells generally have
very short cell cycles A common regulatory
failure in rapidly cycling embryonic cells is for
the G2 checkpoint to be bypassed. If DNA syn-
thesis is inhibited by a toxicant, the cell ignores
the requirement that all DNA must be replicat-
ed and may proceed directly into a mitosis
phase that results in cell death (Alberts, 1994a).
fj ORiTIGAl. PERiQOS JN DEVELOPMENT
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2.2,8 Apoptosis (Programmed
Cell Death}
Perhaps surprisingly, apoptosis, or pro-
grammed cell death, also is an important
process during development Cell types and
numbers in specific organs are regulated not
only by production of new cells through cell
division, but also by removal of certain cells
through apoptosis (Alberts, 1994b, Brill, 1999)
In some instances, one type of cell is succeeded
by another during a specific developmental
period
Apoptosis is involved in removing webbing
from between the fingers and in regressing the
fetal zone of the adrenal gland (Alberts, 1994b,
Spencer, 1999) Apoptosis is responsible for
eliminating populations of cells in the immune
system that, if they survived, could cause
autoimmune disease (Amsen, 1998)
Apoptosis also plays a critical role in the devel-
oping nervous system, where it occurs in
waves (Naruse, 1995, Rice, 2000; Rodier, 1995).
It begins in proliferative zones and recurs peri-
odically as the nervous system is remodeled
based on the number and kind of connections
each neuron has made. Apoptosis remains
active during the postnatal period because of
on-going nervous system development
Disruption of normal patterns of apoptosis
through altered gene expression or failure of
signaling mechanisms is implicated in a wide
range of pathologies These include autoim-
mune lymphoproliferative diseases and certain
cancers (Landowski, 1997; Ramenghi, 2000)
For example, the persistence of renal stem cells
that are supposed to disappear four to six
weeks prior to birth may make those cells vul-
nerable to postnatal exposures that transform
them into Wdms tumor, a relatively common
childhood cancer (Sharpe CR, 1995). Failure of
apoptosis also is suspected as a cause of autism
(Rodier, 1995)
2.2.3 G&n& Expression
Gene expression, which is the translation of
DNA into RNA and the production of active
proteins from RNA, controls not only cell divi-
sion and apoptosis, but also the metabolic
activity of the cell During development, gene
expression is extraordinarily active a high pro-
portion of genes are being expressed and a
large number of genes are being "switched on"
or "switched off to control cellular activities.
This high level of metabolic activity provides a
wide range of opportunities for environmental
agents to interfere with cell development and
growth.
A toxicant can interact directly with DNA to
disturb gene expression Alternatively, it may
interact with the products of gene expression,
such as enzymes or control molecules (Gregus,
19%). A toxicant may react directly with the
"target" molecule or it may be metabolized to
another compound that is the ultimate toxicant
Reactions can be random in nature if the toxic
agent is highly reactive with a wide range of
chemicals, or they can involve highly specific
interactions between the toxicant and its target.
Exposure to environmental toxicants can affect
many kinds of molecular pathways The path-
ways that are the most vital to continued cell
survival, function, and the error-free transmis-
sion of genetic information are the most impor-
tant to children's environmental health. These
pathways include the following:
• DNA activation and synthesis,
• DNA and protein repair,
• Signal transducbon,
• Cellular metabolism and biotransforma-
tion, and
• Absorption, distribution, and excretion.
For example, signaling •within and between
cells is key to gene expression, cell migration,
and other developmental mechanisms (Hay,
1998, NRC, 2000). Researchers have identified
at least 17 major pathways for developmental
intercellular chemical signaling (NRC, 2000),
and the number is increasing with ongoing
research.
CRITICAL PERIODS ifc DEVf-.
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Environmental contaminants can interfere with
these vital molecular processes and cause per-
manent damage to a child's development
Brain development may be altered when signal
transductaon of neurotransmitters is disrupted
by toxicants such as ethanol, methyl mercury,
and aluminum. Ionizing radiation and other
chemical carcinogens may alter DNA synthe-
sis. Methyl mercury and ionizing radiation
may inhibit cell growth and division in the
developing nervous system (Graeter, 19%), as
well as affect cell survival and migration
(Rodier, 1995). High levels of air pollutants
containing polycyclic aroma be hydrocarbons
may cause abnormal DNA formation (Whyatt,
1998) The effects of exposure to environmen-
tal toxicants may cause significant deficits in
the developing child.
2.2.4 Cellular Metabolism and
Blatrarksformatian of
Environmental Agents
Metabolism and biotransformahon both occur
at a cellular level and their combined effects are
seen throughout the body. Cellular metabo-
lism incorporates all chemical and energy
transformations that occur in our cells as a
result of the breakdown and synthesis of
organic compounds (e.g., food and beverages).
Biotransformation occurs when enzymes
chemically alter a compound, such as a drug, in
the body
Many important metabolic and bio trans forma-
tion processes are poorly developed or are
entirely absent in developing organisms
These processes are important for environmen-
tal health because they can affect how environ-
mental agents are transformed in the body
after exposures. Metabolism may either
increase or decrease the toxicity of a chemical
agent, or make easier or harder its elimination
from the body. Thus, the immaturity of bio-
transformabon processes during development
can be a disadvantage to the fetus or child
when biotransformahon in an adult would
detoxify hazardous substances. In some situa-
tions, immaturity can be an advantage because
biotransformabon in an adult may create a
more hazardous compound through activa-
tion. Given their primary evolutionary func-
tion of detoxifying and eliminating potentially
toxic chemicals, immature or underdeveloped
metabolic pathways are likely, on balance, to
render infants and children more sensitive to
common environmental contaminants. Many
instances of this vulnerability have been identi-
fied (AAP 1999; AAP, 1974; Adam, 1999; de
Wildt, 1999; Faustman, 2000; Graeter, 19%,
Leeder, 1997; Parkinson, 19%, Perera, 1999;
Raunio, 1995; Strolin-Benedetti, 1998).
2.3 How Are Effects During
Critical Periods
identified?
Critical periods of development are identified
based on concerns such as those just discussed
above and actual observations of adverse
effects Laboratory studies may identify specif-
ic biochemical processes that are sensitive to
specific agents, and then epidemiological stud-
ies in humans seek to determine whether the
effect noted in the laboratory is significant in
the real world. In other cases, patterns of
adverse effects such as premature births, birth
defects, and developmental disease are seen
first in a specific population and then an expla-
nation is sought through studies of other
groups or through laboratory investigations of
possible causal mechanisms
During the past three decades, the fields of epi-
demiology and developmental biology have
worked in a complementary fashion to clarify
the general patterns of sensitivity to environ-
mental agents during specific stages of devel-
opment. Knowledge about the timing of
important biochemical and cellular processes
and organ development provides important
leads for epidemiologists studying the devel-
opmental impacts of environmental exposures.
Findings of exposures at particular times in
groups of people who later experience adverse
health effects likewise indicate that particular
biochemical or developmental events may be
sensitive to environmental agents.
8 CH:TIGA1. PSRiOQS JN DEVELOPMENT
-------
It often is difficult to determine whether specif-
ic stages of development are sensitive to
known environmental agents For example, it
may be unclear whether developmental
impacts seen in laboratory animal studies also
are likely to be seen in humans Although the
general developmental patterns in laboratory
animals are similar to those in humans, there
may be important differences in how animals
and humans absorb, metabolize, or respond to
specific agents during specific developmental
stages. The effect of thalidomide exposure,
described below, is a case in point. Animal
studies also are limited by the difficulties of
determining correct doses and dosing patterns
and of measuring an endpoint appropriate to
the human experience
The pharmaceutical thalidomide was used suc-
cessfully in the 1950s to treat nausea and vom-
iting associated with pregnancy. Although not
released for use in the United States, thalido-
mide was marketed in other countries for sev-
eral years beginning in 1956. The drug showed
no apparent toxicity in adult humans or ani-
mals at therapeutic levels (Rogers, 1996), but
caused severe limb deformities in the babies of
women who had taken the drug These defor-
mities were not observed in multi-generational
animal toxicity studies despite the use of dose
levels (per unit body weight) that were much
higher than those administered to pregnant
women Worldwide, an estimated 5,850
infants were born with major limb defects after
their mothers took the drug
Another difficulty with animal and epidemio-
logical studies is that the period of human
exposure may not be precisely known, or the
period of exposure in conventional animal tox-
icity tests may cover many different develop-
mental stages In the chapters that follow, we
present the results of several epidemiologic
studies in which the increased incidence of
adverse reproducbve outcomes, birth defects,
or childhood diseases is linked to exposures
that may have occurred pre- or post-concep-
tion, during early or late pregnancy, or even
postnatally In such cases, the developmental
stage affected commonly is inferred from the
nature of the damage For example, reduced
fertility is taken to imply effects on germ cells
or during the periconceptual period, major
malformations imply effects during organ
development, and growth retardation implies
effects later in pregnancy
These assumptions generally are quite reason-
able and may be helpful in identifying oppor-
tunities for exposure reduction or directions for
further investigation In the discussions that
follow, however, we attempt to maintain the
distinction between (1) critical periods identi-
fied based on inferences from limited numbers
of studies or on general considerations of
developmental patterns, and (2) those infer-
ences that have been confirmed by multiple
studies in which the chain of causality is rela-
tively clear between the biochemical level and
the observed adverse effects
The majority of examples fall into the first cate-
gory Individual studies provide plausible, but
not conclusive, evidence of relationships
between exposures in a given developmental
period and adverse health outcomes.
Therefore, the reader should consider the
cumulative weight of evidence concerning var-
ious effects, and not just individual studies. On
the whole, a rapidly growing body of evidence
indicates that early human development repre-
sents a period with its own unique set of vul-
nerabilities to environmental agents Some of
these vulnerabilities arise because fetuses,
infants, and children are more (or occasionally,
less) sensitive to the effects of specific agents
than adults, because of immaturity. Other spe-
cial vulnerabilities arise owing to the sensitivi-
ty of processes that occur only during early
development (e g, organ development) or the
processes that are much more prominent at this
life stage (e g, apoptosis, rapid cell division).
CRITICAL PERIODS if* DEVFLOPMENT
-------
Adverse Effects of Parental
Exposures Before or Around the
I line of Conception
This chapter discusses available evidence
linking adverse effects in children with
parental exposures to environmental toxicants
before or around the time of conception.
Section 31 summarizes studies of parental
exposures that may damage germ cells
Section 3 2 reviews studies of the adverse
effects associated with exposures of parents
and/or offspring during or just after concep-
tion.
3.1 Environmental Agents
That May Damage
Germ Cells
As discussed in the previous chapter, germ
cells begin to develop before birth and persist
throughout life In men, germ cells continue
to be produced from stem cells throughout
adulthood. In women, mature oocytes are
produced every month from folhcular cells.
Germ cells and their progenitors are sensitive
to a wide range of environmental agents
Exposure to environmental toxicants may
cause premature death of primary oocytes in
the fetus through effects on discrete signaling
pathways involved in apoptosis. This reduc-
tion in gonadal reserves, in turn, may cause
reduced fertility or premature reproductive
failure (Silbergeld, 1999; Tilly, 1998) Male
reproductive stem cells also may be particu-
larly sensitive to environmental exposures
due to their rapid cell cycle
Several studies have associated impaired
reproductive health with damage to germ
cells or their progenitors, including the fol-
lowing:
• A well-publicized example is the nemato-
cide dibromochloropropane (DBCP),
which caused dramatic azoospermia and
infertility among exposed workers
(Goldsmith, 1997; Potashmk, 1995).
Fewer boys than usual were born to
DBCP-exposed workers who were able to
conceive
• Women exposed to cigarette smoke dur-
ing their mother's pregnancy had reduced
fertility (Weinberg, 1989)
• Men exposed to diethylstilbestrol (DES) in
utero were found to have lowered sperm
count and increased frequency of abnor-
mal sperm, but apparently normal fertili-
ty (Bibbo, 1977; Wilcox, 1995)
Fertility clearly can be harmed by hazardous
exposures that affect ovarian function
Women exposed to the toxic agents in ciga-
rette smoke may develop menstrual disorders
and altered reproductive endocrine profiles.
One study shows that smoking 10 or more cig-
arettes per day was related to greater variabil-
ity in menstrual cycle length, an increased fre-
quency of anovulation, and short luteal phase
(Windham, 1999) Many studies show that
cigarette smoking reduces fertility among
women (Baird, 1985, Hartz, 1987; Howe,
1985) Workplace exposures, such as high lev-
els of exposure to nitrous oxide or mercury,
also can impair fertility (Rowland, 1995,
Rowland, 1992) Ovarian toxicity and
impaired fertility can be caused by drugs or
radiation exposure used to treat lymphopro-
10 ORiTIGAi. PERIODS IN OEVF.I.OPMF.NT
-------
liferative disorders or cancer (Blumenfeld,
1998, Gonzalez-Crespo, 1995; Meirow, 1999).
A substantial body of evidence from human
studies demonstrates that exposures to envi-
ronmental agents and medical radiation can
injure germ cells in such a way as to cause
increased incidence of cancer, particularly
leukemia, among offspring of the exposed
individuals (Buckley, 1989, Gardner, 1990;
McKinney, 1991, Roman, 1999) Tables 3 and
4 summarize observed relationships between
preconception exposures of men and women
and increased cancer rates in their children.
As shown in Table 3, paternal exposures to
ionizing radiation have been linked with
leukemia and lymphoma in subsequent chil-
dren. Paternal exposures to benzene also
have been linked to leukemia in children
(Buckley, 1989). One study observed
increased risks of leukemia in the children of
fathers exposed to wood dust (McKinney,
1991) Another study found an association
between paternal occupational exposure to
metals and hepatoblastoma incidence in off-
spring (Buckley, 1989).
Maternal employment in certain occupations
such as the food industry or exposures to ion-
izing radiation have been shown to be associ-
ated with an increased risk of leukemia and
non-Hodgkin's lymphoma (McKinney, 1991;
Draper, 1997) Maternal exposures to metals,
paints, petroleum products, and pigments
prior to conception have been associated with
the development of hepatoblastoma in off-
spring (see Table 4) As noted in Section 2.3
not all studies distinguish exposures before
conception from exposures during pregnancy
(Buckley, 1989, McKinney, 1999) This limita-
tion makes it difficult to identify the precise
stage at which adverse effects occur, and
poses problems for women trying to under-
stand potential reproductive risks in the
workplace These studies should not be inter-
preted as strong evidence for a link between
parental exposures to certain toxicants and
cancer in offspring because some of the stud-
ies investigated small numbers of affected
parents or involved exposures to multiple tox-
icants (McKinney, 1991) or did not report a
statistically significant increase in the inci-
dence of a particular cancer (Draper, 1997).
