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                                               CRmCAi. PERIODS :N DEVELOPMENT

         (Critical Periods  m Development
                 OCHP Paper Series on Children's
                    Health and the Environment
                             Paper 2OO3-2
            Prepared by Kara Altshuler,* Michael Berg,* Linda M Frazier,**
      Jim Laurenson,* Janice Longstreth,* William Mendez,* and Craig A. Molgaard*
                              February 2QQ3
* ICF Consulting, Inc.
** University of Kansas School of Medicine-Wichita
This paper is being distributed for purposed of information sharing and discussion only. The
opinions and findings expressed in this paper are those of the authors and do not necessarily
represent those of the U S. Environmental Protection Agency or of the Office of Children's
Health Protection. No official Agency endorsement should be inferred from the paper.
       CR:TICA!. f»ER:OD8 iN OEVEi.OPMF.NT

Ac 1m ow 1 cclg'mcTi is
 This paper, the second in the Office of Children's Health Protection's Paper Series on Children's
 Health and the Environment,  reviews crucial stages in human development from  conception
 through adolescence and the implications of environmental insults or exposures at these differ-
 ent stages.

 Many individuals and  organizations assisted in preparing this paper  The  authors at ICF
 Consulting and the colleagues who helped them relied largely on the results of a scientific litera-
 ture review for OCHP by the University of Kansas, School of Medicine at Wichita,  which was
 completed in early 2001. OCHP appreciates the invaluable suggestions of the following internal
 EPA peer reviewers: David Chen, Brenda Foos, Gary Kimmel, Amal Mahfouz,  Gregory Miller,
 and Onyemaechi Nweke, and the following external peer reviewers Cynthia F Bearer of the
 Department of Pediatrics and  Neurosciences at Case Western Reserve University School of
 Medicine, Ruth Etzel of the School of Public Health and Health Services at George Washington
 University, Daniel  Goldstein of Monsanto, and Philip )  Landrigan  of the  Department of
 Community and Prevents live Medicine at the Mount Sinai School of Medicine.
                                               CfimCAi. PERIODS Ht DEVELOPMENT

 lame  or  Contents
1.      Introduction	    1
2.      What Are Critical Periods of Development and Why Are They Critical?	2
       2.1    Major Stages of Development from Conception to Adulthood  	2
              2.1.1   Germ Cell Development    	2
              212   Embryonic and Fetal Development During Pregnancy ..      .... 2
              2.1.3   Ongoing Development During Childhood	    	5
       2.2    Why Certain Developmental Stages May Be Especially
             Vulnerable to Environmental Exposures	   5
              221   Control of Cell Division	   6
              222   Apoptosis (Programmed Cell Death)	7
              223   Gene Expression  	7
              224   Cellular Metabolism and Biotransformation of
                     Environmental Agents	    	     .... 8
       2 3    How Are Effects During Critical Periods Identified?	8
3      Adverse Effects of Parental Exposures Before or Around the Time of Conception  . .10
       31    Environmental Agents That May Damage Germ Cells	      ... .10
       3.2    Environmental Agents That May Cause Damage At or Just
             After Conception	  13
4.      Adverse Effects of Environmental Exposures During Pregnancy  	15
       41    Genera] Pattern of Fetal Development and Environmental
             Toxicity During Pregnancy	  15
       4 2    Adverse Effects During Pregnancy  	  16
              4.21   Early Fetal Death   	16
              4.2 2   Congenital Malformations	      	16
              4.2.3   Growth Deficits During Pregnancy and Pre-Term Birth    	18
              4.2.4   Pregnancy Complications  and Late Fetal Death	        . .18
5      Adverse Effects of Exposures During Childhood       	    .         .19
       5.1    Neonatal Mortality	19
       5 2    Growth Deficits During Early Childhood	           20
       5.3    Functional Deficits and Delayed or Impaired Functional Maturation  ...  20
       5 4    Effects on Puberty and Sexual Maturation	21
       5 5    Cancer In Children  	22
6.      Adverse Effects of Early Exposures That May Be Delayed Until Adulthood	27
       61    Cancers That Develop Later in Life ..     ...        .      	27
       6 2    Other Effects Later in Life   	        28
7      Summary     	     	  30
References   .     ..      	       	    	31
   ,V  CRsTIGAl. Pf-R-008 IN QEVE1.OPMF.NT

The course of human development from con-
ception to adulthood is extremely complex. A
huge number of biochemical, physical, and
organizational processes  must be  precisely
coordinated  to assure orderly development,
maintain health, and avoid disease  Because
of the complexity, there are numerous oppor-
tunities for "things to go wrong." Children at
particular developmental  stages  may be
uniquely vulnerable to influences that have
little impact  at other points in their develop-
ment or on adults

This paper reviews  crucial  stages in human
development from  conception through  ado-
lescence and the implications of environmen-
tal insults or exposures at those different
stages It focuses on the developmental stages
during which children may be particularly
sensitive  to exposures  to environmental
agents or may be at risk of adverse effects that
would not occur if exposures occurred during
adulthood. Identifying these "critical" periods
is essential to developing strategies that pro-
tect children from adverse health effects asso-
ciated with environmental exposures

The remainder of this paper is divided into six
chapters.  Chapter  2 defines  the  important
stages of early human development. The sub-
sequent  chapters review  the evidence of
adverse impacts of environmental exposures
on key periods  of  germ  cell development
(Chapter 3), pregnancy (Chapter 4); and infan-
cy, early childhood, and adolescence (Chapter
5)   Chapter 6  briefly discusses  potential
adverse effects  of  environmental  exposures
during development that  may  not become
manifest until adulthood. Chapter 7 summa-
rizes the  major  findings and data gaps con-
cerning the impacts of environmental factors
during   key  periods   of  development
Following Chapter 7 is a list of references used
in this paper.

