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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
ence.
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sarily represent those of the U.S. Environmental Protection Agency or of the Office of Children's
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CRITICAL PERIODS IN DEVELOPMENT
Critical Periods in Development
OCHP Paper Series on Children's

Health and the Environment
Paper 2003-2
Prepared by Kara Altshuler,* Michael Berg,* Linda M. Frazier,**
Jim Laurenson,* Janice Longstreth,* William Mendez,* and Craig A. Molgaard**
February 2003
* 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.
ii
Acknowledgments
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 J. Landrigan of the Department of
Community and Preventative Medicine at the Mount Sinai School of Medicine.
iii
Table of Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
2.
What Are Critical Periods of Development and Why Are They Critical? . . . . . . . . . . .2
2.1
2.2
2.3
Major Stages of Development from Conception to Adulthood . . . . . . . . . . . . .2
2.1.1
Germ Cell Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
2.1.2
Embryonic and Fetal Development During Pregnancy . . . . . . . . . . . .2
2.1.3
Ongoing Development During Childhood . . . . . . . . . . . . . . . . . . . . . .5
Why Certain Developmental Stages May Be Especially
Vulnerable to Environmental Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
2.2.1
Control of Cell Division . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
2.2.2
Apoptosis (Programmed Cell Death) . . . . . . . . . . . . . . . . . . . . . . . . . . .7
2.2.3
Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
2.2.4
Cellular Metabolism and Biotransformation of
Environmental Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
How Are Effects During Critical Periods Identified? . . . . . . . . . . . . . . . . . . . . . .8
Adverse Effects of Parental Exposures Before or Around the Time of Conception . . .10
3.
3.1
Environmental Agents That May Damage Germ Cells . . . . . . . . . . . . . . . . . . .10
3.2
Environmental Agents That May Cause Damage At or Just
After Conception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Adverse Effects of Environmental Exposures During Pregnancy . . . . . . . . . . . . . . . . .15
4.
4.1
General Pattern of Fetal Development and Environmental
Toxicity During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
4.2
Adverse Effects During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
4.2.1
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
Adverse Effects of Exposures During Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19
5.
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
Adverse Effects of Early Exposures That May Be Delayed Until Adulthood . . . . . . .27
6.
6.1
Cancers That Develop Later in Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
6.2
Other Effects Later in Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
7.
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
iv
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 subsequent 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 listed 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.
What Are Critical Periods of

Development and Why Are They
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. Specific 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 Cell Development
Germ cells are the sperm and egg cells. They
carry the genetic informationDNAfrom
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
numbering
in
the
oocytesinitially
millionsdegenerate 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.
Figure 1. Sensitive or Critical Stages of Human Development
Reprinted with permission of W.B. Saunders Co. (Moore, 1998)
As shown in Figure 1, 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 11th
Table 1. Stages of Prenatal and Postnatal Organ Structural Development

Sources: Benes, 1998; Dietert, 2000; Johnsen, 2000; Moore, 1977;
Needleman, 2000; Rice, 2000; WorldOrtho, 2002
Organ System
Early Prenatal
Mid-Late
Prenatal
Postnatal
Central nervous system
3-16 weeks
17-40 weeks
Continues into adulthood
Ear
4-16 weeks
17-20 weeks
Heart
3-8 weeks
Immune system
8-16 weeks
17-40 weeks
Immunocompetence:
0-1+ years Immune memory:
1-18 years
Kidneys
4-16 weeks
17-40 weeks
Nephrons mature in outer cortical

region, providing ability to
concentrate urine
Limbs
4-8 weeks
Lungs
3-16 weeks
Palate
6-10 weeks
Reproductive system
7-9 weeks
Skeleton
1-12 weeks
Teeth
12-16 weeks
> 80% of alveoli are formed after

birth to age 8-10
10-40 weeks
Sexual maturation, breast, and cervix

development: 9-16 years
Ossification continues for ~25 years
17-24+ weeks
During later stages of prenatal development,

environmental exposures can result in
impaired growth, physiological defects, or
functional deficiencies, as shown in the third
17-40 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 diethylstilbestrol (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.
Primary dentition: 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 sections, 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 patterns 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.
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 active
from birth through three years of age, and
myelination, 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 developmental 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 adulthood (Moscicki, 1996). 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 hormonesecreting organs, which can be affected by
environmental factors.
2.2
Why Certain Developmental