Animal studies provide supporting evidence
that exposures during prenatal life can affect
future reproductive function in adult organ-
isms For example, prenatal exposure to cer-
tain highly chlorinated chemicals such as
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
or polychlorinated biphenyl-169 (PCB-169)
was associated with reduced sperm produc-
Tafoje 3. Association Between Preconception Exposures
in Men and Cancer in Offspring
Cose to
Cancer That
Benzene3
Diagnostic
X-raysb
Ionizing
radiationb>c
Metals8
Wood dust"
Not quantified
Not quantified
> 100 mSv
(milliSievert)
> 100 mSv
> 10mSv
1-5 mSv
Not quantified
Not quantified
Preconception
Preconception
& months prior to conception
Lifetime preconception
6 months prior to conception
Preconception
Before birth
Preconception
Leukemia
Leukemia
Leukemia/non-Hodg kin's
lymphoma
Leukemia
Leukemia
Acute lymphoblastc leukemia
Hepatoblastoma
Leukemia
• Buckley, 1989, " McKinney. 1991, c Roman. 1999
GRITICAi. PERIODS Hi
-------
Tabie 4. Association Between Preconception Exposures
in Women and Cancer in Offspring
Exposure
Dose to
Mother
Cancer That
Food industry3
Metal dusts,
petroleum products,
paints, pigmentsb
Radiation0
Not quantified Preconception or prenatal
Not quantified Preconception or prenatal
Not quantified Preconception
Leukemia/non-Hodgkin's
lymphoma
Hepato blastema
Leukemia/non-Hodgkin's
lymphoma
• McKmney, 1991, " Buckley, 1989, c Draper. 1997
tion in male rats (Gray, 1998, Loeffler, 1999).
This effect occurred after a single dose of
TCDD (Gray, 1997). In another example,
reduced sperm production was seen in rats
that were exposed to DES during gestation
(Sharpe RM, 1995). Ovarian toxicity has been
demonstrated in experimental animals after
exposures to lead, 1,3-butadiene epoxides, 4-
vinylcyclohexene, cyclophosphamide, hexa-
chlorobenzene, and other compounds (Doerr,
1996, Doerr, 1995; Foster, 1992; Junaid, 1997;
Plowchalk, 1992)
As with humans, exposures of test animals
during germ cell development are associated
with increased risk of cancer in offspring. An
excellent review of the literature on thus sub-
ject can be found in an article by Anderson
(2000) Among the agents causing increased
cancer incidence in offspring after paternal
exposures are x-rays, DES, urethane, and
drugs such as some chemotherapy agents.
Exposure to these agents has been associated
with development of lung cancer, leukemia,
lymphoma, and bver tumors in offspring
Preconception exposures of female laboratory
animals to x-rays, DES, 7,12-dimethyl-
benz[a]anthracene, N-nitrosodiethylamme, or
urethane have been associated with develop-
ment of lung cancer and uterine adenocarci-
nomas in the offspring
Genetic research has suggested mechanisms
by which some of these adverse effects may
occur. Studies have shown that both smoking
and pesticide exposure can increase aneu-
ploidy (an abnormal number of chromo-
somes) in sperm cells (Harkonen, 1999,
Padungtod, 1999). Other studies illustrate
how exposure to combustion byproducts may
directly damage DNA in sperm cells. For
example, benzo[a]pyrene, a common product
of tobacco and other combustion, can react
with DNA to form adducts, which are DNA
bases that have been chemically changed so
that they do not resemble normal DNA
(Zenzes, 1999). The studies reported that the
frequency of DNA adducts is highest in the
sperm of smokers, with lower but still
detectible levels in non-smokers Such
adducts may be a potential cause of mutations
that could affect fertility and the health of any
offspring.
Research on female germ cells also has shown
that oocyle (egg cell) DNA can be altered by
toxic exposures in the preconception period.
For example, alcohol exposure can disrupt
chromosome duplication, resulting in aneu-
CRiTICAl.
IN OEVP1.OPM6.NT
-------
ploidy in the embryo (Kaufman, 1997) Also,
exposure to 1,3-butadiene can induce changes
in the chromosome structure of pre-ovulatory
oocytes at doses that are not lethal to the cell
(Paccierotti, 1998).
3.2 Environmental Agents
That May Cause
Damage At or Just
After Conception
The period during and shortly after concep-
tion also is a vulnerable time during which
environmental exposures can affect the health
of the embryo Known or suspected mecha-
nisms for these effects include genetic alter-
ation of male or female gametes, transfer of
toxicants in semen to the microenvirortment
of the conceptus (the cell mass at conception),
disruption of checkpoint control mechanisms
(discussed in Section 2.21), or other unknown
mechanisms (Alberts, 1994a; Olshan, 1993)
Disruption of checkpoint control mechanisms
could explain, in part, the ability of certain
toxicants to cause the embryo to die following
exposures that occur shortly after conception.
As discussed in Section 2.3, it often is difficult
to distinguish effects caused by exposures in
the more distant past from exposures in the
period around conception.
Despite these technical difficulties, a number
of studies have linked paternal penconceptu-
al exposures to adverse outcomes during
pregnancy and childhood For example,
increases in spontaneous abortions and other
types of fetal death have been observed in
populations in which the father was exposed
to anesthetic gases, lead, mercury, organic sol-
vents, pesticides, or welding fumes (Anttila,
1995; Arbuckle, 1999; Arbuckle, 1998; Cohen,
1980; Kristensen, 1993, Lindbohm, 1991a;
Lindbohm, 1991b, Olshan, 1993, Savitz, 1997;
Savitz, 1994; Taskinen, 1989) Congenital mal-
formations have been linked with paternal
exposure to anesthetic gases, marijuana, pesti-
cides, tobacco, welding fumes, and possibly
lead (Blatter, 1997, Garcia, 1998a; Kristensen,
1997, Olshan, 1993, Sallmen, 1992; Savitz,
1994, Wilson, 1998, Zhang, 1992) Pre-term
delivery and low birth weight have been asso-
ciated with exposure of the father to lead, pes-
ticides, or solvents (Kristensen, 1993, Lin,
1998, Min, 1996; Savitz, 1997) Penconceptual
exposures as well as paternal preconception
exposures also may have contributed to the
elevated cancer risks in children shown in
Table 3.
Other studies have demonstrated the presence
of a wide variety of environmental toxicants
in semen (Arbuckle, 1999, Pacifici, 1995,
Schecter, 19%; Stachel, 1989) These findings
may be significant given the evidence that tox-
icant exposures can affect sperm count, motil-
ity, and morphology (Lemasters, 1998, Vine,
1994)
A few studies distinguish between the effects
of women's pre-conception and periconceptu-
al exposures on reproductive outcomes.
Studies of Yusho and Yu-Cheng disease
describe the effects of food contaminated with
polychlorinated biphenyls (PCBs) and poly-
chlorinated dibenzofurans, including in utero
and lactational exposure to infants (Aoki,
2001, Lucier, 1987). PCBs and other endocrine
disrupters may be transferred to children
through the placenta four to five years after
the maternal exposure occurred and con-
tribute to decreased birth weight (Lucier,
1987). Alterations in neural function, devel-
opmental delays, and intellectual impair-
ments have been observed in children
exposed to PCBs, but the particular period of
exposure was not described (Aoki, 2001).
Isotopic studies indicate that maternal expo-
sure to lead may occur prior to conception,
during a subsequent pregnancy, lead from
skeletal stores can be mobilized and trans-
ferred to the fetus through the bloodstream,
resulting in exposure during a critical period
of prenatal development (Gulson, 1998;
CRITICAL PERIODS :tt
13
-------
Gulson, 1997; Han, 2000). Most women expe-
rience limited lead exposure during pregnan-
cy and the postnatal period, but their long-
term skeletal stores may contain large quanti-
ties of lead that can become mobilized at an
accelerated rate and impact the development
of their offspring. In addition, greater mobi-
lization of skeletal lead occurs during the
postnatal period than during pregnancy,
resulting in increased exposure to breast-feed-
ing infants (Gulson, 1998). As with men's
exposures, it is likely that some of the effects
attributed to preconception exposures may in
fact be due to exposures near conceptioa
14 CR:TICA!. PERIODS IN OFVEi.OPMf.NT
-------
VI /• J9 /* ^ v]
Adverse Eriects ox Environmental
Exposures During Pregnancy
This chapter summarizes available informa-
tion linking adverse effects in children with
environmental exposures during pregnancy.
The exposure period addressed in this chapter
occurs after the period addressed in Chapter 3
(before or around the time of conception) and
before the period addressed in Chapter 5
(childhood) Section 4.1 describes the general
pattern of fetal development and environmen-
tal toxicity during pregnancy. Section 4 2
describes a range of adverse effects that can
occur during pregnancy.
4.1 General Pattern of
Fetal Development and
Environmental Toxicity
During Pregnancy
As discussed in Chapter 2, the period of rapid
embryonic and fetal development during
pregnancy is associated with increased sensi-
tivity to specific environmental agents
During this period, complex and rapid change
is normal, from the molecular level through
all the biochemical and physical processes
that determine the course of development
Cell division, migration, differentiation, and
apoptosis all must occur in the correct
sequence in the correct spatial orientation,
coordinated through a large number of con-
trol and signaling systems.
During early fetal life, a wide variety of genes
are sequentially activated and inactivated,
providing a number of targets for environ-
mental exposures. The interaction of genes
with environmental conditions (broadly
defined) is believed to account for a quarter to
a half of all developmental defects (NRC,
2000) Fetal and embryonic exposures to envi-
ronmental toxicants also may increase the risk
for cancers in adults and may be responsible
for childhood cancers that have been linked to
preconception exposures (Hoover, 2000;
Lichtenstein, 2000)
Interference with repair or defense pathways
is one mechanism by which environmental
exposures may produce adverse health effects
in children. Experimental studies suggest that
defects in DNA repair may result in vulnera-
bility to specific toxicants during develop-
ment. For example, the effects of
benzo[a]pyrene on the developing fetus have
been studied in transgenic mice that are miss-
ing p53, a tumor suppressor gene important
for DNA repair (Nicol, 1995). These animals
show an increased sensitivity to
benzo[a]pyrene exposure and an increased
death rate when exposed to the chemical dur-
ing gestation. Damage to related genes in
humans likewise could increase sensitivity to
agents that damage genetic material.
Environmental agents also can affect cell
migration during fetal development
Exposures to ionizing radiation and methyl
mercury, for example, have been shown to
affect the migration of neurons (cells that will
form the nervous system and brain) during
development (Rodier, 1995) Schizophrenia is
thought to result, in part, from abnormal neu-
ronal migration (Beckmann, 1999, Bunney,
1995, Bracha, 1991), but the role of prenatal
exposures to environmental agents in causing
this disease is not clear.
During the course of embryonic and fetal
development, individual cells also differenti-
CRIT1CA:. PERIODS :N OSVFi.QPMENT
-------
ate, assuming the specific form and function
associated with their final role in the body
This process is under the control of inter- and
intra-cellular signaling processes. If cells fail
to differentiate properly, organ function may
be compromised and fetal survival may be
endangered Many cancers disrupt proper
cell differentiation or cause differentiated cells
to revert to more primitive forms (Bisogno,
2002; Shimada, 2001) Exposures to environ-
mental agents may disrupt proper cell differ-
entiation either by damaging genetic material
or by interfering with normal cell signaling
(Anderson, 2000).
Undifferentiated cells also may be more vul-
nerable than differentiated cells to toxic
effects Chemicals shown to affect specific
types of undifferentaated cells include ethanol
(Mullikin-Kilpatnck, 1995), manganese (Di
Lorenzo, 1996), nicotine (Berger, 1998), and
TCDD (Murante, 2000).
4.2 Adverse Effects During
Pregnancy
This section summarizes the literature sup-
porting the sensitivity of prenatal develop-
ment to insult by environmental exposures.
As noted in Section 2.3, attributing specific
adverse effects to exposures during specific
time periods is not always possible. For this
reason, we concentrate on several effects that
are detected during pregnancy or at birth and
therefore can be attributed to prenatal expo-
sures with a high degree of confidence These
include early fetal death, congenital malfor-
mations, growth deficits during pregnancy
and pre-term birth, and pregnancy complica-
tions and late fetal death. Subsequent chap
ters address effects seen during childhood
and adulthood that may arise from exposures
during sensitive time periods.
4.2.1 Early Fetal Death
Early fetal death can be caused by exposure to
environmental agents in the penconcepbon
period (approximately the first two weeks
after fertilization) or in later prenatal develop-
ment. Clinically, this effect is manifested as a
spontaneous abortion during early pregnan-
cy. A wide variety of compounds have been
shown to cause early fetal death. Heavy caf-
feine intake, smoking, and cocaine use by
pregnant women, for example, can cause
increased rates of spontaneous abortion
(Infante-Rivard, 1993; Ness, 1999). Workplace
exposure to antineoplastic drugs or to sol-
vents in the periconception and/or prenatal
period also has been linked to an increased
risk of miscarriage (Lindbohm, 1990;
Lipscomb, 1991, Taskmen, 1994, Valanis,
1999)
Some studies have associated spontaneous
abortion with women's exposure to environ-
mental contaminants at relatively low levels
One study noted this effect for chlorination
byproducts found in drinking water (Waller,
1998), although another study did not (Savitz,
1995). Indicators of maternal pesticide expo-
sure during pregnancy also have been associ-
ated with increased risk of miscarriage
(Arbuckle, 1998; Nurminen, 1995). Animal
studies also have associated fetal death with
pesticide exposure (Leoni, 1989, Perreault,
1992; Varma, 1987).
4.2.2 Congenital Malformations
Congenital malformations arise from the fail-
ure of specific organ systems or structures to
form and develop properly. As discussed in
Chapter 2, the bulk of major malformations
are thought to arise from developmental
defects during the early stages of organ devel-
opment in the first trimester of pregnancy.
Both the type of anomaly and the specific
organ affected by exposure during organ
development are highly dependent on the
agent and the gestational age at which the
exposure occurs. Well-studied examples of
the variability and specificity of such effects
include rubella (Miller, 1982) and diethyl-
shlbestrol (DES) (Wilcox, 1995). Rapid cell
division during organ development has been
suggested to account for some of the increased
sensitivity to environmental exposures during
this period (Rogers, 1996).
16 CRiTIGA!. PERiOOS IN OF.VF.1.OPMF.NT
-------
Birth defects are a leading cause of infant mor-
tality. The relationship between exposures to
environmental agents and specific types of
abnormalities has been studied extensively
Texts by Schardein (2000) and Shepard (2001)
provide useful overviews of the current state
of knowledge, including the following well-
established examples of human teratogens
(chemicals that cause birth defects):
• Pharmaceuticals such as anticancer agents,
sex hormones, certain anticonvulsants,
and certain psychotropics may cause
abnormalities of the nervous system and
other organs
• Infectious agents such as cytomegalovirus,
syphilis, and toxoplasma gondii produce a
wide range of malformations
• Intensive ionizing radiation administered
for diagnostic or therapeutic purposes can
affect fetal development
• Substance abuse, such as maternal alcohol
abuse during pregnancy, can cause fetal
alcohol syndrome, producing symptoms
including craniofacial anomalies (abnor-
mal development of the head and face)
and microcephaly (greatly reduced skull
size) Maternal cocaine abuse can lead to
cardiovascular and brain defects.