This paper discusses a broad range of chil-
dren's environmental health issues, but avoids
the technical details of specific studies or
methods, and does not present EPA policies
or positions on these issues.  Interested read-
ers can find additional information in the pri-
mary literature and the more detailed review
articles and textbooks  cited throughout the
paper and ksted at the end of the document.
Further,  this  paper  discusses   potential
adverse effects from exposure to many toxi-
cants and physical agents, some of which are
not environmental in origin.  While EPA gen-
erally does not have the authority to address
non-environmental exposures (e.g, drugs or
medical x-rays), information regarding poten-
tial adverse effects from these exposures is
included because  many of these adverse
effects are similar to the adverse effects caused
by exposure to environmental contaminants
                                               CRITICAL PERIODS :N

           What Are  Critical  Periods 01
           Development  ami Why  Are 1  oey
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
Individual development proceeds from the
formation  of  germ cells (sperm  and  egg)
through fertilization, embryonic  and  fetal
development (both of which take place during
pregnancy), infancy, early  childhood, and
adolescence  Sped he events during each of
these broad developmental stages may create
sensitivity  to  environmental  influences
Damage from environmental exposures may
occur and manifest itself immediately or may
not appear until subsequent stages of devel-
opment or after development is complete.

2.1.1  Germ Celt Development
Germ cells are the sperm and egg cells. They
carry the genetic information —DNA —from
each parent.  The combination  of genetic
material from sperm and egg cells provide the
unique genetic  blueprint  for  each  child
Environmental toxicants that harm germ cells
can affect an adult's own fertility as well as the
health of the offspring.
Germ cells begin development in fetal life,
even though they do not mature until puber-
ty.  In the male fetus, primordial germ cells
develop  in utero  From puberty throughout
adulthood, these cells undergo cell division,
mitosis  and meiosis,  to  produce  mature
sperm  In  females, primordial germ  cells
undergo mitosis and the first phase of meiosis
during fetal life   Most  of these  primary
oocytes-mitially   numbering   in    the
millions-degenerate naturally until, by puber-
ty, only about 400,000 remain as primary folli-
cles  During each menstrual cycle, a group of
these follicles ripen, with  typically only one
resuming meiosis to form the egg  released
during ovulation. During each stage, the pri-
mordial germ cells in both sexes as well as pri-
mary oocytes in females can be damaged by
environmental  exposures  (Anderson, 2000,
Lemasters, 1993)  Results of such  damage
may include reduced  fertility later in life or
offspring with  congenital health problems
(Loeffler, 1999, Silbergeld,  1999)

2.1,2 Embryonic and Fetal
       Development  During
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 Critic*! St*s«« of Human Development
 Reprinted with permission of W.B SaundersCo. (Moore, 1998)
As shown in Figure \, prenatal development
is often divided into three stages:  periconcep-
tual (generally the 2 weeks following fertiliza-
tion), embryonic (3  to 7 weeks), and fetal (8 to
38 weeks).  During the periconceptual period,
the zygote  undergoes rapid  cell division,
implants into the wall of the uterus, and forms
a simple embryo.  During this period,  haz-
ardous environmental  exposures usually
cause fetal death rather than injury (Sadler,
2000).  Lethal effects during this period would
result in  a  spontaneous  abortion  only
detectable biochemically, for instance via  a
transiently positive serum  pregnancy test
(Hakim, 1995; Rowland, 1995; Wilcox, 1988).

Most major organs begin to form during the
embryonic period, with growth and develop-
ment continuing through the remainder  of
pregnancy and into infancy for some systems.
During the early period of organ development,
which varies  by organ system from 3-8 weeks
to 12-16 weeks,  the basic structures  of the
organs are established, as shown in the  second
column of Table 1. Disruption of development
during this period can result in major disrup-
tions in the large-scale structure of organs or
other structures (Bertollini, 1985; Omtzigt,
1992;  Rodriguez-Pinilla, 2000).   This  type of
damage may result in fetal death, but is more
likely to take the form of major physical mal-
formations (congenital anomalies).  Note that
Table 1 refers predominantly  to  structural
development and does not provide a compre-
hensive list of all systems.  "Ear," for example,
refers to the major physical structures of the
auditory system, whereas auditory function is
not manifest before about 28 weeks gestational
age. Also, Table 1 presents only a brief sum-
mary of  the most important developmental
events.  More detailed discussions of specific
developmental milestones and potential envi-
ronmental effects on those milestones are pro-
vided in the following sections.

Both the organ  affected by exposure during
this period and the resulting type of anomaly
are highly dependent on both the agent and the
gestational age at which the exposure occurs.
For example, rubella infection before  the
                                                 CRITiCAi. PERIODS iN DEVE1.QPMF.NT

               Table 1, Stages of Prenatal and Postnatal Organ Structural Development
                              s' 3er.es., «0?: Dl»t«:t. 2000; Johntsn. 7000; Moor*. 1977;
                               Htealeman, 2000; Rice. 2000; WortSOHhc, 2002
 Organ System          Early Prenatal
 Central nervous system   3-16 weeks
 Ear                    4-16 weeks
 Heart                  3-8 weeks
 Immune system          8-16 weeks


 Reproductive system

4-16 weeks

4-8 weeks
3-16 weeks

6-10 weeks
7-9 weeks

1-12 weeks
12-16 weeks
17-40 weeks
17-20 weeks

17-40 weeks

17-40 weeks
17-40 weeks
10-40 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  diethylshlbestrol  (DES).   This
exposure was found to cause genital anomalies
twice as often among male children of women
who took the medication before  the 11th week
of gestation as compared to those male chil-
dren exposed later in gestation (Wilcox, 1995).
Other effects of DES exposure are discussed in
subsequent chapters