Stages May Be Especially
Vulnerable to Environmental
Exposures
This section briefly reviews some of the underlying 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 biotransforma

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-
Table 2. Checkpoints in the Cell Cycle

Source: Alberts, 1994a
Key Checkpoint
Control Molecules
Conditions Needed to
Pass Checkpoint
Growth
G1 cyclin-dependent
protein kinases
Adequate cell growth,

favorable environment
Synthesis of DNA
Re-replication blocking factors
One copy of DNA made
G2
Growth
G2 cyclin-dependent
protein kinases
All DNA replicated, adequate cell

growth, favorable environment
Mitosis,
Cytokinesis
M-phase promoting factor
All chromosomes aligned on

protein spindle
Phase
Activities
G1
The cell cycle consists of four distinct phases, each regulated by specific control molecules and 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 Cell 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; Iatropoulos, 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 throughout 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).
2.2.2 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 Wilms 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 Gene 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 proportion 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,
1996). 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 pathways 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 transduction,
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.
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
transduction of neurotransmitters is disrupted
by toxicants such as ethanol, methyl mercury,
and aluminum. Ionizing radiation and other
chemical carcinogens may alter DNA synthesis. Methyl mercury and ionizing radiation
may inhibit cell growth and division in the
developing nervous system (Graeter, 1996), as
well as affect cell survival and migration
(Rodier, 1995). High levels of air pollutants
containing polycyclic aromatic 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
Biotransformation of
Environmental Agents
Metabolism and biotransformation 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 biotransforma
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
transformation processes during development
can be a disadvantage to the fetus or child
when biotransformation in an adult would
detoxify hazardous substances. In some situa
tions, immaturity can be an advantage because
biotransformation 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, 1996;
Leeder, 1997; Parkinson, 1996; 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.
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 developmental stages. In the chapters that follow, we
present the results of several epidemiologic
studies in which the increased incidence of
adverse reproductive 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 reasonable 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).
Adverse Effects of Parental

Exposures Before or Around the
Time 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 3.1 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
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 follicular 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:
10
A well-publicized example is the nemato

cide dibromochloropropane (DBCP),
which caused dramatic azoospermia and
infertility among exposed workers
(Goldsmith, 1997; Potashnik, 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;
Ovarian toxicity and
Rowland, 1992).
impaired fertility can be caused by drugs or
radiation exposure used to treat lymphopro-
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
One study observed
(Buckley, 1989).
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 offspring (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 offspring (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 understand 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 organisms. 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-
Table 3. Association Between Preconception Exposures

in Men and Cancer in Offspring
Dose to
Father
Exposure
Cancer That
Developed in Child
Exposure Period
Benzenea
Not quantified
Preconception
Leukemia
Diagnostic
X-raysb
Not quantified
Preconception
Leukemia
Ionizing
radiationb,c
> 100 mSv

(milliSievert)
6 months prior to conception
Leukemia/non-Hodgkin's
lymphoma
> 100 mSv
Lifetime preconception
Leukemia
> 10 mSv
6 months prior to conception
Leukemia
1-5 mSv
Preconception
Acute lymphoblastic leukemia
Not quantified
Before birth
Hepatoblastoma
Not quantified
Preconception
Leukemia
Metalsa
Wood
a
dustb
Buckley, 1989;
McKinney, 1991; c Roman, 1999.
11
Table 4. Association Between Preconception Exposures