• Methyl mercury exposure from contami-
nated food may be associated with central
nervous system anomalies, abnormal den-
tition, and mental retardation.
• Maternal endocrine disorders such as dia-
betes meUitus, if poorly controlled, also
increase the risk of congenital anomalies
Occupational exposures to solvents (Khattak,
1999, McMartin, 1998) or glycol ethers (Knill-
Jones, 1997) just before or during pregnancy
have been associated with increased risk of
birth defects Inhalant abuse during pregnan-
cy has been associated with craniofacial
abnormalities (Jones, 1998, Wilkins-Haug,
1997)
Birth defects have been associated with occu-
pational or environmental pesticide exposures
in some studies (Filkins, 1998). Maternal
exposure to pesticides, either occupahonally
or during home use, has been associated with
increased risk of birth defects (Shaw, 1999,
Garcia, 1999) Other studies have not found
such a link, possibly because epidemic logical
studies often combine all pesticide exposures
together into a single exposure category. This
approach increases the likelihood of missing a
true association with a specific pesticide
(Garcia, 1998b, Nurmmen, 1995).
Several "ecological" studies link indicators of
chemical exposure during pregnancy, usually
pesticide use, to increased risk of birth defects.
Ecological studies evaluate the relationships
between patterns of disease incidence in spe-
cific populations or geographic areas and
indicators of potential environmental expo-
sures, such as land use or proximity to pollu-
tion sources. Because exposures are not
directly measured, ecological studies must be
interpreted cautiously, the observed patterns
of disease incidence may actually be associat-
ed with factors not included in the analysis
Ecological studies have found, compared with
control area, elevated rates of birth defects in
California counties with extensive agricultur-
al activities (Schwartz, 1988) and in areas with
high grain production in Norway (Kristensen,
1997). These findings suggest a relationship
between pesticide exposures and birth
defects, but are not strong enough by them-
selves to indicate a cause-effect relationship.
Nonetheless, these findings are consistent
with animal research showing an increase in
limb defects resulting from exposure to cer-
tain fungicides (Chernoff, 1979; Larsson, 1976;
Maci, 1987) and organophosphate insecticides
(Byrne, 1983). A similar ecological study,
however, found only weak evidence for a rela-
tionship between agricultural production and
birth defects in counties in New York State
(Lin, 1994)
CRIT1CA-. PERIODS :
-------
4.2,3 Growth Deficits During
Pregnancy and Pre-Term
Birth
During pregnancy, the human embryo and
fetus grow rapidly, from less than a milligram
(one-thousandth of a gram or about 000004
ounces) to an average of about 3,000 grams (7
pounds) This rapid growth is necessary to
prepare the fetus for independent existence
outside the womb Thus, defects in fetal
growth can have major impact on neonatal
health and mortality. Fetal growth retarda-
tion and pre-term birth are serious health
problems that may be related to poor mater-
nal weight gam, substance abuse, placenta!
insufficiency, gestational hypertension, or
other conditions Growing evidence also links
specific environmental exposures to fetal
growth deficits and pre-term birth
Numerous studies have associated cigarette
smoking during pregnancy with fetal growth
retardation. The reduction in birth weight is
dose-dependent (Center, 1995; Ellard, 1996).
Smoking one to two packs per day in the sec-
ond trimester, for example, increases the risk
of growth deficit by two to five times
(Sprauve, 1999) Exposure to environmental
tobacco smoke also has been associated with
reduced birth weight (Eskenazi, 1995,
Windham, 1999). Smoking cessation during
pregnancy was found to reverse the effect
(Das, 1998)
Low-level exposure to PCBs in utero has been
associated with reduced birth weight and
reduced growth during early childhood
(Lucier, 1987, Patandin, 1998). Other effects
include obesity in adolescence that also has
been linked to prior exposure to PCBs
(Gladen, 2000)
4.2.4 Pregnancy Complications
and Late FetaS Death
Some types of environmental exposures can
increase the risk of certain pregnancy compli-
cations. These complications then can
increase the risk for pre-term birth, late fetal
death (stillbirth), or other adverse outcomes.
For example, maternal smoking increases the
risk for placenta previa (attachment of the
placenta in an abnormal position in the
uterus), placenta! abruption (premature sepa-
ration of the placenta from the uterus), and
stillbirth (Chelmow, 1996, DiFranza, 1995;
Shiverick, 1999, Sibai, 1995).
Increased risk of preeclampsia (pregnancy-
induced hypertension) has been linked to
heavy maternal coffee consumption, occupa-
tional exposure to solvents, and possibly envi-
ronmental exposure to lead (Bogden, 1995;
Hewitt, 1998, Rabmowitz, 1987, Wergeland,
1997) Tobacco smoking, paradoxically,
appears to lower the risk for preeclampsia
(Zhang, 1999)
Increased risk of stillbirth also has been asso-
ciated with environmental exposures during
middle to late pregnancy Implicated sub-
stances include arsenic, lead, mercury, pesti-
cides, and possibly chlorinated disinfection
byproducts (Golub, 1998; Nurminen, 1995,
Pastore, 1997, Schuurs, 1999).
IS OR:TIGA!. PERiOQS IN OEVEI.OPMF.NT
-------
Ul~c I* f f i"-<
verse Jtttects ot exposures
During' Criilclkoocl
Exposures to environmental agents can cause
adverse effects that are initiated or first
become apparent in children. As discussed in
Chapter 2, major cellular structures of the
brain and other systems continue to develop
into childhood. For example, neuron migra-
tion, cell proliferation, and synapse formation
occur rapidly from birth through three years
of age, and myelination continues for about 10
years (Rice, 2000) and potentially longer
(Benes, 1998) Also, the immune system
develops extensively during early childhood
as immune memory is established (Dietert,
2000). Behavioral, emotional, and cognitive
development during childhood also can be
affected by environmental exposures
Adverse developmental effects seen during
this period take a wide variety of forms,
including neonatal mortality, growth deficits,
and defects or delays in functional develop-
ment Sexual maturation and puberty also
may be affected by environmental exposures
in utero or during childhood. In addition,
childhood cancers occur in a pattern that is
intimately connected with specific develop-
mental processes and is distinct from the pat-
tern in adults.
This chapter discusses a wide range of
adverse health outcomes that are manifested
during infancy, early childhood, and adoles-
cence in the following order:
• Neonatal mortality;
• Growth deficits during early childhood,
• Functional deficits and delayed or
impaired functional maturation;
• Effects on puberty and sexual maturation;
and
• Childhood cancer
As noted previously, the precise timing of the
exposures responsible for the observed effect
may not be clear in all cases For example,
studies of maternal occupation may involve
exposures occurring both before and after
conception In the following discussion, we
take care to indicate the strength of evidence
for the relationship between exposures during
particular developmental periods and adverse
effects.
5.1 Neonatal Mortality
Complications related to short gestation and
low birth weight (see Sections 4.2.3 and 4.2.4 in
this report) account for about one-third of
infant mortality in the United States (Sowards,
1999, US DHHS, 2000) Congenital malforma-
tions (discussed in Section 4.2.2 of this report)
also are a leading contributor to this mortality.
A number of specific environmental exposures
during preconception, periconception, and
pregnancy have been found to be associated
with increased risk of such effects, and as a
result, an increased risk of neonatal mortality.
In addition to the previously noted causes of
neonatal death, limited evidence links specific
environmental exposures to sudden infant
death syndrome (SIDS) Well-controlled stud-
ies suggest that maternal smoking during
pregnancy, maternal smoking status after
CRITICAi. PERIODS Hi
19
-------
delivery, and postnatal exposure to environ-
mental tobacco smoke (due to maternal smok-
ing or the presence of other smokers in the
household) all are associated with elevated
risk of SIDS, and that SIDS risk is associated
with increasing intensity of exposure to
household tobacco smoke (Blair, 1996;
Haglund, 1990; Klonoff-Cohen, 1995; Malloy,
1988, Taylor, 1995). In 1997, the California
Environmental Protection Agency reported
that there was sufficient evidence to find a
causal association between environmental
tobacco smoke and SIDS (CA EPA, 1997).
Other studies have found a higher SIDS risk
among children exposed to toxicants such as
tobacco and cocaine in utero (Aim, 1998;
Milerad, 1998; Ostrea, 1997). The presence of
potentially confounding factors, including
multiple birth, allergies, apnea, sex of child,
mother's age, and socioeconomic status, how-
ever, suggests that these studies should be
interpreted cautiously While many of these
factors have been researched as primary caus-
es of SIDS, they also are relevant as confound-
ing factors when investigating tobacco smoke
and cocaine use during pregnancy.
5.2 Growth Deficits During
Early Childhood
Early childhood is a critical time in develop-
ment because many organ systems are grow-
ing and continuing to mature Many environ-
mental exposures have been associated with
early childhood growth retardation, which
may in turn be associated with adverse health
outcomes (Osmond, 2000). Growth deficits
may be associated with high-level exposures
to toxicants, which cause acute adverse
effects, or they may be associated with rela-
tively low exposures, where no other obvious
symptoms are seen. Sometimes, reduced
growth can be traced to a specific underlying
defect in functional development, as dis-
cussed in Section 5.3.
Environmental contaminants known to cause
growth retardation during childhood include
lead, PCBs, and tobacco Chronic lead expo-
sure has been linked to decreased growth dur-
ing childhood. In a large study of children
under seven years old, each increment in
average blood lead levels of 10 Hg/dL was
associated with an average decrease in height
of 1 57 cm and an average decrease in head
circumference of 0.52 cm (Ballew, 1999). In a
similar study of Greek children aged six to
nine years, height decreased 0.86 cm and head
circumference decreased 0.33 cm for every 10
Hg/dL increase in blood lead (Kafourou,
1997)
Growth during childhood also has been stud-
ied in individuals who were prenatally
exposed to marijuana or tobacco. Maternal
marijuana use was found to be associated
with reduced head circumference at birth, and
the effect persisted into adolescence (Fried,
1999). As noted in Section 423, prenatal PCB
exposures appears to retard growth during
pregnancy and into childhood (Patandin,
1998)
5.3 Functional Deficits and
Delayed or impaired
Functional Maturation
As discussed in Chapter 2, many organ sys-
tems continue to mature during childhood
These developmental processes include
myelination of the central nervous system,
development of immune memory, maturation
of the lungs and kidney, and, later in child-
hood, sexual maturation and puberty
Many adverse effects on development in late
pregnancy and infancy show themselves as
functional deficits in organs or systems,
instead of overt malformations or growth
retardation (Naruse, 1995, Rice, 2000) The
pathologic processes leading to these defects,
which may be associated with environmental
exposures, are initiated at the time of expo-
sure, but the effects typically are not detected
until after the child is born. For example,
exposure to neurotoxins such as lead, PCBs,
and methyl mercury during the critical period
of middle to late pregnancy has been associat-
ed with the development of neurobehavioral
effects in exposed children (Grandjean, 1999,
20 ORiTICAI. PER-O08 IN DEVELOPMENT
-------
Stewart, 2000, Tang, 1999) Congenital rubel-
la is a classic example in which both structur-
al birth defects and functional deficits occur,
including functional deficits involving the
central nervous system (Chess, 1978),
increased incidence of diabetes, thyroid and
other endocrine disorders, and vascular dis-
ease (Floret, 1980; Sever, 1985).
Functional deficits thought to be associated
with environmental exposure are seen in the
respiratory system. Prenatal exposure to
tobacco smoke has been associated with
deficits in respiratory function, as well as with
persistent pulmonary hypertension among
newborns (Bearer, 1997; Stick, 19%, US NIH,
1993) Increased incidence of respiratory ill-
ness and reductions in lung function have
been found to be associated with maternal
smoking (Ware, 1984). There is growing evi-
dence for the connection between exposures
to environmental agents and the severity and
incidence of asthma attacks (Chew, 1999,
Hajat, 1999, Kunber, 1998)
Extensive evidence also supports the relation-
ship between pre- and postnatal exposures to
lead and long-term impairments in neurologi-
cal development. These impairments may
translate into learning deficits and disruptive
or dangerous behavior
There is limited evidence linking children's
exposures to lead to defects in the control of
physiological processes such as energy metab-
olism, cardiac function, and blood pressure.
In one study, adolescents with chronic lead
exposure were more likely to become obese,
even after adjusting for other risk factors
(Kim, 1995) Lead poisoning in adults has
long been linked with increased risk of hyper-
tension, although the relationship in children
is less clear (Loghman-Adham, 1997; Todd,
1996). Children chronically exposed to lead
have been found to exhibit subclimcal alter-
ations in kidney function (Fels, 1998) The
implications of these symptoms for the long-
term maintenance of blood pressure control
and cardiovascular disease risk are not yet
known
5.4 Effects on Puberty and
Sexual Maturation
There is growing concern that environmental
exposures may affect the sexual maturation of
children. This concern has focused primarily
on apparent decreases in the average age of
puberty in some ethnic groups in the United
States and other countries Decreased age at
puberty is a concern because of the increased
risk of impaired stature and earlier onset of
risky behaviors (Halpern, 1997; Meschke,
1997; Wilson, 1994). Changes in age at puber-
ty also might be a symptom of other impair-
ments in endocrine or reproductive function
As discussed in the next section, reduced age
at puberty also may be associated with
increased cancer risks later in life
Some studies show that the age at puberty
and sexual maturation appear to be decreas-
ing in some populations (Fredriks, 2000,
Freedman, 2000, Herman-Giddens, 1997). The
apparent reduction varies across racial and
ethnic groups. In the United States as a
whole, evidence suggests that girls are begin-
ning to develop secondary sexual characteris-
tics at a younger age, although the average
age at menarche, the beginning of the men-
strual function, is generally stable While
some of the observed changes in sexual devel-
opment may be due to improved children's
health and nutrition (Baker, 1985,
Georgopoulos, 1999), exposures to environ-
mental agents also may play a role (Herman-
Giddens, 1997)
Effects on puberty and sexual development
are seen most clearly in children who have
received cytotoxic drugs or high-dose radia-
tion therapy as treatment for cancer
Chemotherapy with alky la ting agents and
other cancer drugs causes pathological
changes in the reproductive systems in both
adolescent females (Nocosia, 1985, Quigley,
CRITICAL PERIODS sK BfVf-.OPMf.NT 21
-------
1989) and males (Matus-Ridley, 1985; Quigley,
1989). Irradiating the head to treat leukemia
has been shown to induce premature puberty
among both girls and boys (Mills, 1997;
Oberfield, 19%; Olgilvy-Stuart, 1994) While
the severity of the effect depends on the age at
which radiation occurs, sexual maturation
may be advanced by 1.5 years or more
(Oberfield, 1996) and the risk of premature
menarche may be increased up to two-fold
(Mills, 1997). Direct irradiation to the gonads
has been associated with delayed puberty
(Mills, 1997), which is consistent with the
known cytotoxic effects of radiabon on the
ovary and testes. Whether the much lower
levels of radiation experienced in everyday
life affect the onset of puberty is unknown.