During  later stages of prenatal  development,
environmental  exposures  can  result  in
impaired  growth, physiological  defects, or
functional deficiencies, as shown in  the third
                                  Continues into adulthood
0-1 + years Immune memory
1-18 years
Nephrons mature in outer cortical
region, providing ability to
concentrate unne
> 80% of alveoli are formed after
birth to age 8-10
Sexual maturation, breast, and cervix
 development  9-16 years
Ossification continues for -25 years
Primary dentation  4 months after
conception to 3 years postnatal
Permanent dentition  3 months after
birth to 25 years
                       column of Table 1. As discussed in the follow-
                       ing secbons, these effects may be manifested as
                       low birth weight,  prematurity, pregnancy com-
                       plications, or  late fetal death (Bogden, 1995;
                       Hewitt, 1998, Rabinowitz, 1987; Wergeland,

                       The patterns of susceptibility summarized
                       above are broad generalizations derived from
                       an extensive body of medical and clinical liter-
                       ature There are many exceptions to these pat-
                       terns and many  unresolved  issues regarding
                       the relationship of adverse  health effects in
                       children and environmental exposures during
                       specific periods of development  Some  of the
                       difficulties in relating exposures during specif-
                       ic critical  developmental periods to observed
                       health impacts are discussed in Section 2 3

2.1,3 Ongoing Development
       During Childhood
Important development processes continue
after birth.  As shown in the last column of
Table 1, major cellular structures of the brain
and other systems continue to develop through
childhood For example, in the brain and nerv-
ous system, neuron migration,  cell prolifera-
tion, and synapse formation are all very acbve
from  birth  through three years of age, and
myelmation, the development of cellular insu-
lation around  nerve fibers, continues for at
least 10 years  (Rice, 2000) and possibly well
into adulthood (Benes, 1998)

The immune system also develops extensively
during early childhood as immune memory is
established (Dietert, 2000). Improper develop-
ment of the immune system can  cause allergies
or autoimmune diseases  Exposure to environ-
mental agents during early childhood  may
affect immune system development and may
contribute to the development of asthma later
in life (Peden, 2000; Weiss, 1998).

Physical growth and maturation of organ sys-
tems continues through adolescence  Puberty
and  sexual maturation are primary develop-
mental milestones of adolescent development
Physiologic and  hormonal changes related to
puberty begin well before adolescence, at ages
six to eight years In girls, the cells of the cervix
begin to mature and develop into a form and
structure that will be consistent  through adult-
hood (Moscicki, 19%). The appearance of sec-
ondary sexual characteristics is marked by the
development of breast buds (thelarche) and is
followed by the onset of menses (menarche)
about two years later.   Boys typically show
signs of puberty two to three years later than
girls. For both genders, puberty  is accompa-
nied by a rapid increase in height (Needleman,
2000).  The process  of sexual  maturation is
accompanied by complex interactions between
the  central nervous system and hormone-
secreting organs, which can be  affected  by
environmental factors.
2.2   Why Certain Developments!
       Stages May && Especially
       Vulnerable to Environmental
This section briefly reviews some of the under-
lying biological reasons for the  sensitivity of
specific developmental stages to environmen-
tal exposures Concepts introduced in this sec-
tion will be helpful in understanding the exam-
ples presented in later chapters

The rapid and diverse nature of processes that
occur in  critical developmental  periods give
rise to concerns about special  vulnerability
during early life stages  Some processes, such
as sexual maturation, occur only during cer-
tain periods of development. Other processes
such as apoptosis, or programmed cell death,
occur more widely during development and
are less  prominent during adulthood  Cell
division in most organs occurs much faster
during development than in  adulthood
Finally, many complex processes need to be
effectively coordinated during development,
which  requires the cellular and intercellular
signaling systems to work correctly.

The following sections of this chapter briefly
discuss four important processes and instances
where environmental exposures have  dis-
turbed these processes, resulting in adverse
developmental impacts

•   Control of cell division,

•   Apoptosis,

•   Gene expression, and

•   Cellular metabolism and biotransfbrma-
    tion of environmental agents

As will be seen in the following sections, cell
division and apoptosis are more active in cer-
tain developmental stages, resulting in vulner-
abilities to environmental influences that are
unique to early development. Gene expression
is ubiquitous throughout development  and
strongly modulates responses to environmen-
                                                CRITICAi. PERIODS :* DEVELOPMENT

                            Table 2. Checkpoints in the Ceil Cycie
                                     Source: Alberts, 1SS4a

                 Key Checkpoint
                                                              Conditions Needed to
                                                              f3ss_Chec_kgpjnt ______
                 G, cyclin-dependent
                 protein kinases
                            Adequate cell growth,
                            favorable environment
                Synthesis of DMA  Re-replication blocking factors   One copy of DMA made
G2 cyclin-dependent
protein kinases
M-phase promoting factor
                                                             All DNA replicated, adequate cell
                                                             growth, favorable environment

                                                             All chromosomes aligned on
                                                             protein spindle
 The cell cycle consists of tour distinct phases, each regulated by specific control molecules end characterized by
 specific conditions required to advance to the next phase If the conditions are not met. the cycle will not enter the next
 phase However, if the checkpoint molecules have been inhibited by a toxicant, the cell cycle might advance before all
 conditions are met, leading to unfavorable results such as cell death
tal  stimuli   The metabolism  of pollutants
strongly affects the nature and  magnitude of
responses to environmental  exposures,  and
patterns of metabolism and biotransformation
change in important ways throughout devel-

Other complex processes in the development
of the  central nervous system include cell
migration, axon development (the "wiring" of
the nervous system), synaptogenesis (develop-
ment of connections between nerve cells), and
synaptic plasticity (changes in  the pattern of
neurological connections associated with learn-
ing and other developmental processes) Less
is known about potential environmental influ-
ences on these processes, and therefore they are
not covered in this paper. The reader is urged
to review other literature concerning neurolog-
ical  development including a  review article
regarding critical periods of vulnerability for
the developing nervous system (Rice, 2000).