in Women and Cancer in Offspring
Exposure
Dose to
Mother
Exposure Period
Food industrya
Not quantified
Preconception or prenatal
lymphoma
Metal dusts,
petroleum products,
paints, pigmentsb
Not quantified
Preconception or prenatal
Hepatoblastoma
Radiationc
Not quantified
Preconception
lymphoma
McKinney, 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, 4vinylcyclohexene, 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 this 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 liver tumors in offspring.
Preconception exposures of female laboratory
animals to x-rays, DES, 7,12-dimethyl
benz[a]anthracene, N-nitrosodiethylamine, or
urethane have been associated with develop
12
Cancer That
Developed in Child
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
Such
detectible levels in non-smokers.
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 oocyte (egg cell) DNA can be altered by
toxic exposures in the preconception period.
For example, alcohol exposure can disrupt
chromosome duplication, resulting in aneu-
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
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 microenvironment
of the conceptus (the cell mass at conception),
disruption of checkpoint control mechanisms
(discussed in Section 2.2.1), 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 periconceptu
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 solvents, 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). Periconceptual
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, 1996; 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 polychlorinated dibenzofurans, including in utero
and lactational exposure to infants (Aoki,
2001; Lucier, 1987). PCBs and other endocrine
disruptors may be transferred to children
through the placenta four to five years after
the maternal exposure occurred and contribute 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 exposure 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;
13
Gulson, 1997; Han, 2000). Most women expe

rience limited lead exposure during pregnan
cy and the postnatal period, but their longterm 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 conception.
14
Adverse Effects of 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
an
increased
sensitivity
to
show
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-
15
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 undifferentiated cells include ethanol
(Mullikin-Kilpatrick, 1995), manganese (Di
Lorenzo, 1996), nicotine (Berger, 1998), and
TCDD (Murante, 2000).
4.2
Adverse Effects During

Pregnancy
This section summarizes the literature supporting 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 periconception
period (approximately the first two weeks
after fertilization) or in later prenatal develop
ment. Clinically, this effect is manifested as a
16
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 solvents in the periconception and/or prenatal
period also has been linked to an increased
risk of miscarriage (Lindbohm, 1990;
Lipscomb, 1991; Taskinen, 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 exposure 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
stilbestrol (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).
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 wellestablished 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 mellitus, if poorly controlled, also
increase the risk of congenital anomalies.
Occupational exposures to solvents (Khattak,
1999; McMartin, 1998) or glycol ethers (KnillJones, 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
Maternal
in some studies (Filkins, 1998).
exposure to pesticides, either occupationally
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 epidemiological
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; Nurminen, 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 themselves 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).
17
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 0.00004
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 gain, substance abuse, placental
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 (Conter, 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).
18
4.2.4 Pregnancy Complications

and Late Fetal 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), placental abruption (premature sepa
ration of the placenta from the uterus), and
stillbirth (Chelmow, 1996; DiFranza, 1995;
Shiverick, 1999; Sibai, 1995).
Increased risk of preeclampsia (pregnancyinduced 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; Rabinowitz, 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 substances include arsenic, lead, mercury, pesti
cides, and possibly chlorinated disinfection
byproducts (Golub, 1998; Nurminen, 1995;
Pastore, 1997; Schuurs, 1999).
Adverse Effects of Exposures

During Childhood
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 developmental processes and is distinct from the pattern 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
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 (Alm, 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, however, 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 discussed in Section 5.3.
Environmental contaminants known to cause
growth retardation during childhood include
lead, PCBs, and tobacco. Chronic lead exposure has been linked to decreased growth dur
20
ing childhood. In a large study of children

under seven years old, each increment in
average blood lead levels of 10 g/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
g/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 4.2.3, 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 childhood, 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 exposure, 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;
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, 1996; 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; Kimber, 1998).
Extensive evidence also supports the relationship 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 hypertension, although the relationship in children
is less clear (Loghman-Adham, 1997; Todd,
1996). Children chronically exposed to lead
have been found to exhibit subclinical alter
ations in kidney function (Fels, 1998). The
implications of these symptoms for the longterm 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
1985;
health
and
nutrition
(Baker,
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 alkylating agents and
other cancer drugs