Specific evidence regarding the effects of envi-
ronmental chemical pollution on the age of
puberty in humans is limited and has been
difficult to acquire. Epidemiological tech-
niques for detecting changes in populations
such as earlier onset of puberty generally
depend on large sample sizes. The studies to
date provide only limited evidence for an
association between exposure to environmen-
tal toxicants and decreased age of puberty
• One study has linked precocious sexual
development in children with a higher
frequency of exposure to certain hair care
and cosmetics products (Zimmerman,
1995) The authors speculated that expo-
sures to estrogenic compounds in the
products may have increased the risk of
premature puberty
• Another study attempted to link pubertal
development in offspring to estimates of
perinatal maternal PCB exposures
(Gladen, 2000) The mothers' PCB body
burdens (measured during pregnancy
and lactation) were found to be positively
associated with the weight of their daugh-
ters as they approached puberty, but the
daughters' age at menarche was found to
be unaffected at the relatively low expo-
sure levels seen in the study
• No significant connection to environmen-
tal pollution could be confirmed in an
industrialized area of Puerto Rico with a
well-documented increase in rates of pre-
mature puberty (Freni-Titulaer, 1986;
Saenz de Rodriguez, 1985).
A large number of laboratory animal studies
have shown that chemical exposures can have
profound effects on sexual development For
example, female and male animals exposed
prenatally and perinatally to PCBs experi-
enced delayed puberty and reduced sperm
counts, respectively (Faqi, 1998; Gray, 1998;
Restum, 1998) Other chemicals showing
effects on sexual maturation in animals
include TCDD, bisphenol A, 4-nonylphenol,
vinclozolin, p,p'-DDE, phthalates, gemstem,
and others (Ashby, 1998; Chapin, 1999; Gray,
1998; Hurst, 2000; Levy, 1995; Monosson,
1999; Mucignat-Caretta, 1995, Sumpter, 1995;
Yu, 1996). Effects on puberty have been seen
in both male and female animals, and the bio-
chemical mechanisms for the effects seem to
vary with the agent involved.
5.5 Cancer In Children
Childhood cancers tend to be qualitatively
different from cancers in adults, involving dif-
ferent organs and cell types. Researchers have
questioned whether exposures to specific
agents might increase the rates of cancers in
children through mechanisms different from
those causing adult cancers Another key
question is whether sensitivity to carcinogens
is greater during the prenatal period and
childhood than during adulthood Human
and animal studies provide only partial
answers to these questions.
There is general agreement that a small num-
ber of agents may cause cancer in children
after prenatal exposures, apparently through
mechanisms that are unique to those develop-
mental stages (Anderson, 2000). The scientif-
ic evidence is strong for the induction of clear-
cell carcinoma in the daughters of women
exposed to DES and for the development of
increased risk of leukemia in children exposed
22 CRITICAL PER-008 IN DEVELOPMENT
-------
prenatally or during early childhood to high
levels of ionizing radiation (Olshan, 2000).
There also is a wide range of agents for which
the evidence of human cancer causation due
to prenatal exposures is suggestive, but not
confirmed. Table 5 lists a number of studies
that suggest a relationship between prenatal
exposures and childhood cancer
A wider range of agents has been proven to be
carcinogenic in laboratory animals after pre-
natal exposures. Table 6 lists examples of
studies illustrating the association in experi-
mental animals between the development of
cancer in offspring andprenatal exposure of
pregnant females to x-rays, ethylnitrosourea
(ENU), 7,12-dimethylbenz[a]anthracene
(DMBA), and 5-azacytidine The cancers
range from skin and nervous system tumors
to ovarian and lymphoid tumors
Some epidemic logical evidence suggests that
children may be more sensitive to the carcino-
genic effects of certain chemicals than adults
are Children exposed to trichloroethene
(TCE) in drinking water appear to exhibit
risks of leukemia greater than those predicted
based on adult experience (Plon, 1997) The
results of case-controlled investigations con-
ducted in Woburn, Massachusetts, and Dover
Township, New Jersey, suggested that prena-
tal exposure to chemicals in drinking water
may lead to an elevated risk of leukemia or
central nervous system cancer in children
(MDPH, 1997, NJDHSS, 2001) The Woburn
study observed a significant trend between
maternal consumption of drinking water con-
taminated with organic agents, namely TCE,
and increased incidence of childhood cancer
in their offspring during the period 1969
through 1989 (MDPH, 1997). Despite a high-
er-than-ex pec ted overall incidence of child-
hood cancer from 1979 through 1991, the
Dover Township report found a statistically
significant association only between con-
sumption of well water contaminated with
TCE, tetrachloroethylene, and styrene-acry-
lonitrile, and elevated risk of leukemia and
central nervous system cancer in female chil-
dren under age five (NJDHSS, 2001)
Exposure to the ultraviolet radiation in sun-
light during childhood also has been associat-
ed with a greater risk for melanoma skin can-
cer than the same exposure during adulthood
(Autier, 1998) Children who receive
chemotherapy or radiation for a primary can-
cer also are at increased risk of developing
additional malignancies (Plon, 1997).
CRITICAL PERIODS SI* DEVELOPMENT 23
-------
Table 5. Exposures During Pregnancy and Childhood Cancer
Exposure
Dose
Cancer That
Developed
References
Benzene
(employment in
metal refining and
processing)
Not quantified
Acute nonlymphocytic
leukemia
Shu, 1988
Cigarette smoke
10 cigarettes
daily
Any childhood cancer
(50 percent increased risk),
non-Hodgkm's lymphoma,
acute lymphoblastic
leukemia, and Wilms
tumor (doubled risk)
Stiemfeldt, 1986
Diethylstlbestrol
Not quantified
Vaginal adenocarcmoma
in female children
Waggoner, 1994
Gasoline
Not quantified
Acute nonlymphocytic
leukemia, acute
lymphocyte
leukemia
Shu, 1988
Ionizing radiation
2 mSv
(milhSievert)
Leukemia
Petridou, 1996
Ionizing radiation
Not quantified
Thyroid cancer
Antonelli, 1996,
Lund, 1999
Personal services
industry (beauty
shop workers,
laundry or catering
workers, domestics)
Not quantified
Leukemia
Lowengart, 1987
Pesticides
(occupatonal
exposure)
Not quantified
Acute lymphocytic
leukemia
Shu, 1988
Phenytom (drug)
Not quantified
Neuroblastoma,
lymphoblastic
lymphoma
Keren, 1989,
Murray, 1996
TCE,
tetrachloroethylene,
and styrene-
acrylomtnle tnmer
Not quantified
Acute lymphocytic
leukemia, brain
and central nervous
system cancers in
female children
under age five
NJDHSS, 2001
Tnchloroethylene (TCE)
Not quantified
Childhood leukemia
MDPH, 1997
CR:TICA!. PERIODS IN QFVEI.OPMF.NT
-------
0
31
TICAi. PERIODS :Cf DEVU-.QPMENT 25
Table
Type of Exposure
A »f ma! Exposure* Dose
6: Associations Between Prenatal Exposures jjrtd
Cancer In Laboratory Animals
Source Asiderssrs, 2000
Prenatal Exposures Resulting in Cancer
Gestations! Sensitive
Exposure Exposure
Periad(s)1" PeriodCs)"
Hamster/SG ENU 0 2 or 0 5 mmol/kg 7-14
Mouse/B6WHT X-ray 200 Radd
Mouse/A/C5 Urethane 25 mg/mouse
Mouse/86 ENU 0 5 mmol/kg
Mouse/B6C3 ENU 0 5 mmol/kg
tumors
60 mg/kg
12, 16-18
12,16-18
12, 16-18
17-21, 1x
14,15,17 -
12-18, 1x
12, 14,16,18
12, 14,16, 18
Mouse/C3HeB/FeJ ENU 1 0, 25. or 50 mg/kg 1 0. 1 3, 1 5. adult
Mouse/C3HneNC ENU 0 4 mmol/kg
tumors
Mouse C57L/J ENU 0 5 mmol/kg
Mouse DBA/2J ENU 0 5 mmol/kg
16, 19
12, 14,16,18
12,14,16,18
9-1 4 (05 mmol/kg)
16-18
16-18
16-18
17-21
All groups
12-18
All groups
All groups
10-15
Both groups
14-18
14-18
Period of
Highest
Sensitivity5
12-13
NA
1 6-1 8,
fewer lung tumors
in male offspring
from GD 1 2
NA
< 8 hr before birth
15
12-14
No significant difference
16
15
19
16, 18
16
Cancer
Type
Skin tumors
Skin tumors
Lung tumors
Ovarian tumors
Lung tumors
Lung tumors
Nervous system
Kidney tumors
Lung tumors
Lung tumors
Nervous system
Lymphoid tumors
Lymphoid tumors
-------
o
3
O
•V
ffl
S
s
as
5
£3
O
-0
rn
Table 6 (continued)
Prenatal Exposures Re&uiiing in Cancer
Type of
Animal Exposure*
Mouse /NMRI 5-Azacytdine
DMBA
Mouse/NMRI X-ray
DMBA
Mouse SWR/J ENU
Rabbit ENU
Exposure
Dose
1 or 2 mg/mouse
60 mg/kg
0 88-1 2 Gray
60 mg/kg
0 5 mmol/kg
50 mg/kg
60 mg/kg
Gestations!
Exposure
Periodfs)"
12-16, 1x
12, 14,16
6-20, 1 x
6-20, 1 x
11-13, 14-16
6-20, 1 x
12. 14, 16, 18
8,10
1 0-1 9, 1 5-24
Sensitive
Exposure
Periods}'
14(2mgonly), 16
1 2 1 mg/kg,
1 6 both doses
6-15
10-20
14-16
All groups
12-18
All groups
All groups
Period of
Highest
Sensitivity*
16
Increase GD 16,
1 mg/kg Decrease
GD 1 4, 2 mg/kg
11 (males) 6-11 (females)
15-20
NA
8-13
All similar
8
NA
Cancer
Type
Lung tumors
Lymphoid tumors
Lymphoid tumors
Lung tumors
Ovanan tumors
Ovanan tumors
Lymphoid tumors
Nervous system
tumors
Nervous system
tumors
• Abbreviations used DMBA (7.1 2-dimethylbenz[a]anthracene) and ENU (ethylnitrosourea)
" Provided in gestatonal days (GD)
c 1 x indicates a single exposure on each of the days indicated
" Rad = Radiation absorbed dose, basic unit of measurement for absorbed radiant energy
NA, not applicable (sensitive range indicated in previous column)
-------
Adverse Effects ot Early
Hxposurcs 1 oat May Be Delayed
Until Adulthood
The studies reviewed in Chapters 3 and 4
focused primarily on the effects of environ-
mental exposures during early stages of
development that are manifested during these
periods. As discussed in Chapter 5, however,
many effects of prenatal exposures become
clinically significant only at later stages in
infancy or later in childhood In this chapter,
we briefly discuss effects of environmental
exposures during early development that do
not develop until adulthood Sections 6.1 and
6 2 describe cancers and other effects, respec-
tively, that develop later in life.
Detecting long-term or latent impacts of early
exposure in humans is difficult, because large
populations may need to be studied for long
periods. Nonetheless, both animal and
human studies clearly support the existence of
delayed effects of exposures early in develop-
ment In many cases, agents that cause
adverse effects after exposures in adults cause
similar effects after exposures occurring early
in development The challenge is to identify
instances in which early exposures cause
effects in adults that are qualitatively different
or quantitatively greater than those that
would be seen after adult exposures. Such
studies are difficult to perform, and as a
result, definitive identification of delayed
effects is challenging.
6.1 Cancers That Develop
Later in Life
Table 5 above identifies childhood cancers
that have been linked to prenatal or early
postnatal exposures in human studies In
these cases, observable increases in risk clear-
ly occur soon after exposures. In contrast, rel-
atively little information is available to make
judgments about the relative risk of cancers
occurring with longer latency periods It
seems likely, however, that increased risks of
some tumor types may persist past adoles-
cence Several studies of children of fathers
occupahonally exposed to ionizing radiation,
for example, have found that increased risks
of leukemia seem to persist to age 25
(Anderson, 2000) Similarly, elevated cancer
risks from prenatal exposure to DES, although
concentrated in late adolescence, also persist
into early adulthood (Waggoner, 1994).
Breast cancer risk is increased by x-ray thera-
py, and the risk is greatest if exposure occurs
during ages 10 to 14 (Hoffman-Goetz, 1998;
Miller, 1989; Tinger, 1997), which is a critical
period of breast development. This finding
raises the question whether studies that inves-
tigate exposure in the years of adulthood just
before breast cancer develops are capturing
the important window of exposure in adoles-
cence (Ardies, 1998; Hoyer, 2000) In addition,
studies suggest that exposure to low-level
diagnostic radiation during infancy or child-
hood may increase the risk of breast cancer,
young girls appear to be particularly suscepti-
ble to radiation injury that can result in long-
term effects (Hoffman-Goetz, 1998). These
considerations also may be important in stud-
ies of the potential increase in breast cancer
risk through exposure to exogenous estro-
genic compounds such as certain pesticides
and PCBs (Dich, 1997; Wolff, 1995).
Lung cancer research suggests that exposures
to environmental agents during adolescence
may have greater risks than the same expo-
CRITICA:. PSRIODS !N DEVPLOPMENT
-------
sures later in life. Among a group of
Norwegian men, those who began smoking as
teenagers had a 50 percent greater lung cancer
risk than those who took up smoking at ages
20 to 29 (Engeland, 19%). The effect was
smaller but still significant among women and
persisted even when controlling for age-spe-
cific background cancer risks and years of fol-
low-up. Increased risk from early exposures
to tobacco smoke could be associated with
increased levels of persistent chemical dam-
age to DNA ("DNA adducts") (Wiencke,
1999)
The increased levels of exogenous hormone
exposure associated with early puberty could
be a risk factor for cancer later in life (Wolff,
1997). A recent study has demonstrated that
women who attain their adult height at a
younger age, which is indicative of early
puberty, have an increased risk of breast can-
cer (Li, 1997) Breast cancer risk also increases
with early age at menarche (Hoffman-Goetz,
1998; Kumar, 1995; Russo, 1998). Behavioral
changes associated with early puberty also
may increase cancer risks in women.