2.2.1   Control of CeH  Division
Rapid cell division is a primary driver of devel-
opment The cell cycle, the process of cell divi-
sion and growth, involves  the  interaction of
many   metabolic  and  control  pathways
(Alberts, 1994a; latropoulos,  1996;  Lodish,
                                1999)  In most mammalian tissues, the cell
                                cycle consists of four distinct phases, as shown
                                in Table 2  The cell cycle involves continuous
                                DNA transcription and  synthesis of a  wide
                                variety of proteins

                                All  DNA  must  be  successfully  replicated
                                before cell division can occur.  Cell growth is
                                regulated by at least nine  growth factor pro-
                                teins (Alberts, 1994a);  normal  cell growth
                                requires that these proteins work properly.

                                As indicated in Table 2, checkpoints through-
                                out the cell cycle prevent entry into the next
                                phase of the cycle if previous stages are not
                                complete (Alberts, 1994a).   Each of the  more
                                than 210 cell types in the human body has its
                                own usual cell cycle length, ranging from  a few
                                hours to  several months  or longer  A  shorter
                                cycle, implying more rapid metabolic activity,
                                generally makes cells more vulnerable  to toxi-
                                cant effects.  Embryonic cells generally  have
                                very short cell cycles  A common regulatory
                                failure in rapidly cycling  embryonic cells is for
                                the G2 checkpoint to be bypassed. If DNA syn-
                                thesis is inhibited by a toxicant, the cell ignores
                                the requirement that all DNA must be replicat-
                                ed and may proceed directly into a  mitosis
                                phase that results in cell death (Alberts, 1994a).

2.2,8 Apoptosis (Programmed
       Cell Death}
Perhaps  surprisingly,  apoptosis,  or  pro-
grammed cell death, also is an important
process during development  Cell types and
numbers in specific organs are regulated not
only by production of new cells  through cell
division,  but also by removal of certain  cells
through apoptosis (Alberts, 1994b, Brill, 1999)
In some instances, one type of cell  is succeeded
by another during  a specific developmental

Apoptosis is involved in removing  webbing
from between the fingers and in regressing the
fetal zone of the adrenal gland (Alberts, 1994b,
Spencer,  1999)   Apoptosis is responsible for
eliminating populations of cells in the immune
system that,  if  they survived, could cause
autoimmune   disease   (Amsen,    1998)
Apoptosis also plays a critical role in the devel-
oping  nervous system, where it occurs in
waves (Naruse, 1995, Rice, 2000; Rodier, 1995).
It begins in proliferative zones and recurs peri-
odically as the nervous  system is remodeled
based on the number and kind of connections
each neuron has made.  Apoptosis remains
active during the postnatal period because of
on-going nervous system development

Disruption  of  normal patterns of apoptosis
through altered gene expression  or  failure of
signaling mechanisms is implicated in a wide
range of  pathologies  These include autoim-
mune lymphoproliferative diseases and certain
cancers (Landowski, 1997;  Ramenghi, 2000)
For example, the persistence of renal stem cells
that are  supposed  to disappear four to six
weeks prior to birth may make those  cells vul-
nerable to postnatal exposures that transform
them into Wdms tumor, a relatively  common
childhood cancer (Sharpe CR, 1995). Failure of
apoptosis also is suspected as a cause  of autism
(Rodier, 1995)
2.2.3 G&n& Expression
Gene expression,  which is  the translation of
DNA into RNA and the production of active
proteins from RNA, controls not only cell divi-
sion and  apoptosis, but also  the metabolic
activity of the cell  During development, gene
expression is extraordinarily active a high pro-
portion of genes are being expressed and a
large number of genes are being "switched on"
or "switched off to control cellular activities.
This high level of metabolic activity provides a
wide range of opportunities for environmental
agents to interfere with cell development and

A toxicant can interact directly with DNA to
disturb gene expression Alternatively, it may
interact with the products of gene expression,
such as enzymes or control molecules (Gregus,
19%).  A toxicant may  react directly with the
"target" molecule or it may be metabolized to
another compound that is the ultimate toxicant
Reactions can be random in nature if the toxic
agent is highly reactive with a wide range of
chemicals, or they can involve  highly specific
interactions between the toxicant and its target.

Exposure to environmental toxicants can affect
many kinds of molecular pathways The path-
ways  that are the most vital to continued cell
survival, function, and the error-free transmis-
sion of genetic information are the most impor-
tant to children's environmental health. These
pathways include the following:

•   DNA activation and synthesis,

•   DNA and protein repair,

•   Signal transducbon,

•   Cellular  metabolism and biotransforma-
    tion, and

•   Absorption, distribution, and excretion.

For example, signaling •within and between
cells is key to gene expression, cell migration,
and other developmental  mechanisms  (Hay,
1998, NRC, 2000).  Researchers have identified
at least 17 major pathways for developmental
intercellular  chemical signaling (NRC, 2000),
and the number is increasing with ongoing
                                                CRITICAL PERIODS ifc DEVf-.

Environmental contaminants can interfere with
these vital molecular processes and cause per-
manent damage  to a  child's  development
Brain development may be altered when signal
transductaon of neurotransmitters is disrupted
by toxicants such as ethanol, methyl mercury,
and aluminum.  Ionizing radiation and  other
chemical carcinogens may alter DNA synthe-
sis.   Methyl mercury and ionizing radiation
may inhibit cell growth and division in the
developing nervous system (Graeter,  19%), as
well as affect cell survival and migration
(Rodier, 1995).  High levels of air pollutants
containing  polycyclic aroma be hydrocarbons
may cause abnormal DNA formation  (Whyatt,
1998)  The effects of exposure to environmen-
tal toxicants may  cause significant deficits in
the developing child.