causes pathological
changes in the reproductive systems in both
adolescent females (Nocosia, 1985; Quigley,
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, 1996; 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 radiation 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 exposure levels seen in the study.
22
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 premature 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, genistein,
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 developmental stages (Anderson, 2000). The scientif
ic evidence is strong for the induction of clearcell carcinoma in the daughters of women
exposed to DES and for the development of
increased risk of leukemia in children exposed
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 prenatal 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 epidemiological 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-expected overall incidence of childhood 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 sunlight 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).
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-Hodgkins lymphoma,
acute lymphoblastic
leukemia, and Wilms
tumor (doubled risk)
Stjernfeldt, 1986
Diethylstilbestrol
Not quantified
Vaginal adenocarcinoma
in female children
Waggoner, 1994
Gasoline
Not quantified
Acute nonlymphocytic
leukemia, acute
lymphocytic
leukemia
Shu, 1988
Leukemia
Petridou, 1996
Ionizing radiation
2 mSv
(milliSievert)
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
(occupational
exposure)
Not quantified
Acute lymphocytic
leukemia
Shu, 1988
Phenytoin (drug)
Not quantified
Neuroblastoma,
lymphoblastic
lymphoma
Koren, 1989;
Murray, 1996
TCE,
tetrachloroethylene,
and styreneacrylonitrile trimer
Not quantified
Acute lymphocytic
leukemia, brain
and central nervous
system cancers in
female children
under age five
NJDHSS, 2001
Trichloroethylene (TCE)
Not quantified
Childhood leukemia
MDPH, 1997
24
25
ENU
ENU
ENU
ENU
Mouse/C3HeB/FeJ
Mouse/C3HneNC
tumors
Mouse C57L/J
Mouse DBA/2J
Mouse/A/C5
ENU
Urethane
Mouse/B6WHT
Mouse/B6C3
tumors
X-ray
Hamster/SG
ENU
ENU
Animal
Mouse/B6
Type of
Exposurea
0.5 mmol/kg
0.5 mmol/kg
0.4 mmol/kg
12, 14, 16, 18
12, 14, 16, 18
16, 19
10, 13, 15, adult
12, 14, 16, 18

12, 14, 16, 18
60 mg/kg
10, 25, or 50 mg/kg
12-18, 1x
14, 15, 17
0.5 mmol/kg
0.5 mmol/kg
17-21, 1x
14-18
14-18
Both groups
10-15
All groups
All groups
12-18
All groups
17-21
16-18
12, 16-18
25 mg/mouse
16-18
16-18
12, 16-18
12, 16-18
200 Radd
9-14 (0.5 mmol/kg)
Sensitive
Exposure
Period(s)b
7-14
Gestational
Exposure
Period(s)b,c
0.2 or 0.5 mmol/kg
Exposure
Dose
Prenatal Exposures Resulting in Cancer
Table 6: Associations Between Prenatal Exposures and

Cancer in Laboratory Animals
Source: Anderson, 2000
16
16, 18
19
15
No significant difference
16
12-14
15
< 8 hr before birth
NA
16-18;
fewer lung tumors
in male offspring
from GD 12
NA
12-13
Period of
Highest
Sensitivityb
Lymphoid tumors
Lymphoid tumors
Nervous system
Lung tumors
Kidney tumors
Lung tumors
Nervous system
Lung tumors
Lung tumors
Ovarian tumors
Skin tumors
Lung tumors
Skin tumors
Cancer
Type
26
ENU
Rabbit
10-19, 15-24
60 mg/kg
NA, not applicable (sensitive range indicated in previous column)
8, 10
12, 14, 16, 18
11-13, 14-16
6-20, 1x
50 mg/kg
0.5 mmol/kg
0.88-1.2 Gray
60 mg/kg
6-20, 1x
6-20, 1x
12-16, 1x
12, 14,16
Gestational
Exposure
Period(s)b,c
Abbreviations used: DMBA (7,12-dimethylbenz[a]anthracene) and ENU (ethylnitrosourea)

Provided in gestational days (GD)
1x indicates a single exposure on each of the days indicated
Rad = Radiation absorbed dose, basic unit of measurement for absorbed radiant energy
ENU
Mouse SWR/J
X-ray
DMBA
60 mg/kg
DMBA
Mouse/NMRI
Mouse/NMRI
1 or 2 mg/mouse
5-Azacytidine
Animal
Exposure
Dose
Type of
Exposurea
All groups
All groups
12-18
14-16
All groups
6-15
10-20
14 (2 mg only), 16
12: 1 mg/kg;
16: both doses
Sensitive
Exposure
Period(s)b
Prenatal Exposures Resulting in Cancer
Table 6 (continued)
Lung tumors
Lymphoid tumors
Cancer
Type
NA
All similar
NA
8-13
Nervous system
tumors
Nervous system
tumors
Lymphoid tumors
Ovarian tumors
Ovarian tumors
11 (males) 6-11 (females) Lymphoid tumors