Decreases in the age of first intercourse and
early use of oral contraceptives have been
found to increase the risk of cervical cancer
significantly (Daling, 1996) Boys who under-
go puberty early will have more years of
exposure to endogenous androgen produc-
tion, and the incidence of prostate cancer has
been increasing in parallel with reduced age
at puberty (Garnick, 1996).
Table 6 summarizes data from a small portion
of the many laboratory studies that link pre-
natal exposures in animals to the develop-
ment of cancer in offspring These studies
show that such exposures cause tumors that
occur early in development and are manifest-
ed throughout life. Thus, increased cancer
risks m animals due to prenatal exposures
clearly are not limited to the immediate post-
natal period. The authors of the review from
which these data are taken (Anderson, 2000)
do not, however, indicate how cancer risks
differ through different life stages, so it is not
possible to conclude whether prenatal expo-
sures result in higher risks than exposures
after birth. Technical issues, such as compar-
ing dose levels resulting from exposures of
differing duration in different life stages,
make such comparisons difficult.
6.2 Other Effects Later in
Life
In Chapters 4 and 5, we discussed health
impacts of early environmental exposures that
could persist into adulthood. Malformations
of major organs, delays in development, or
defects in function associated with these expo-
sures may have lifelong consequences. There
also is limited evidence for a number of non-
cancer effects of early exposures that might
not become apparent until late in life. Even
though most of these effects have not been
linked directly to environmental agents, the
observed patterns of occurrence demonstrate
the possibility that such exposures may con-
tribute to adverse health outcomes in later life.
One area of concern is neurological and neu-
rodegenerative disease. Laboratory studies
suggest that exposures to specific
organometallic compounds early in life may
result in a loss of neurons, causing impair-
ments in behavioral function in older animals
(Barone, 1995). Multiple sclerosis is a poten-
tially fatal disease whose symptoms generally
begin to occur around age 40. The disease
shows a geographic pattern of occurrence and
other features suggesting that environmental
exposures, perhaps infection, prior to age 10
may be important risk factors (Kurtzke, 2000,
Rice 2000) Also, early environmental expo-
sures to lead may contribute to the develop-
ment of Alzheimer's disease This suggestion
is based on the finding that the functions of
several genes thought to be associated with
high risk of Alzheimer's disease also are
affected by lead exposures (Claudio, 1997;
Onalaja, 2000, Prince, 1998) Epidemiologic
studies are needed to confirm this association.
Reproductive health in adults also can be
affected by exposures to environmental
28 CRITICAL PGRiOOS IN DEVELOPMENT
-------
agents in childhood Early menopause can be
caused by exposure to chemotherapeutic
agents during adolescence (Meirow, 1999)
This effect is thought to be associated with
depletion of the viable oocytes Cigarette
smoking also can result in early menopause
(Cramer, 1996), although no studies separate
the impacts of smoking during adolescence
from those of smoking in adulthood. The
impact of exposures to environmental pollu-
tants on menopause has not yet been estab-
lished
Osteoporosis is a major public health problem
in the elderly Bone density in children and
adolescents can be strongly affected by envi-
ronmental agents including aluminum, cad-
mium, hexachlorobenzene, and lead
(Andrews, 1988, Capdevielle, 1998, Katsuta,
1994, Long, 1992, Mason, 1990; Rosen, 1997,
Rosen, 1989) Because bone density in adults
is highly correlated with peak bone density
achieved during adolescence, long-term fol-
low up of lead-exposed children has been sug-
gested to determine if early exposures have
any long-term impacts on bone density and
osteoporosis (Rosen, 1997)
Early exposures to environmental agents may
have other impacts on the generalized aging
process While the biochemical and physio-
logical processes associated with aging are not
well understood, exposures to environmental
toxicants during critical life stages could
reduce the number of healthy cells available to
maintain important physiological activities
(Barone, 2000, Rice, 2000) Further, the aging
process involves programmed cell death, or
apoptosis Exposures to environmental
agents can cause disordered apoptosis during
embryonic development, which may increase
the risk for neurodegenerative illnesses such
as Alzheimer's and Parkinson's disease (Brill,
1999)
CRITICAL PERIODS :N DEVELOPMENT 29
-------
£>ummarv
There are strong biological reasons for believ-
ing that humans at specific periods in their
early development may be especially sensitive
to exposures to environmental agents The
fragility, speed, and complexity of early
development clearly provide many targets for
specific interactions with environmental
agents that are not present at later life stages
Development is a continuum, progressing
from germ cells through embryo, fetus, infant,
child, adolescent, and adult It is not always
possible to identify exactly when a damaging
exposure occurred or which stage of develop-
ment has been affected. Sufficient knowledge
is available, however, to identify many key
events and processes and to delineate general
patterns in sensitivity.
The current state of knowledge is insufficient
to definitively rank or quantitatively compare
vulnerability to environmental agents across
developmental stages, except for a few envi-
ronmental agents Identifying certain periods
as "critical" therefore is primarily qualitative,
based on the observed patterns of effect and
the cumulative weight of evidence Using
these criteria, germ cell development, fertil-
ization, embryonic and fetal growth, child-
hood, and adulthood all qualify as "critical"
stages Each stage is affected by known and
varying sets of environmental agents in ways
that can result in serious adverse effects on
health The response to a given level of envi-
ronmental exposure may vary greatly during
development, as measured in laboratory stud-
ies. Differences in sensitivity to environmental
agents are often difficult to measure, because
different life stages imply different patterns of
uptake, metabolism, and excretion of toxi-
cants and different repair and compensatory
mechanisms Each stage of development also
may be uniquely sensitive to environmental
agents and the accelerated rates of some
processes (e.g, cell division) and the complex
processes occurring during maturation (cell
signaling, migration, differentiation) This
combination of factors gives rise to concerns
over early environmental exposures. This
paper focused on the particular sensitivities of
children to environmental effects. Each devel-
opmental stage, including adulthood, howev-
er, possesses specific characteristics that create
additional sets of sensitivities, making them
"critical" for certain kinds of effects.
The current challenge is to interpret and apply
the available data to improve the health of
children and the general population, and to
establish priorities for additional research that
can better support risk reduction efforts
Several new laws, regulations, programs, and
policies have been developed in recent years
for assessing and managing the risk of repro-
ductive and developmental environmental
agents (US EPA, 2000, US EPA, 1998a; US
EPA, 1998b).
30 CRiTICA!. PERiOas IN QEV51.OPMF.NT
-------
Ref
•crcnccs
AAP (American Academy of Pediatrics), Committee on Environmental Health. Handbook of
Pediatric Environmental Health American Academy of Pediatrics Elk Grove Village, 1999
AAP (American Academy of Pediatrics), Committee on Environmental Hazards The
susceptibility of the fetus and child to chemical pollutants. Pediatrics 1974; 53:777-862.
Adam W, Lazarus M, Saha-Moller CR, et al. Biotransformation with peroxidases. Adv
Biochem Eng Biotechnol 1999; 63 73-108.
Alberts B, Bray D, Lewis ], Raff M, Roberts K, Watson JD. Molecular Biology of the Cell, 3rd ed
New York, Garland Publishing, Inc, 1994a, pp 863-90
Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Molecular Biology of the Cell, 3rd ed.
New York, Garland Publishing, Inc., 1994b, pp 1076,1128,1174-5,1238
Aim G, Milerad J, Wennergren G, et al. A case-control study of smoking and sudden infant
death syndrome in the Scandinavian countries, 1992-1995. The Nordic Epidemiological SIDS
Study Arch Dis Child 1998; 78 329-34.
Amsen D, Kruisbeek AM Thymocyte selection, not by TCR alone. Immunol Rev 1998,165 209-
29.
Anderson LM, Diwan BA, Fear NT, Roman E Critical windows of exposures for children's
health: cancer in human epidemiological studies and neoplasms in experimental animal models
Environ Health Perspect 2000,108(Suppl 3) 573
Andrews JE, Courtney KD, Donaldson WE. Impairment of calcium homeostasis by
hexachlorobenzene (HCB) exposure in Fischer 344 rats J Toxicol Environ Health 1988; 23:311-
20
Antonelli A, Miccoli P, Derzhitski VE, et al. Epidemiologic and clinical evaluation of thyroid
cancer in children from the Gomel region (Belarus) World J Surg 1996; 20-867-71.
Anttila A, Sallmen M. Effects of parental occupational exposure to lead and other metals on
spontaneous abortion. J Occup Environ Med 1995; 37.915-21
Aoki Y Polych lor mated biphenyls, polychlonnated dibenzo-p-dioxins, and poly chlorinated
dibenzofurans as endocrine disruptors-what we have learned from Yusho disease Environ Res
2001, 86(l)-2-ll
Arbuckle TE, Schrader SM, Cole D, et al 2,4-Dicholrophenoxyacetic acid residues in semen of
Ontario farmers Reprod Toxicol 1999,13.421-9
CRITICAL PERIODS :Cf DEVEi.QS'MEIMT J1
-------
Arbuckle TE, Sever LE Pesticide exposures and fetal death: a review of the epidemiologic
literature. Cnt Rev Toxicol 1998; 28:229-70
Ardies CM, Dees C. Xenoestrogens significantly enhance risk for breast cancer during growth
and adolescence Med Hypotheses 1998; 50 457-64.
Ashby ], Tinwell H. Uterotrophic activity of bisphenol A in the immature rat Environ Health
Perspect 1998; 106:719-20
Autier P, Dore JF Influence of sun exposures during childhood and during adulthood on
melanoma risk EPIMEL and EORTC Melanoma Cooperative Group European Organization
for Research and Treatment of Cancer Int J Cancer 1998; 77:533-7
Baird DD, Wilcox AJ. Cigarette smoking associated with delayed conception JAMA 1985;
253.2979-83.
Baker ER Body weight and the initiation of puberty. Clm Obstet Gynecol 1985; 28 573-9
Ballew C, Khan LK, Kaufmann R, Mokdad A, Miller DT, Gunter EW Blood lead concentration
and children's anthropometnc dimensions in the Third National Health and Nutrition
Examination Survey (NHANES IE), 1988-1994. J Pediatr 1999,134 623-30.
Barone S Jr, Das KP, Lassiter TL, White LD Vulnerable processes of nervous system
development: a review of markers and methods. Neurotoxicol 2000, 21:15-36
Barone S Jr, Stanton ME, Mundy WR Neurotoxic effects of neonatal triethyltm (TET) exposure
are exacerbated with aging 1995, Neurobiol Aging, 16:723-35.
Bearer C, Emerson RK, O'Riordan MA, Roitman E, Shackleton C. Maternal tobacco smoke
exposure and persistent pulmonary hypertension of the newborn Environ Health Perspect
1997; 105.202-6.
Beckmann H Developmental malformations in cerebral structures of schizophrenic patients.
Eur Arch Psychiatry Clin Neurosci 1999; 249(SuppI 4).44-7
Benes FM. Brain development, VH. Human brain growth spans decades. Am J Psychiatry
1998,155:1489
Berger F, Gage FH, Vijayaraghavan S Nicotinic receptor-induced apoptotic cell death of
hippocampal progenitor cells. J Neurosci 1998; 18 6871-81.
Bertollini R, Mastroiacovo P, Segru G. Maternal epilepsy and birth defects: a case-control study
in the Italian Mihcentric Registry of Birth Defects (IPIMC) Eur J Epidemiol 1985,1.67-72
Bibbo M, Gill WB, Azizi F, et al. Follow-up study of male and female offspring of DES-exposed
mothers. Obstet Gynecol 1977,49-1-8.
Bisogno G, Pilz T, Perilongo G, et al. Undifferenbated sarcoma of the bver in childhood: a
curable disease Cancer 2002, 94(l):252-7
32 CRiTIGA!. PfiRiOQS IN OEVei.OPMf.NT
-------
Blair PS, Fleming PJ, Bensley D, et al Smoking and the sudden infant death syndrome, results
from 1993-5 case-control study for confidential inquiry into stillbirths and deaths in infancy. Br
Med J1996, 313-195-198
Blatter BM, Hennens R, Bakker M, Roelveld N, Verbeek AL, Zielhuis GA Paternal
occupational exposure around conception and spina bifida in offspring Am J Ind Med 1997,
32:283-91.
Blumenfeld Z, Ritter M, Shen-Orr Z, Shariki K, Ben Shahar M, Haim N. Inhibin A
concentrations in the sera of young women during and after chemotherapy for lymphoma
correlation with ovarian toxicity. Am J Reprod Immunol 1998, 39.33-40
Bogden JD, Kemp FW, Han S, et al. Dietary calcium and lead interact to modify maternal blood
pressure, erythropoiesis, and fetal and neonatal growth in rats during pregnancy and lactation.
J Nutr 1995; 125.990-1002.
Bracha HS, Torrey EF, Bigelow LB, Lohr JB, Linington BB. Subtle signs of prenatal
maldevelopment of the hand ectoderm in schizophrenia: a preliminary monozygob'c twin
study Biol Psychiatry 1991; 30:719-25
Brill A, Torchinsky A, Carp H, Toder V. The role of apoptosis in normal and abnormal
embryonic development J Assist Reprod Genet 1999,16 512-9.
Buckley JD, Sather H, Ruccione K, et al A case-control study of risk factors for hepatoblastoma-
a report from the children's cancer study group. Cancer 1989, 64:1169.
Bunney BG, Potkin SG, Bunne WE Jr New morphological and neuropathological findings in
schizophrenia a neurodevelopmental perspective. Clin Neurosci 1995, 3 81-8.
Byrne DH, Kitos PA Teratogeruc effects of cholmergic insecticides in chick embryos IV. The
role of tryptophan in protecting against limb deformities Biochem Pharmacol 1983; 32 2881-90.
CA EPA (California Environmental Protection Agency). Health effects of exposure to
environmental tobacco smoke Sacramento, CA. California Environmental Protection Agency,
Office of Environmental Health Hazard Assessment, 1997
Capdevielle MC, Hart LE, Goff J, Scanes CG Aluminum and acid effects on calcium and
phosphorus metabolism in young growing chickens. Arch Environ Contain Toxicol 1998, 35:82-
8.
Chapin RE, Delaney J, Wang Y, et al The effects of 4-nonylphenol in rats: a multigeneration
reproduction study Toxicol Sci 1999; 52.80-91.
Chelmow D, Andrew DE, Baker ER. Maternal cigarette smoking and placenta previa Obstet
Gynecol 19%; 87:703-6.
Chernoff N, Kavlock RJ, Rogers EH, Carver BD, Murray S. Perinatal toxicity of maneb, ethylene
thiourea, and ethylene bisisothiocyanate sulfide in rodents J Toxicol Environ Health 1979;
5:821-34
Chess S, Fernandez P, Korn S Behavioral consequences of congenital rubella. J Pediatr 1978;
93 699-703.