2.2.4  Cellular Metabolism and
        Blatrarksformatian of
        Environmental Agents
Metabolism and biotransformahon both  occur
at a cellular level and their combined effects are
seen throughout the body.  Cellular metabo-
lism incorporates all chemical and energy
transformations that  occur in our cells as a
result  of the breakdown and  synthesis of
organic compounds (e.g., food and beverages).
Biotransformation occurs  when  enzymes
chemically alter a compound, such as a drug, in
the body

Many important metabolic and bio trans forma-
tion  processes are poorly developed or are
entirely  absent  in developing organisms
These processes are important for environmen-
tal health because  they can affect how environ-
mental agents are transformed in  the  body
after  exposures.   Metabolism may either
increase or decrease the toxicity of a  chemical
agent,  or make easier or harder its elimination
from the body.  Thus, the immaturity of bio-
transformabon processes during development
can be a disadvantage to the  fetus or child
when  biotransformahon in an  adult would
detoxify hazardous substances.  In some situa-
tions, immaturity can be an advantage because
biotransformabon in an adult may  create a
more hazardous compound through activa-
tion.  Given their primary evolutionary func-
tion of detoxifying and eliminating potentially
toxic chemicals, immature or underdeveloped
metabolic pathways are likely, on balance, to
render infants and  children  more sensitive to
common environmental contaminants. Many
instances of this vulnerability have been identi-
fied (AAP 1999; AAP, 1974; Adam, 1999; de
Wildt, 1999;  Faustman, 2000; Graeter, 19%,
Leeder,  1997; Parkinson,  19%, Perera, 1999;
Raunio,  1995; Strolin-Benedetti, 1998).

2.3   How Are Effects  During
        Critical  Periods
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 develop-
mental stages  In the chapters that follow, we
present the results of several epidemiologic
studies  in which  the increased  incidence of
adverse reproducbve outcomes, birth defects,
or childhood diseases is linked to exposures
that may have occurred pre- or post-concep-
tion, during early or late pregnancy, or even
postnatally  In such cases, the developmental
stage affected commonly is inferred from the
nature of the damage  For example, reduced
fertility is taken to imply effects on germ cells
or during  the periconceptual period, major
malformations imply  effects during organ
development, and growth retardation implies
effects later in pregnancy

These assumptions generally are quite reason-
able and may be helpful in identifying oppor-
tunities for exposure reduction or directions for
further investigation  In the discussions that
follow, however, we attempt to maintain the
distinction between (1) critical periods identi-
fied based on inferences from limited numbers
of studies  or on  general  considerations of
developmental patterns, and (2)  those  infer-
ences that have  been confirmed  by multiple
studies in which the chain of causality is rela-
tively clear between the biochemical level and
the observed adverse effects

The majority of examples fall into the first cate-
gory  Individual studies provide plausible, but
not conclusive, evidence  of relationships
between exposures  in a given developmental
period and  adverse  health   outcomes.
Therefore,  the reader should consider  the
cumulative weight of evidence concerning var-
ious effects, and not just individual studies. On
the whole, a rapidly growing body of evidence
indicates that early human development repre-
sents a period with its own unique set of vul-
nerabilities to environmental agents Some of
these  vulnerabilities arise  because  fetuses,
infants, and children are more (or occasionally,
less) sensitive to the effects of specific agents
than adults, because of immaturity. Other spe-
cial vulnerabilities arise owing to the sensitivi-
ty of  processes that occur only during early
development (e g, organ development) or the
processes that are much more prominent at this
life stage (e g, apoptosis, rapid cell division).
                                                 CRITICAL PERIODS if* DEVFLOPMENT

           Adverse  Effects  of  Parental
           Exposures  Before or  Around the
            I line  of  Conception
This chapter  discusses  available evidence
linking  adverse  effects  in  children with
parental exposures to environmental toxicants
before  or around the time  of conception.
Section 31 summarizes  studies of parental
exposures  that  may  damage germ  cells
Section 3 2 reviews studies of the adverse
effects associated with exposures of parents
and/or offspring during or just after concep-

3.1   Environmental Agents
       That May Damage
       Germ Cells
As discussed in  the previous chapter, germ
cells begin to develop before birth and persist
throughout life  In men, germ cells continue
to be produced  from stem cells throughout
adulthood.  In women,  mature oocytes are
produced every  month from  folhcular cells.
Germ cells and their progenitors are sensitive
to a wide range of environmental agents
Exposure to environmental  toxicants  may
cause premature death of primary oocytes in
the fetus through effects on discrete signaling
pathways involved in apoptosis. This reduc-
tion in  gonadal reserves, in turn, may cause
reduced fertility or premature reproductive
failure  (Silbergeld, 1999; Tilly, 1998)   Male
reproductive stem cells also may be particu-
larly sensitive to environmental exposures
due to their rapid cell cycle

Several  studies  have associated impaired
reproductive health with  damage to germ
cells or  their progenitors, including the fol-
•  A well-publicized example is the nemato-
   cide  dibromochloropropane  (DBCP),
   which caused dramatic azoospermia and
   infertility   among   exposed  workers
   (Goldsmith, 1997;   Potashmk,  1995).
   Fewer  boys than usual  were born to
   DBCP-exposed workers who were able to

•  Women exposed to cigarette smoke dur-
   ing their mother's pregnancy had reduced
   fertility (Weinberg, 1989)

•  Men exposed to diethylstilbestrol (DES) in
   utero were found  to have lowered sperm
   count and increased frequency of abnor-
   mal sperm, but apparently normal fertili-
   ty (Bibbo, 1977; Wilcox, 1995)

Fertility clearly can be harmed by hazardous
exposures  that affect  ovarian function
Women exposed to the toxic  agents in ciga-
rette smoke may develop menstrual disorders
and altered reproductive endocrine profiles.
One study shows that smoking 10 or more cig-
arettes per day was related to greater variabil-
ity in menstrual cycle length, an increased fre-
quency of anovulation, and short luteal phase
(Windham, 1999)  Many studies show that
cigarette smoking  reduces fertility among
women (Baird, 1985, Hartz,  1987; Howe,
1985) Workplace exposures, such as high lev-
els of exposure to nitrous oxide or mercury,
also  can  impair fertility (Rowland,  1995,
Rowland,  1992)    Ovarian  toxicity  and
impaired fertility can be caused by drugs or
radiation exposure  used to treat lymphopro-

liferative  disorders or cancer  (Blumenfeld,
1998, Gonzalez-Crespo, 1995; Meirow, 1999).