15-20
Lung tumors
16
Increase: GD 16,
1 mg/kg Decrease:
GD 14, 2 mg/kg
Period of
Highest
Sensitivityb
Adverse Effects of Early

Exposures That 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.
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
occupationally 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).
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.
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 childhood may increase the risk of breast cancer;
young girls appear to be particularly suscepti
ble to radiation injury that can result in longterm 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).
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
Lung cancer research suggests that exposures

to environmental agents during adolescence
may have greater risks than the same expo-
27
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, 1996). 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 damage 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 undergo 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 prenatal 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 manifested throughout life. Thus, increased cancer
risks in animals due to prenatal exposures
clearly are not limited to the immediate postnatal 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
28
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 noncancer 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 contribute 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
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

lowup 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).
29
Summary
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, childhood, 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
30
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).
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About the Paper Series

CRITICAL PERIODS IN DEVELOPMENT

Critical Periods in Development

OCHP Paper Series on Children's

Prepared by Kara Altshuler,* Michael Berg,* Linda M. Frazier,**

Jim Laurenson,* Janice Longstreth,* William Mendez,* and Craig A. Molgaard**

* ICF Consulting, Inc.

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

Major Stages of Development from Conception to Adulthood . . . . . . . . . . . . .2

Germ Cell Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2

Embryonic and Fetal Development During Pregnancy . . . . . . . . . . . .2

Ongoing Development During Childhood . . . . . . . . . . . . . . . . . . . . . .5

Why Certain Developmental Stages May Be Especially

Vulnerable to Environmental Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

Control of Cell Division . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

Apoptosis (Programmed Cell Death) . . . . . . . . . . . . . . . . . . . . . . . . . . .7

Cellular Metabolism and Biotransformation of

How Are Effects During Critical Periods Identified? . . . . . . . . . . . . . . . . . . . . . .8

Environmental Agents That May Damage Germ Cells . . . . . . . . . . . . . . . . . . .10

Environmental Agents That May Cause Damage At or Just

After Conception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

Adverse Effects of Environmental Exposures During Pregnancy . . . . . . . . . . . . . . . . .15

General Pattern of Fetal Development and Environmental

Toxicity During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15

Adverse Effects During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Early Fetal Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Growth Deficits During Pregnancy and Pre-Term Birth . . . . . . . . . .18

Pregnancy Complications and Late Fetal Death . . . . . . . . . . . . . . . . .18

Adverse Effects of Exposures During Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

Neonatal Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

Growth Deficits During Early Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20

Functional Deficits and Delayed or Impaired Functional Maturation . . . . . . .20

Effects on Puberty and Sexual Maturation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21

Cancer In Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22

Cancers That Develop Later in Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27

Other Effects Later in Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28

CRITICAL PERIODS IN DEVELOPMENT

The course of human development from con

cy, early childhood, and adolescence (Chapter

CRITICAL PERIODS IN DEVELOPMENT

What Are Critical Periods of

The first section of Chapter 2 briefly reviews

Individual development proceeds from the

CRITICAL PERIODS IN DEVELOPMENT

Germ cells begin development in fetal life,

Figure 1. Sensitive or Critical Stages of Human Development

Reprinted with permission of W.B. Saunders Co. (Moore, 1998)

As shown in Figure 1, prenatal development

during this period can result in major disrup

CRITICAL PERIODS IN DEVELOPMENT

Table 1. Stages of Prenatal and Postnatal Organ Structural Development

Central nervous system

Continues into adulthood

Nephrons mature in outer cortical

> 80% of alveoli are formed after

Sexual maturation, breast, and cervix

During later stages of prenatal development,

CRITICAL PERIODS IN DEVELOPMENT

week of gestation may cause congenital heart

Primary dentition: 4 months after

column of Table 1. As discussed in the follow