CRITICAL PERIODS iN DEVELOPMENT 33
-------
Chew FT, Goh DY, Ooi BC, Sharom R, Hui JK, Lee BW. Association of ambient air-pollution
levels with acute asthma exacerbation among children in Singapore. Allergy 1999, 54.320-9
Claudio L, Lee T, Wolff MS, Wetmur JG. A murine model of genetic susceptibility to lead
bioaccumulation. Fundam Appl Toxicol 1997; 35.84-90.
Cohen EN, Gift HC, Brown BW, et al. Occupational disease in dentistry and chronic exposure
to trace anesthetic gases J Am Dent Assoc 1980,101 21-31.
Center V, Cortmovis I, Rogari P, Riva L. Weight growth in infants born to mothers who
smoked during pregnancy. BMJ 1995; 310:768-71
Cramer DW, Xu H. Predicting age at menopause Maruntas 1996, 23.319-26
Daling JR, Madeleine MM, McKnight B, et al. The relationship of Human Papillomavirus-
related cervical tumors to cigarette smoking, oral contraceptive use, and prior Herpes Simplex
Virus Type 2 infection Cancer Epidemiol Biomarkers Prev 1996, 5 541-48
Das TK, Moutquin JM, Lindsay C, Parent JG, Fraser W Effects of smoking cessation on
maternal airway function and birth weight Obstet Gynecol 1998; 92:201-5
de Wildt SH, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and
drug disposibon Clin Pharmacokinet 1999; 37:485-505
Dich J, Zahm SH, Hanberg A, Adami HO Pesticides and cancer. Cancer Causes Control 1997;
8 420-43.
Dietert RR, Etzel R, Chen D, et al. Workshop to identify critical windows of exposure for
children's health, immune and respiratory systems Environ Health Perspect 2000; 108(Suppl
3):483-90.
DiFranza JR, Lew RA. Effect of maternal cigarette smoking on pregnancy complications and
sudden infant death. J Fam Pract 1995,40 385-94
Di Lorenzo D, Ferrari F, Agrati P, et al. Manganese effects on the human neuroblastoma cell
line SK-ER3. Toxicol Appl Pharmacol 1996,140.51-7
Doerr JK, Holhs EA, Sipes IG. Species difference in the ovarian toxicity of 1,3-butadiene
epoxides in B6C3F1 mice and Sprague-Dawley rats. Toxicology 1996; 113.128-36.
Doerr JK, Hooser SB, Smith BJ, Sipes IG Ovarian toxicity of 4-vinylcyclohexene and related
olefins in B6C3F1 mice role of diexpoxides. Chem Res Toxicol 1995, 8.963-9
Draper GJ, Little MP, Sorahan T, et al Cancer in offspring of radiation workers: a record
linkage study. BMJ 1997, 3151181
Ellard GA, Johnstone FD, Prescott RJ, Ji-Xian W, Jian-Hua M Smoking during pregnancy: the
dose dependence of birthweight deficits. Br J Obstet Gynaecol 19%, 103:806-13
Engeland A, Haldorsen T, Andersen, Tretli S The impact of smoking habits on lung cancer
risk 28 years' observation of 26,000 Norwegian men and women. Cancer Causes Control 19%,
7366-76
34 CRiTICA!. PERiOOS IN OEVei.OPMF.NT
-------
Eskenazi B, Bergmann JJ Passive and active maternal smoking during pregnancy, as measured
by serum cotinine, and postnatal smoke exposure. I. Effects on physical growth at 5 years. Am
J Epidemiol 1995; 142(Suppl 1) S10-8
Faqi AS, Dalsenter PR, Merker HJ, Chahoud 1 Effects on developmental landmarks and
reproductive capability of 3,3',4,4'-ter.rachlorobiphenyl and 3,3',4,4',5-pentachlorobiphenyl in
offspring of rats exposed during pregnancy. Hum Exp Toxicol 1998, 17365-72
Faustman EM, Silbernagel SM, Fenske RA, Burbacher TM, Ponce RA Mechanism underlying
children's susceptibility to environmental toxicants Environ Health Perspect 2000, 108(Suppl
Pels LM, Wunsch M, Baranowski J, et al Adverse effects of chronic low level lead exposure on
kidney function- a risk group study in children. Nephrol Dial Transplant 1998; 13 2248-56.
Filkms K. Pesticides. In: Reproductive Hazards of the Workplace Frazier LM, Hage ML, eds.
New York, John Wiley & Sons, 1998, pp 192-256.
Floret D, Rosenberg D, Hage GN, Mortnet P. Hyperthyroidism, diabetes mellitus and the
congenital rubella syndrome. Acta Paediatr Scand 1980, 69 259-61
Foster WG, Penbck JA, McMahon A, Lecavalier PR. Ovarian toxicity of hexachlorobenzene in
the superovulated female rat. ) Biochem Toxicol 1992; 7:1-4.
Fredriks AM, van Buuren S, Burgmeijer RJ, Meulmeester JF, Beuker RJ, Brugman E, Roede M],
Verloove-Vanhonck SP, Wit JM. Continuing posihve secular growth change in The
Netherlands, 1955-1997 Pediatr Res 2000, 47:316-23.
Freedman DS, Khan LK, Serdula MK, Srinivasan SR, Berenson GS. Secular trends in height
among children during 2 decades. The Bogalusa Heart Study Arch Pediatr Adolesc Med 2000,
154155-61
Freni-Titulaer LW, Cordero JF, Haddock L, Lebron G, Martinez R, Mills JL Premature
thelarche in Puerto Rico A search for environmental factors. Am J Dis Child 1986, 140:1263-7
Fried PA, Watkinson B, Gray R Growth from birth to early adolescence in offspring prenatally
exposed to cigarettes and marijuana Neurotoxicol Teratol 1999; 21.513-25.
Garcia AM, Fletcher T, Benavides FG, Orts E. Parental agricultural work and selected
congenital anomalies Am J Epidemiol 1999, 149 64-74
Garcia AM Occupational exposure to pesticides and congenital malformations: a review of
mechanisms, methods and results. Am J Ind Med 1998a, 33:232-40
Garcia AM, Benavides FG, Fletcher T, Orts E. Paternal exposure to pesticides and congenital
malformations. Scand } Work Environ Health 1998b; 24 473-80
Gardner MJ, Snee MP, Hall AJ, et al Results of case-control study of leukemia and lymphoma
among young people near Sellafield nuclear plant in West Cumbria. BMJ 1990; 300:423.
Garnick MB, Fair WR. Prostate cancer emerging concepts. Part II Ann Intern Med 1996;
125-205-12
CRITICAL PERIODS :(* DEVELOPMENT
-------
Georgopoulos N, Markou K, Theodoropoulou A, et al Growth and pubertal development in
elite female rhythmic gymnasts. J Clin Endocrinol Metab 1999, 84 4525-30
Gladen BC, Ragan NB, Rogan WJ. Pubertal growth and development and prenatal and
lactational exposure to poly chlorinated biphenyls and dichlorodiphenyl dichloroethane
Pediatr 2000; 136-490-6.
Goldsmith JR. Dibromochloropropane: epidemiological findings and current questions. Ann N
Y Acad Sci 1997, 837.300-6.
Golub MS, Macintosh MS, Baumrind N Developmental and reproductive toxicity of inorganic
arsenic: animal studies and human concerns. ] Toxicol Environ Health B Crit Rev 1998,1.199-
241.
Gonzalez-Crespo MR, Gomez Reino JJ, Merino R, et al Menstrual disorders in girls with
systemic lupus erythematosus treated with cyclophosphamide. Br J Rheumatol 1995, 34 737-41
Graeter LJ, Mortensen ME. Kids are different developmental variability in toxicology.
Toxicology 1996, 111 15-20
Grandjean P, Budtz-Jorgensen E, White RF, et al. Methylmercury exposure biomarkers as
indicators of neurotoxicity in children aged 7 years Am J Epidemiol 1999; 150 301-5.
Gray LE JR. Xenoendocrme disrupters laboratory studies on male reproductive effects Toxicol
Lett 1998; 102-103 331-3
Gray LE JR, Ostby JS, Kelce WR. A dose-response analysis of the reproductive effects of a
single gestational dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male Long Evans Hooded rat
offspring Toxicol Appl Pharmacol 1997; 14611-20
Gregus A, Klaassen CD. Mechanisms of toxicity In Casarett &. Doull's Toxicology the Basic
Science of Poisons, 5th ed Klaassen CD, ed. New York, McGraw-Hill, 1996, pp 35-74
Gulson BL, Mahaffey KR, Jameson CW, et al Mobilization of lead from the skeleton during the
postnatal period is larger than during pregnancy. J Lab Chn Med 1998,131(4).324-9.
Gulson BL, Jameson CW, Mahaffey KR, et al. Pregnancy increases mobilization of lead from
maternal skeleton. J Lab CUn Med 1997,130(l):51-62.
Haglund B, Cnattingius S Cigarette smoking as a risk factor for sudden infant death
syndrome- A population-based study. Am J Pubbc Health 1990; 80:29-31
Hajat S, Haines A, Goubet SA, Atkinson RW, Anderson HR. Association of air pollution with
daily GP consultations for asthma and other lower respiratory conditions in London. Thorax
1999, 54:597-605.
Hakim RB, Gray RH, Zacur H. Infertility and early pregnancy loss Am J Obstet Gynecol 1995,
1721510-7.
Halpern CT, Udry JR, Suchindran C. Testosterone predicts initiation of coitus in adolescent
females. Psychosom Med 1997, 59-161-71.
3C CRsTICAI. PERIODS IN DEVELOPMENT
-------
Han S, Pfizenmaier DH, Garcia E, et al Effects of lead exposure before pregnancy and dietary
calcium during pregnancy on fetal development and lead accumulation. Environ Health
Perspect 2000; 108(6) 527-31
Harkonen K, Viitanen T, Larsen SB, Bonde JP, Lahdetie J Aneuploidy in sperm and exposure
to fungicides and lifestyle factors. Environ Mol Mutagen 1999, 34 39-46.
Hartz AJ, Kelber S, Borkowf H, Wild R, Gillis BL, Riinm AA. The association of smoking with
clinical indicators of altered sex steroids—a study of 50,145 women Public Health Rep 1987;
102 254-9
Hay JG. Molecular biology. In Environmental and Occupational Medicine, 3rd ed. Rom WN,
ed. Philadelphia, Lippincott-Raven, 1998, pp. 113-136
Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and
menses in young girls seen in office pracbce A study from the Pediatric Research in Office
Settings Network Pediatrics 1997; 99 505-12.
Hewitt JB, Tellier L. Risk of adverse outcomes in pregnant women exposed to solvents. J
Obstet Gynecol Neonatal Nurs 1998; 27'521-31
Hoffman-Goetz L, Apter D, Demark-Wahnefried W, Goran MI, McTiernan A, Reichman ME.
Possible mechanisms mediating an association between physical activity and breast cancer.
Cancer 1998; 83 621-8.
Hoover RN. Cancer-nature, nurture or both N Engl ] Med 2000; 343135-6
Howe G, Westhoff C, Vessey M, Yeates D Effects of age, cigarette smoking, and other factors
on fertility, findings in a large prospective study. Br Med J Clin Res Ed. 1985, 290.1697-700.
Hoyer AP, Jorgensen T, Grandjean P, Hartvig HB Repeated measurements of organochlorine
exposure and breast cancer risk (Denmark) Cancer Causes Control 2000; 11.177-84
Hurst CH, DeVito MJ, Setzer RW, Birnbaum LS Acute administration of 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) in pregnant Long Evans rats association of measured
tissue concentrations with developmental effects Toxicol Sci 2000; 53-411-20.
latropoulos MJ, Williams GM Proliferation markers Exp Toxicol Pathol 1996,48175-81
Infante-Rivard C, Fernandez A, Gauthier R, David M, Rivard GE. Fetal loss associated with
caffeine intake before and during pregnancy JAMA 1993; 270:2940-3.
Johnsen D, Tianoff N The oral cavity In- Nelson Textbook of Pediatrics, 16th ed. Berhman RE,
Kliegman RM, Jenson HB, eds. Philadelphia, WB Saunders Company, 2000, pp. 1109-1121.
Jones HE, Balster RL. Inhalant abuse in pregnancy. Obstet Gynecol Clin North Am 1998;
25:153-67.
Junaid M, Chowdhuri DK, Narayan R, Shanker R, Saxena DK. Lead-induced changes in ovarian
follicular development and maturation in mice J Toxicol Environ Health 1997, 50.31-40.
PERIODS stt
-------
Kafourou A, Topuloumi G, Makropoulos V, Loutradi A, Papanagiotou A, Hatzakis A. Effects
of lead on somatic growth of children. Arch Environ Health 1997, 52-377-83.
Katsuta O, Hiratsuka H, Matsumoto J, et al. Cadmium-induced osteomalacic and osteopetrohc
lesions in ovanectomized rats. Toxicol Appl Pharmacol 1994; 126:58-68.
Kaufman MH. The teratogenic effects of alcohol following exposure during pregnancy, and its
influence on the chromosome constitution of the pre-ovulatory egg. Alcohol 1997; 32:113-28.
Khattak S, K-Moghtader G, McMartin K, et al Pregnancy outcome following gestational
exposure to organic solvents: A prospective controlled study. JAMA 1999; 281:1106-1109
1 Kim R, Hu H, Rotnitzky A, Bellinger D, Needleman H. A longitudinal study of chronic lead
exposure and physical growth in Boston children Environ Health Perspect 1995; 103:952-7
Kimber I Allergy, asthma and the environment: an introduction. Toxicol Lett 1998,102-3-301-6.
I Klonoff-Cohen HS, Edelstein SL, Lefkowitz ES, et al. The effect of passive smoking and tobacco
i exposure through breast milk on sudden infant death syndrome. JAMA 1995; 273 795-798
: Knill-Jones R, Candela S, Dale I, et al. Congenital malformation and maternal occupational
exposure to glycol ethers. Occupational Exposure and Congenital Malformations Working
Group. Epidemiology 1997; 8-355-63.
Koren G, Demitrakoudis D, Weksberg R, et al. Neuroblastoma after prenatal exposure to
phenytom. cause and effect? Teratology 1989,40:157-162.
Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L Birth defects among offspring of
Norwegian farmers, 1967-1991 Epidemiology 1997; 8:547-44.
: Kristensen P, Irgens LM, Daltveit AK, Andersen A. Perinatal outcome among children of men
exposed to lead and organic solvents in the printing industry Am J Epidemic 11993,137:134-44.
Kumar NB, Lyman GH, Allen K, Cox CE, Shaapira DV. Timing of weight gain and breast
cancer risk Cancer. 1995,15; 76 243-9
Kurtzke JF. Multiple sclerosis in time and space - geographic clues to cause J Neurovirol 2000;
6S134-40.