A substantial body of evidence from human
studies demonstrates that exposures to envi-
ronmental agents and medical radiation can
injure germ cells in such a way as to cause
increased incidence  of cancer,  particularly
leukemia, among  offspring of the exposed
individuals  (Buckley, 1989, Gardner,  1990;
McKinney, 1991, Roman,  1999)  Tables 3 and
4 summarize observed relationships between
preconception exposures  of men and women
and  increased cancer rates in their children.
As shown in Table 3, paternal  exposures  to
ionizing  radiation have been  linked  with
leukemia and  lymphoma in subsequent chil-
dren.  Paternal exposures to benzene also
have been linked to leukemia  in children
(Buckley,  1989).    One  study  observed
increased risks of leukemia in the children of
fathers exposed to wood  dust (McKinney,
1991)  Another study found an association
between  paternal  occupational exposure  to
metals and hepatoblastoma incidence in off-
spring (Buckley, 1989).

Maternal employment in certain occupations
such as the food industry or exposures to ion-
izing radiation have been shown to be associ-
ated with an increased risk of leukemia and
                              non-Hodgkin's  lymphoma (McKinney, 1991;
                              Draper, 1997)  Maternal exposures to metals,
                              paints,  petroleum products, and pigments
                              prior to conception have been associated with
                              the development of hepatoblastoma  in off-
                              spring (see Table 4)  As noted in Section 2.3
                              not all studies  distinguish exposures before
                              conception from exposures during pregnancy
                              (Buckley, 1989, McKinney, 1999)  This limita-
                              tion makes it difficult to identify the precise
                              stage at which adverse effects  occur, and
                              poses problems for women  trying to  under-
                              stand  potential reproductive  risks  in  the
                              workplace These studies should not be inter-
                              preted as  strong evidence for a link between
                              parental exposures to certain toxicants and
                              cancer in offspring because some of the stud-
                              ies  investigated small  numbers  of affected
                              parents or involved exposures to multiple tox-
                              icants (McKinney,  1991) or did not report a
                              statistically significant  increase  in the  inci-
                              dence of a particular cancer (Draper, 1997).

                              Animal studies provide  supporting evidence
                              that exposures during prenatal life can affect
                              future reproductive function in adult organ-
                              isms  For example, prenatal exposure to cer-
                              tain highly chlorinated chemicals such  as
                              2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
                              or  polychlorinated biphenyl-169 (PCB-169)
                              was associated  with reduced sperm produc-
                   Tafoje 3. Association Between Preconception Exposures
                              in Men and Cancer in Offspring
               Cose to
                                           Cancer That
 Wood dust"
Not quantified
Not quantified

> 100 mSv
> 100 mSv
> 10mSv
1-5 mSv
Not quantified
Not quantified

& months prior to conception

Lifetime preconception
6 months prior to conception
Before birth

Leukemia/non-Hodg kin's
Acute lymphoblastc leukemia
 • Buckley, 1989, " McKinney. 1991, c Roman. 1999
                                                GRITICAi. PERIODS Hi

                  Tabie 4. Association Between Preconception Exposures
                            in Women and Cancer in Offspring
                    Dose to
                                                          Cancer That
 Food industry3

 Metal dusts,
 petroleum products,
 paints, pigmentsb
                  Not quantified  Preconception or prenatal
                  Not quantified  Preconception or prenatal
                  Not quantified  Preconception
Hepato blastema
 • McKmney, 1991, " Buckley, 1989, c Draper. 1997
tion in male rats (Gray, 1998, Loeffler, 1999).
This effect occurred after  a  single dose of
TCDD (Gray, 1997).   In another example,
reduced sperm production was seen in rats
that were exposed to DES during gestation
(Sharpe RM, 1995). Ovarian toxicity has been
demonstrated in experimental animals after
exposures to  lead, 1,3-butadiene epoxides, 4-
vinylcyclohexene, cyclophosphamide, hexa-
chlorobenzene, and other compounds (Doerr,
1996,  Doerr, 1995; Foster, 1992; Junaid, 1997;
Plowchalk, 1992)

As with  humans, exposures  of test animals
during germ  cell development are associated
with increased risk of cancer in offspring.  An
excellent review of the literature on thus sub-
ject can be found in an article by  Anderson
(2000) Among the agents causing increased
cancer incidence in offspring after paternal
exposures  are x-rays, DES,  urethane,  and
drugs such as some  chemotherapy  agents.
Exposure to these agents has  been associated
with development of  lung  cancer,  leukemia,
lymphoma,  and bver tumors in  offspring
Preconception exposures of female laboratory
animals  to  x-rays,  DES,  7,12-dimethyl-
benz[a]anthracene, N-nitrosodiethylamme, or
urethane have been associated with develop-
                                            ment of lung cancer and uterine adenocarci-
                                            nomas in the offspring

                                            Genetic research has suggested mechanisms
                                            by which  some of these adverse effects may
                                            occur. Studies have shown that both smoking
                                            and  pesticide exposure can  increase aneu-
                                            ploidy (an  abnormal number of  chromo-
                                            somes) in  sperm  cells (Harkonen, 1999,
                                            Padungtod,  1999).   Other  studies  illustrate
                                            how exposure to combustion byproducts may
                                            directly damage DNA in sperm  cells.  For
                                            example, benzo[a]pyrene, a common product
                                            of tobacco and other combustion, can react
                                            with  DNA to form  adducts, which are DNA
                                            bases that have been chemically changed so
                                            that  they do not  resemble normal DNA
                                            (Zenzes, 1999).  The studies reported that the
                                            frequency of DNA  adducts is highest in the
                                            sperm of smokers,  with lower  but  still
                                            detectible  levels  in non-smokers    Such
                                            adducts may be a potential cause of mutations
                                            that could affect fertility and the health of any

                                            Research on female germ cells also has shown
                                            that oocyle (egg cell) DNA can be altered by
                                            toxic  exposures in the preconception period.
                                            For example, alcohol exposure can disrupt
                                            chromosome duplication, resulting  in aneu-
                        IN OEVP1.OPM6.NT

ploidy in the embryo (Kaufman, 1997)  Also,
exposure to 1,3-butadiene can induce changes
in the chromosome structure of pre-ovulatory
oocytes at doses that are not lethal to the cell
(Paccierotti, 1998).