Landowski TH, Qu N, Buyuksal I, Painter JS, Dal ton WS. Mutations in the Fas antigen in
patients with multiple myeloma Blood 1997, 90-4266-70
Larsson KS, Arnander C, Cekanova E, Kjellberg M. Studies of teratogenic effects of the
dithiocarbamates maneb, mancozeb, and propineb. Teratology 1976,14-171-83
Leeder JS, Kearns GL. Pharmacogenetics in pediatrics Peds Clin North America 1997; 44(1) 55-
77.
: Lemasters GK. Occupational exposures and effects on male and female reproduction In:
' Environmental and Occupational Medicine, 3rd ed. Rom WN, ed Philadelphia, Lippincott-
Raven, 1998, 223-244.
38 CfiiTIGAl. PER-Q08 IN OeVEi.OPMF.NT
-------
Lemasters GK, Schulte PA. Biologic markers in the epidemiology of reproduction. In
Molecular Epidemiology Principles and Practices Schulte PA, Perra FA, eds San Diego,
Academic Press, Inc., 1993, pp 385-406
Leoru V, Fabiam L,Marinelli G, et al. PCB and other organochlorine compounds in blood of
women with or without miscarriage a hypothesis of correlation. Ecotoxicol Environ Saf 1989
Feb, 17(1) 1-11
Levy JR, Faber KA, Ayyash L, Hughes CL Jr The effect of prenatal exposure to the
phytoestrogen gemstein on sexual differentiation in rats. Proc Soc Exp Biol Med 1995; 208.60-6.
Li CI, Malone KE, White E, Dating JR. Age when maximum height is reached as a risk factor
for breast cancer among young U S. women. Epidemiology 1997; 8 559-65
Lichtenstem P, Holm NV, Verkasalo PK, et al Environmental and heritable factors in the
causation of cancer Analyses of cohorts of twins from Sweden, Denmark and Finland. N Engl
J Med 2000, 343:135-6.
Lin S, Hwang SA, Marshall EG, Marion D. Does paternal occupational lead exposure increase
the risks of low birth weight or prematurity? Am J Epidemic 11998; 148173-81.
Lin S, Marshall EG, Davidson GK. Potential parental exposure to pesticides and limb reduction
defects. Scand J Work Environ Health 1994, 20166-79.
Lindbohm ML, Hemminki K, Bonhomme MG, et al. Effects of paternal occupational exposure
on spontaneous abortions. Am J Public Health 1991a; 811029-33
Lindbohm ML, Sallmen M, Anttila A, Taskinen H, Hemminki K. Paternal occupational lead
exposure and spontaneous abortion Scand J Work Environ Health 1991b, 17:95-103
Lindbohm ML, Taskinen H, Sallmen M, et al Spontaneous abortions among women exposed to
organic solvents Am J Ind Med 1990,17 449-463
Lipscomb JA, Fenster L, Wrensch M, et al. Pregnancy outcomes in women potentially exposed
to occupational solvents and women working in the electronics industry J Occup Med 1991,
33.597-604.
Lodish H, Berk A, Zipursky SL, Matsudaira P. Molecular cell biology, 4th ed. New York, WH
Freeman and Company, 1999.
Loeffler DC, Peterson RE Interactive effects of TCDD and p,p'-DDE on male reproductive tract
development in in utero and lactationally exposed rats. Toxicol Appl Pharmacol 1999; 154:28-39
Loghman-Adham M Renal effects of environmental and occupational lead exposure Environ
Health Perspect 1997; 105 928-39.
Long GJ, Rosen JF. Lead perturbs epidermal growth factor (EGF) modulation of intracellular
calcium metabolism and collagen synthesis in clonal rat osteoblasbc (ROS 17/28) cells. Toxicol
Appl Pharmacol 1992; 114.63-70.
Lowengart RA, Peters JM, Ciciom C, et al Childhood leukemia and parents' occupational and
home exposures JNCI1987; 79 39
PFR1QD8 :N DEVELOPMENT
-------
Lucier GW, Nelson KG, Everson RB, et al. Placenta! markers of human exposure to
poly chlorinated biphenyls and polychlorinated dibenzofurans Environ Health Perspect 1987;
76:79-87
Lund E, Galanti MR. Incidence of thyroid cancer in Scandinavia following fallout from atomic
bomb testing an analysis of birth cohort effects. Cancer Causes Control 1999,10.181-7
Maci R, Arias E Teratogenic effects of the fungicide maneb on chick embryos Ecotoxicol
Environ Saf 1987; 13:169-73.
Malloy MH, Kleinman JC, Land GH, et al. The association of maternal smoking with age and
cause of infant death. Am } Epidemiol 1988; 128:46-55.
Mason HJ, Somervaille LJ, Wright AL, Chettle DR, Scott MC Effect of occupational lead
exposure on serum 1,25-dihydroxyvitamin D levels Hum Exp Toxicol 1990; 9 29-34
Matus-Ridley M, Sicosia SV, Meadows AT. Gonadal effects of cancer therapy in boys. Cancer
1985; 55.2353-63.
McKinney PA, Juszczak E, Findlay E, et al. Pre- and perinatal risk factors for childhood
leukemia and other malignancies a Scottish case control study. Br J Cancer 1999; 801844-51
McKinney PA, Alexander FE, Cartwnght RA, Parker L. Parental occupations of children with
leukemia in west Cumbria, north Humberside, and Gateshead BMJ1991; 302:681.
McMartin KI, Chu M, Kopecky E, et al. Pregnancy outcome following maternal organic solvent
exposure A meta-analysis of epidemiologic studies. Am J Ind Med 1998; 34 288-92.
MDPH (Massachusetts Department of Public Health), Bureau of Environmental Health
Assessment. Woburn Childhood Leukemia Follow-up Study. 1997. Accessed 5/22/02 at
http://www.state.ma.us/dph/beha/cau/reports/woburn/wobleuk2 pdf
Meirow D. Ovarian injury and modern options to preserve fertility in female cancer patients
treated with high dose radio-chemotherapy for hetnato-oncological neoplasms and other
cancers. Leuk Lymphoma 1999, 33 65-76.
Meschke LL, Silbereisen RK The influence of puberty, family processes, and leisure activities
on the timing of first sexual experience. ] Adolesc 1997; 20:403-18.
Milerad J, Vege A, Opdal SH, Rognum TO Objective measurements of nicotine exposure in
victims of sudden infant death syndrome and other unexpected child deaths. J Pediatr 1998;
133-232-6.
Miller AB, Howe GR, Sherman GJ, et al. Mortality from breast cancer after irradiation during
fluoroscopic examinations in patients being treated for tuberculosis. N Engl J Med 1989,
321.1285-9
Miller E, Cradock-Watson ]E, Pollock TM. Consequences of confirmed maternal rubella at
successive stages of pregnancy. Lancet 1982, 2 781-4
Mills JL, Fears TR, Robison LL, Nicholson HS, Sklar CA, Byrne J Menarche in a cohort of 188
long-term survivors of acute lymphoblastic leukemia. J Pediatr 1997; 131 598-602.
40 CRiTICAI. P£R:Q38 IN DEVELOPMENT
-------
Min Yl, Correa-Villasenor A, Stewart PA Parental occupational lead exposure and low birth
weight Am J Ind Med 1996,30.569-78
Monosson E, Kelce WR, Lambritht C, Ostby J, Gray LE Jr Peripubertal exposure to the
androgenic fungicide, vinclozolin, delays puberty, inhibits the development of androgen-
dependent tissues, and alters androgen receptor function in the male rat. Toxicol Ind Health
1999,15.66-79
Moore KL, Persaud TVN. The Developing Human Clinically Oriented Embryology, 6lh ed
Philadelphia W B Saunders, 1998, p 548
Moore KL. Before We Are Born: Basic Embryology and Birth Defects, 2nd ed. Philadelphia, WB
Saunders, 1977
Moscicki AB. Genital HPV infections in children and adolescents Obstet Gynecol Clin North
Am 1996; 23:675-97.
Mucignat-Caretta C, Caretta A, Cavaggioru A. Pheromonally accelerated puberty is enhanced
by previous experience of the same stimulus Physiol Behav 1995, 57:901-3.
Mullikin-Kilpatrick D, Mehta ND, Hildebrandt JD, Trieistman SN. Bi is involved in ethanol
inhibitaon of L-type calcium channels in undifferenhated but not differentiated PC-12 cells Mol
Pharmacol 1995,47 997-1005
Murante FG, Gasiewicz TA. Hematopoietic progenitor cells are sensitive targets of 2,3,7,8-
tetrachlorodibenzo-p-dioxin in C57BL/6J mice. Toxicol Sci 2000,54 374-83
Murray JC, Hill RM, Hegetnier S, Hurwitz RL. Lymphoblastic lymphoma following prenatal
exposure to phenytom J Pediatr Hematol Oncol 1996; 18(2):241-3
Naruse I, Keino H. Apoptosis in the developing CNS Prog Neurobiol 1995, 47135-55.
Needleman RD Growth and development In: Nelson Textbook of Pediatrics, 16th ed.
Berhman RE, Kliegman RM, Jenson HB, eds Philadelphia, WB Saunders Company, 2000,
pp.33,45-46,54.
Ness RB, Grisso JA, Hirschinger N, et al. Cocaine and tobacco use and the risk of spontaneous
abortion. N Engl J Med 1999; 340.333-9
Nicol CJ, Harrison ML, Laposa RR, Gimelshtem IL, Wells PG A teratologic suppressor role for
p53 in benzo[a]pyrene-treated transgenic p53 deficient mice. Nat Genet 1995; 10181-7.
NJDHSS (New Jersey Department of Health and Senior Services), Division of Epidemiology,
Environmental and Occupational Health Case-control Study of Childhood Cancers in Dover
Township (Ocean County), New Jersey. Volumes I-IV. 2001 Accessed 5/22/02 at
http-//www.state nj us/health/eoh/hhazweb/dovertwp.htm.
Nocosia SV, Matus-Ridley M, Meadows AT. Gonadal effects of cancer therapy in girls. Cancer
1985; 55:2364-72.
NRC: National Research Council Scientific Frontiers in Developmental Toxicology and Risk
Assessment Washington D.C., National Academy Press, 2000, pp 88-153
CRITICAL PERIODS :N DEVELOPMENT 41
-------
Nurminen T. Maternal pesticide exposure and pregnancy outcome. J Occup Environ Med
1995; 37 935-40
Oberfield SE, Soranno D, Nirenberg A, et al. Age at onset of puberty following high-dose
central nervous system radiation therapy. Arch Pediatr Adolesc Med 1996,150:589-92
Olgilvy-Stuart AL, Clayton PE, Shalet SM. Cranial irradiation and early puberty. J Clin
Endocrinol Metab 1994; 78.1282-6
Olshan AF, Anderson L, Roman E, Fear N, Wolff M, Whyatt R, Vu V, Diwan BA, Potishman N.
Workshop to identify critical periods of exposure for children's health: cancer work group
summary. Env Health Persp 2000; 108 (Suppl 3): 595-7
Olshan AF, Faustman EM Male-mediated developmental toxicity Annu Rev Publ Health
1993,14.159-81.
Omtzigt JG, Los FJ, Grobbee DE, et al The risk of spma bifida aperta after first-trimester
exposure to valproate in a prenatal cohort. Neurology 1992,42:119-25.
Onalaja AO, Claudio L Genetic susceptibility to lead poisoning. Environ Health Perspect 2000,
108(Suppl l):23-8.
Osmond C, Barker DJP Fetal, infant and childhood growth are predictors of coronary heart
disease, diabetes and hypertension in adult men and women Environ Health Perspect 2000;
108(Suppl 3):545-54
Ostrea EM Jr, Ostrea AR, Simpson PM. Mortality within the first 2 years in infants exposed to
cocaine, opiate, or cannabmoid during gestation Pediatrics 1997,100 79-83
Paccierotti F, Adler ID, Anderson D, et al Genetic effects of 1,3-butadiene and associated risk
for heritable damage. Mutat Res 1998;397.93-115
Pacifici R, Altieri I, Gandini L, et al Environmental tobacco smoke nicotine and cotmine
concentration in semen. Environ Res 1995,68 69-72.
Padungtod C, Hassold TJ, Millie E, et al Sperm aneuploidy among Chinese pesticide factory
workers scoring by the FISH method Am J Ind Med 1999,36 230-8
Parkinson A. Bio transformation of xenobiotics In Casarett & Doull's Toxicology: The Basic
Science of Poisons, 5th ed Klaassen CD, Amdur MO, Doull J, eds. New York, McGraw-Hill,
1996, pp. 113-86.
Pastore LM, Hertz-Picciotto I, Beaumont J] Risk of stillbirth from occupational and residential
exposures Occup Environ Med 1997, 54 511-8
Patandin S, Koopman-Esseboom C, de Ridder MA, Weisgla-Kuperus N, Sauer PH Effects of
environmental exposure to poly chlorinated biphenyls and dioxins on birth size and growth in
Dutch children Pediatr Res 1998; 44 538-45.
Peden DB. Development of atopy and asthma candidate environmental influences and
important periods of exposure Environ Health Perspect 2000,108(Suppl 3) 475-82
42 CRITICAL PSRIO08 IN OEVF.I.OPMF.NT
-------
Perera FP, Jedrychowski W, Rauh V, Whyatt RM. Molecular epidemiologic research on the
effects of environmental pollutants on the fetus Environ Health Perspect 1999; 107(Suppl
3)-451-60.
Perreault SD, Jeffay S, Poss P, Laskey JW. Use of the fungicide carbendazim as a model
compound to determine the impact of acute chemical exposure during oocyle maturation and
fertilization on pregnancy outcome in the hamster. Toxicol Appl Pharmacol 1992 Jun,
114(2).225-31
Petridou E, Trichopoulos D, Dessypns N, et aJ Infant leukemia after in utero exposure to
radiation from Chernobyl. Nature 1996,382:303-4.
Plon SE, Peterson LE Childhood cancer, heredity and the environment. In Principles and
Practice of Pediatric Oncology, 3rd ed Pizzo PA, Poplack DG, eds Philadelphia, Lippincott-
Raven, 1997, pp. 11-36
Plowchalk DR, Mattison DR. Reproductive toxicity of cyclophosphamide of the C57BL/6N
mouse 1 Effects on ovarian structure and function Reprod Toxicol 1992; 6 411-12
Potashruk G, Porath A Dibromochloropropane (DBCP): a 17-year reassessment of testicular
function and reproductive performance J Occup Environ Med 37.1287-92,1995
Prince M. Is chronic low-level lead exposure in early life an etiologic factor in Alzheimer's
disease? Epidemiology 1998,9(6):618-21
Quigley C, Cowell C, Jimenez M, et al. Normal or early development of puberty despite
gonadal damage in children treated for acute lymphoblastic leukemia N Engl J Med 1989;
321143-51
Rabinowitz M, Bellinger D, Leviton A, Needleman H, Schoenbaum S. Pregnancy hypertension,
blood pressure during labor, and blood lead levels Hypertension 1987,10 447-51
Ramenghi U, Bonissom S, Migliareth, et al. Deficiency of the Fas apoptosis pathway without ;
Fas gene mutations is a familial trait predisposing to development of autoimmune diseases and
cancer Blood 2000; 95 3176-82
Raumo H, Husgafvel-Pursianen K, Antilla S, Hietanen E, Hirvonen A, Pelkonen O. Diagnosis
of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility- ;
a review. Gene 1995,159.113-21. I
Restum JC, Bursian S], Giesy JP, et al. Multigenerational study of the effects of consumption of
PCB-contaminated carp from Saginaw Bay, Lake Huron, on mink. 1. Effects on mink
reproduction, kit growth and survival, and selected biological parameters J Toxicol Environ
Health 1998; 54:343-75
Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system
evidence from human and animal models. Environ Health Perspect 2000,108(Suppl 3):511-33
Rodier PM. Developing brain as a target of toxicity Environ Health Perspect 1995; 103(Suppl
6).73-76
GRITICAi. PERIODS Hf DeVEi.Oi»M£NT 43
-------
Rodriguez-Pinilla E, Arroyo I, Fondevilla J, Garcia MJ, Martinez-Frias ML Prenatal exposure to
valproic acid during pregnancy and limb deficiencies: a case-control study Am J Med Genet
2000; 90:376-81.
Rogers JM, Kavlock, RJ. Developmental toxicology In Casarett & Doull's Toxicology. The Basic
Science of Poisons, 5th ed. Klaassen CD, ed. New York, McGraw-Hill, 1996, pp 301-331.
Roman E, Doyle P, Maconochie N, et al Cancer in children of nuclear industry employees.
report on children aged under 25 years from nuclear industry family study. BMJ1999; 318-1443.
Rosen JF. Clinical applications of L-line X-ray fluorescence to estimate bone lead values in lead-
poisoned young children and in children, teenagers, and adults from lead-exposed and non-
lead-exposed suburban communities in the United States. Toxicol Ind Health 1997,13 211-8.
Rosen JF, Pounds JG. Quantitative interactions between Pb2+ and Ca2+ homeostasis in
cultured osteoclastic bone cells Toxicol Appl Pharmacol 1989; 98:530-43.
Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ. Nitrous oxide and
spontaneous abortion in female dental assistants Am J Epidemiol 1995,141-531-8
Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ Reduced fertility among
women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med
1992,327993-7.
Russo IH, Russo J Role of hormones in mammary cancer initiation and progression.
J Mammary Gland Biol Neoplasia 1998, 3.49-61
Sadler TW, Langman J. Langman's medical embryology, 8th ed. Philadelphia, Lippmcott-
Wilhams & Wilkins, 2000.
Saenz de Rodriguez CA, Gongiovanni AM, Conde de Borrego L. An epidemic of precocious
development in Puerto Rican children. J Pediatr 1985 107.393-6
Sallmen J, Lindbohm ML, Anttila A, Taskmen H, Hemminki K. Paternal occupational lead
exposure and congenital malformations J Epidemiol Community Health 1992, 46.519-22.
Savitz DA, Arbuckle T, Kaczor D, Curtis KM Male pesticide exposure and pregnancy outcome.
Am J Epidemiol 1997; 146.1025-36.
Savitz DA, Andrews KW, Pastore LM Drinking water and pregnancy outcome in central
North Carolina: source, amount, and trihalomethane levels. Environ Health Perspect 1995;
103:592-6.
Savitz DA, Sonnenfeld NL, Olshan AF. Review of epidemiologic studies of paternal
occupational exposure and spontaneous abortion. Am J Ind Med 1994; 25.361-83.
Schardem JL. Chemically Induced Birth Defects. New York, Marcel Deckker, Inc 2000.
Schecter A, McGee H, Stanley JS, Boggess K, Brandt-Rauf P Dioxins and dioxm-hke chemicals
in blood and semen of American Vietnam veterans from the state of Michigan Am J Lid Med
1996; 30:647-54.
44 CRiTICAI. PERIODS IN Of.VF.l.OPMf.NT
-------
Schuurs AH. Reproductive toxicity of occupational mercury. A review of the literature. J Dent
1999, 27.249-56.
Schwartz DA, LoGerfo JP Congenital lunb reduction defects in the agricultural setting Am J
Pubbc Health 1988; 78:654-8.
Sever JL, South MA, Shaver KA. Delayed manifestations of congenital rubella. Rev Infect Dis
1985, 7(Suppl 1) S164-9.
Sharpe CR, Franco EL Etiology of Wilms1 tumor Epidemiol Rev 1995,17.415-3Z
Sharpe KM, Fischer JS, Millar MM, Jobhng S, Sumpter JP Gestational and lactational exposure
of rats to xenoestrogens results in reduced teshcular size and sperm production Environ
Health Perspect 1995,103:1136-43
Shaw GM, Wasserman CR, O'Malley CD, Nelson V, Jackson RJ Maternal pesticide exposure
from multiple sources and selected congenital anomalies. Epidemiology 1999; 10.60-6.
Shepard TH Catalog of Teratogenic Agents. 10th edition Baltimore, Johns Hopkins University
Press, 2001
Srumada H, Umehara S, Monobe Y, et al International neuroblastoma pathology classificahon
for prognostic evaluation of patients with peripheral tumors a report from the Children's
Cancer Group Cancer 2001 Nov 1, 92(9) 2451-61
Shivenck KT, Salafia C. Cigarette smoking and pregnancy I. ovarian, uterine and placental
effects Placenta 1999; 20 265-72.
Shu XO, Gao YT, Brinton LA, et al. A population-based case-control study of childhood
leukemia in Shanghai Cancer 1988, 62:635
Sibai BM, Gordon T, Thorn E, et al Risk factors for preeclampsia in healthy nulliparous
women: a prospective multicenter study. The Nabonal Institute of Child Health and
Development Network of Maternal-Fetal Medicine Units Am J Obstet Gynecol 1995,172:642-8
Silbergeld EK, Flaws JA. Chemicals and menopause: effects on age at menopause and on health
status in the postmenopausal period J Women's Health 1999,8 227-34.
Sowards KA What is the leading cause of infant mortality? A note on the interpretation of
official statistics Am J Public Health 1999, 89:1752-4
Spencer SJ, Mesiano S, Lee JY, Jaffe RB. Proliferation and apoptosis in the human adrenal
cortex during the fetal and perinatal periods implications for growth and remodeling. J Clin
Endocrinol Metab 1999, 84.1110-5.
Sprauve ME, Lindsay MK, Drews-Botsch CD, Graves W. Racial patterns in the effects of
tobacco use on fetal growth. Am } Obstet Gynecol 1999,181S22-7.
Stachel B, Dogherty RC, Lahl U, Schlosser M, Zeschumar B. Toxic environmental chemicals in
human semen: analytical method and case studies. Andrologia 1989; 21 282*91.
CRITICAL PERIODS if* DEVELOPMENT 45
-------
Stewart P, Reihman J, Lonkey E, Darvill T, Pagano J Prenatal PCB exposure and neonatal
behavioral assessment scale (NBAS) performance. Neurotoxicol Teralol 2000; 22:21-9.
Sbck SM, Burton PR, Gurrin L, Sly PD, LeSouef PN. Effects of maternal smoking during
pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet
1996, 348:1060-4
Stjernfeldt M, Berglund K, Lindsten ], Ludvigsson ]. Maternal smoking during pregnancy and
risk of childhood cancer. Lancet 1986,1(8494):!350-2.
Strolin-Benedetti M, Tipton KF Monoamine oxidases and related amine oxidases as phase I
enzymes in the metabolism of xenobiotics J Neural Transm Suppl 1998; 52.149-71
Sumpter JP. Feminized responses in fish to environmental estrogens. Toxicol Lett 1995; 737-42
Tang HW, Huel G, Campagna D, Helher G, Boissinot C, Blot P. Neurodevelopmental
evaluation of 9-month-old infants exposed to low levels of lead in utero. involvement of
monoamme neurotransmitters. J Appl Toxicol 1999; 19-167-72
Taskinen H, Kyyronen P, Hemminki K, et al. Laboratory work and pregnancy outcome J
Occup Environ Med 1994; 36 311-319
Taskinen H, Anttila A, Lindbohm ML, Sallmen M, Hemminki K Spontaneous abortions and
congenital malformations among the wives of men occupationally exposed to organic solvents
Scand J Work Environ Health 1989; 15:345-52.
Taylor JA, Sanderson M. A reexaminanon of the risk factors for the sudden infant death
syndrome. J Pediatr 1995; 126:887-891
Tilly JL. Molecular and genetic basis of normal and toxicant-induced apoptosis in female germ
cells Toxicol Lett 1998; 102-103 497-501
Tinger A, Wasserman TH, Klein EE, et al. The incidence of breast cancer following mantle field
radiation therapy as a function of dose and technique. Int J Radiat Oncol Biol Phys 1997, 37
865-70
Todd AC, Wetmur JG, Molme JM, Godgold JH, Levin SM, Landngan PJ Unraveling the
chronic toxicity of lead: an essential priority for environmental health Environ Health Perspect
1996; 104(Suppl 1) 141-6
US DHHS: U S Department of Health and Human Services. Healthy People 2010, Conference
Edition. Washington, DC, 2000, Objectives 16-12,16-36
US EPA. U.S. Environmental Protection Agency The EPA Children's Environmental Health
Yearbook Supplement 2000. Accessed at http //www epa gov/children/whatwe/educathtm
(2000).
US EPA U S Environmental Protection Agency Research Plan for Endocrine Disrupters
Washington, DC 1998a EPA/600/R-98/087.
•
US EPA U.S Environmental Protection Agency The EPA Children's Environmental Health
Yearbook 1998b. Accessed at http //www.epa.gov/children/whatwe/educathtm (1998b)
40 CRiTIOAi. PER-OOS IN OPVE1.OPMF.NT
-------
US NIH (National Institutes of Health) and U.S. Environmental Protection Agency, Office of
Research and Development, Office of Air and Radiation. Respiratory Health Effects of Passive
Smoking- Lung Cancer and Other Disorders The Report of the U.S. Environmental Protection
Agency. NIH Publication No 98-3605. Bethesda, MD 1993.
Valams B, Vollmer WM, Steele P. Occupational exposure to anhneoplastac agents- self-reported
miscarriages and stillbirths among nurses and pharmacists. J Occup Environ Med 1999,41.632-8
Varma DR Epidemiological and experimental studies on the effects of methyl isocyanate on
the course of pregnancy Environ Health Perspect 1987; 72.153-7
Vine MF, Margolin BH, Morrison HI, Hulka BS. Cigarette smoking and sperm density: a meta-
analysis. Fertil Stenl 1994, 61:35-43.
Waggoner SE, Mittendorf R, Biney N, Anderson D, Herbst AL. Influence of in utero
diethylstilbestrol exposure on the prognosis and biologic behavior of vaginal clear-cell
adenocarcinoma. Gynecol Oncol 1994, 55:238-44
Waller K, Swan SH, DeLorenze G, Hopkins G Trihalomethanes in drinking water and
spontaneous abortion Epidemiology 1998, 9134-40
Ware JH, Dockery DW, Spiro A, et al Passive smoking, gas cooking, and respiratory health of
children living in six cites Am Rev Respir Dis 1984,129:366-374.
Weinberg CR, Wilcox AJ, Baird DD. Reduced fecundability in women with prenatal exposure
to cigarette smoking. Am J Epidemiol 1989; 129.1072-8
Weiss ST Environmental risk factors in childhood asthma Clin Exp Allergy 1998; 28(Suppl 5):29-34
Wergeland E, Strand K Working conditions and prevalence of pre-eclampsia, Norway 1989.
hit J Gynaecol Obstet 1997; 58189-%.
Whyatt RM, Santalla RM, Jedrychowski W, et al Relationship between ambient air pollution
and DNA damage in Polish mothers and newborns. Environ Health Perspect 1998;
106(Supp3):821-6
Wiencke JK, Thurston SW, Kelsey KT, et al. Early age at smoking initiation and tobacco
carcinogen DNA damage in the lung. J Natl Cancer Inst 1999; 91:614-9.
Wilcox AJ, Baird DD, Weinberg CR, Hornsby PP, Herbst AL. Fertility among men exposed
prenataUy to diethylstilbestrol. N Engl J Med 1995, 332:1411-6
Wilcox AJ, Weinberg CR, O'Connor JF, et al Incidence of early loss of pregnancy. N Engl J
Med 1988; 319:189-94.
Wilkins-Haug L Teratogen update: toluene. Teratology 1997; 55145-51.
Wilson DM, Killen JD, Hayward C, et al. Tuning and rate of sexual maturation and the onset of
cigarette and alcohol use among teenage girls. Arch Paediatr Adolesc Med 1994; 148 789-95
Wilson PD, Lpffredo CA, Correa-Villasenor A, Ferencz C. Attributable fraction fdr cardiac
malformations. Am J Epidemiol 1998,148-414-23
CRITICAL PERIODS IK
-------
Windham GC, Eaton A, Hopkins 8 Evidence for an association between environmental
tobacco smoke exposure and birthweighfc a meta-analysis and new data. Paediatric Perinat
Epidemiol 1999; 35-57.
Wolff MS, Weston A. Breast cancer risk and environmental exposure Environ Health Perspect
1997,105(Suppl 4) 891-6).
Wolff MS. Pesticides- how research has succeeded and failed in informing policy DDT and the
link with breast cancer Environ Health Perspect 1995; 103(Suppl 6) 87091.
WorldOrtho. Embryology Accessed 6/02 at
http-//www worldortho com/database/etext/embryology.html (2002)
Yu SY, Mizinga KM, Nonavinakere VK, Soliman KF Decreased endurance to cold water
swimming and delayed sexual maturity in the rat following neonatal lead exposure. Toxicol
Lett 1996, 83:135-41
Zenzes MT, Bielecki R, Reed TE. Detection of benzo[a]pyrene diol epoxide-DNA adducts in
sperm of men exposed to cigarette smoke Fertil Steril 1999; 72 330-5
Zhang J, Klebanoff MA, Levine RJ, Puri M, Moyer P. The puzzling association between
smoking and hypertension during pregnancy. Am J Obstet Gynecol 1999,181:1407-13
Zhang J, Savitz DA, Schwingl P], Cai WW A case-control study of paternal smoking and birth
defects In J Epidemiol 1992; 21-273-8.
Zimmerman PA, Francis GL, Poth M. Hormone-containing cosmetics may cause signs of early
sexual development Mil Med 1995,160:628-30.
CRiTIGAI. r>£R:O38 IN OFVSI.OPMF.NT
------- |