3.2   Environmental Agents
       That May Cause
       Damage At or Just
       After Conception
The period during and shortly after concep-
tion also is a vulnerable time during which
environmental exposures can affect the health
of the embryo  Known or suspected mecha-
nisms for these effects include genetic alter-
ation of male or female gametes, transfer of
toxicants in semen to the microenvirortment
of the conceptus (the cell mass at conception),
disruption of checkpoint control mechanisms
(discussed in Section 2.21), or other unknown
mechanisms (Alberts, 1994a; Olshan, 1993)
Disruption of checkpoint control mechanisms
could explain, in part,  the ability of certain
toxicants to cause the embryo to die following
exposures that occur shortly after conception.
As discussed in Section 2.3, it often is difficult
to distinguish effects caused by exposures in
the more distant past from exposures in the
period around conception.

Despite these technical difficulties, a number
of studies have linked paternal penconceptu-
al exposures to adverse  outcomes during
pregnancy and  childhood   For example,
increases in spontaneous abortions and other
types of fetal death have been observed in
populations in which the father was exposed
to anesthetic gases, lead, mercury, organic sol-
vents, pesticides, or welding fumes (Anttila,
1995; Arbuckle, 1999; Arbuckle, 1998; Cohen,
1980; Kristensen, 1993,  Lindbohm, 1991a;
Lindbohm, 1991b, Olshan, 1993, Savitz, 1997;
Savitz, 1994; Taskinen, 1989)  Congenital mal-
formations have been linked with paternal
exposure to anesthetic gases, marijuana, pesti-
cides, tobacco, welding fumes, and possibly
lead (Blatter, 1997, Garcia, 1998a; Kristensen,
1997, Olshan,  1993,  Sallmen,  1992;  Savitz,
1994, Wilson, 1998, Zhang,  1992)   Pre-term
delivery and low birth weight have been asso-
ciated with exposure of the father to lead, pes-
ticides,  or  solvents  (Kristensen, 1993, Lin,
1998, Min, 1996; Savitz, 1997) Penconceptual
exposures as well as paternal preconception
exposures also may have contributed  to the
elevated  cancer risks in children shown in
Table 3.

Other studies have demonstrated the presence
of a wide variety  of environmental toxicants
in semen (Arbuckle, 1999, Pacifici, 1995,
Schecter, 19%; Stachel, 1989) These findings
may be significant given the evidence that tox-
icant exposures can affect sperm count, motil-
ity, and morphology (Lemasters, 1998, Vine,

A few studies distinguish  between the effects
of women's pre-conception and periconceptu-
al exposures  on  reproductive outcomes.
Studies of Yusho and Yu-Cheng  disease
describe the effects of food contaminated with
polychlorinated biphenyls (PCBs) and poly-
chlorinated dibenzofurans, including in utero
and lactational exposure to  infants (Aoki,
2001, Lucier, 1987). PCBs and other endocrine
disrupters may  be transferred to children
through the placenta four to five years after
the  maternal exposure occurred and con-
tribute  to decreased  birth weight  (Lucier,
1987).  Alterations in neural function,  devel-
opmental delays,  and intellectual  impair-
ments have  been  observed  in  children
exposed to PCBs, but the particular period of
exposure was not described  (Aoki,  2001).
Isotopic studies indicate that maternal expo-
sure to lead may occur prior to conception,
during a subsequent pregnancy,  lead from
skeletal stores can be mobilized and trans-
ferred to the fetus through  the bloodstream,
resulting in exposure during a  critical period
of  prenatal  development (Gulson,  1998;
                                               CRITICAL PERIODS :tt

Gulson, 1997; Han, 2000). Most women expe-
rience limited lead exposure during pregnan-
cy and  the postnatal period,  but their long-
term skeletal stores may contain large quanti-
ties of lead that can become mobilized at an
accelerated rate and impact the development
of their  offspring.  In addition, greater mobi-
lization  of skeletal lead occurs during  the
postnatal period  than during pregnancy,
resulting in increased exposure to breast-feed-
ing infants (Gulson, 1998).   As with men's
exposures, it is likely that some of the effects
attributed to preconception exposures may in
fact be due to exposures near conceptioa

               VI                /• J9            /*   ^                           v]
           Adverse  Eriects ox  Environmental

           Exposures  During  Pregnancy
This chapter summarizes available informa-
tion linking adverse effects in children with
environmental exposures during pregnancy.
The exposure period addressed in this chapter
occurs after the period addressed in Chapter 3
(before or around the time of conception) and
before the period  addressed  in  Chapter 5
(childhood) Section 4.1 describes the general
pattern of fetal development and environmen-
tal toxicity during pregnancy.  Section 4 2
describes a range of adverse effects that can
occur during pregnancy.

4.1   General Pattern of
       Fetal  Development and
       Environmental Toxicity
       During  Pregnancy
As discussed in Chapter 2, the period of rapid
embryonic and  fetal development during
pregnancy is associated with increased sensi-
tivity  to  specific  environmental agents
During this period, complex and rapid change
is normal, from  the molecular level through
all the biochemical and  physical  processes
that determine the course of development
Cell division, migration, differentiation, and
apoptosis all must occur in the correct
sequence in the correct spatial orientation,
coordinated through  a large number of con-
trol and signaling systems.

During early fetal life, a wide variety of genes
are sequentially activated and inactivated,
providing a number of targets for environ-
mental exposures.  The interaction of genes
with  environmental conditions  (broadly
defined) is believed to account for a quarter to
a half of all  developmental  defects  (NRC,
2000)  Fetal and embryonic exposures to envi-
ronmental toxicants also may increase the risk
for cancers in adults and may be responsible
for childhood cancers that have been linked to
preconception  exposures (Hoover,  2000;
Lichtenstein, 2000)

Interference with repair or defense pathways
is one mechanism by which environmental
exposures may produce adverse health effects
in children.  Experimental studies suggest that
defects in DNA repair may result in vulnera-
bility to  specific  toxicants during develop-
ment.   For  example,  the  effects   of
benzo[a]pyrene on the developing fetus have
been studied in transgenic mice that are miss-
ing p53, a tumor suppressor  gene important
for DNA repair (Nicol, 1995). These animals
show    an   increased  sensitivity    to
benzo[a]pyrene exposure and an  increased
death rate when exposed to the chemical dur-
ing gestation.   Damage to related genes in
humans likewise could increase sensitivity to
agents that damage genetic material.

Environmental agents also  can  affect  cell
migration  during   fetal   development
Exposures to ionizing radiation and methyl
mercury, for example, have  been  shown to
affect the migration of neurons (cells that will
form the nervous system and brain) during
development (Rodier, 1995) Schizophrenia is
thought to result, in part, from abnormal neu-
ronal migration (Beckmann, 1999, Bunney,
1995, Bracha, 1991), but the role of prenatal
exposures to environmental agents in causing
this disease is not clear.

During  the course of embryonic  and  fetal
development, individual cells also differenti-
                                            CRIT1CA:. PERIODS :N OSVFi.QPMENT

ate, assuming the specific form and function
associated with their final role in the body
This process is under the control of inter- and
intra-cellular signaling processes. If cells fail
to differentiate properly, organ function may
be compromised and fetal  survival may be
endangered  Many  cancers disrupt proper
cell differentiation or cause differentiated cells
to revert to more primitive forms  (Bisogno,
2002; Shimada, 2001)  Exposures to environ-
mental agents may disrupt proper cell differ-
entiation either by damaging genetic material
or by interfering with normal cell  signaling
(Anderson, 2000).

Undifferentiated cells also may be more  vul-
nerable than  differentiated cells  to toxic
effects  Chemicals shown  to affect specific
types of undifferentaated cells include ethanol
(Mullikin-Kilpatnck, 1995),  manganese (Di
Lorenzo, 1996), nicotine (Berger, 1998),  and
TCDD (Murante, 2000).

4.2   Adverse Effects During
This section summarizes the literature sup-
porting the sensitivity of prenatal  develop-
ment to insult by environmental exposures.
As noted  in Section 2.3, attributing specific
adverse effects to exposures during specific
time periods is not always possible. For this
reason, we concentrate on several effects that
are detected during pregnancy or at birth and
therefore can be attributed  to prenatal expo-
sures with a high degree of confidence These
include early fetal death, congenital malfor-
mations, growth  deficits during pregnancy
and pre-term birth, and pregnancy complica-
tions and late fetal death.  Subsequent chap
ters address effects  seen  during childhood
and adulthood that may arise from exposures
during sensitive time periods.

4.2.1 Early Fetal Death
Early fetal death can be caused by exposure to
environmental agents in the penconcepbon
period (approximately the first two weeks
after fertilization) or in later prenatal develop-
ment. Clinically, this effect is manifested as a
spontaneous abortion during early pregnan-
cy.  A wide variety of compounds have been
shown to cause early fetal death. Heavy caf-
feine  intake,  smoking, and  cocaine use by
pregnant women, for example, can  cause
increased rates  of  spontaneous  abortion
(Infante-Rivard, 1993; Ness, 1999). Workplace
exposure to antineoplastic drugs or to sol-
vents in the periconception and/or prenatal
period also has been  linked  to  an  increased
risk  of   miscarriage  (Lindbohm,  1990;
Lipscomb,  1991,  Taskmen,  1994,  Valanis,

Some studies have associated  spontaneous
abortion with women's exposure to environ-
mental contaminants at relatively low levels
One study noted  this effect  for chlorination
byproducts found in drinking water (Waller,
1998), although another study did not (Savitz,
1995).  Indicators  of maternal pesticide expo-
sure during pregnancy also have been associ-
ated  with  increased  risk  of  miscarriage
(Arbuckle, 1998;  Nurminen,  1995).  Animal
studies also have  associated  fetal death with
pesticide exposure  (Leoni,  1989,  Perreault,
1992; Varma,  1987).

4.2.2 Congenital Malformations
Congenital malformations arise from the fail-
ure of specific organ systems or structures to
form and develop properly.  As discussed in
Chapter 2, the bulk of major malformations
are thought  to arise from  developmental
defects during the early stages of organ devel-
opment in  the first trimester of pregnancy.
Both  the type of anomaly  and  the specific
organ  affected by  exposure during  organ
development are  highly dependent on the
agent and the gestational age at which the
exposure occurs.  Well-studied examples of
the variability and specificity of such effects
include rubella (Miller, 1982)  and diethyl-
shlbestrol (DES)  (Wilcox, 1995).  Rapid cell
division during organ development has been
suggested to account for some of the increased
sensitivity to environmental exposures during
this period (Rogers, 1996).

Birth defects are a leading cause of infant mor-
tality. The relationship between exposures to
environmental agents and specific types of
abnormalities has  been studied extensively
Texts by Schardein (2000) and Shepard (2001)
provide useful overviews of the current state
of knowledge, including the following well-
established examples of human teratogens
(chemicals that cause birth defects):

•   Pharmaceuticals such as anticancer agents,
    sex hormones, certain  anticonvulsants,
    and  certain psychotropics may  cause
    abnormalities of the nervous system and
    other organs

•   Infectious agents such as  cytomegalovirus,
    syphilis, and toxoplasma gondii produce a
    wide range of malformations

•   Intensive  ionizing  radiation  administered
    for diagnostic or therapeutic purposes can
    affect fetal development

•   Substance abuse, such as  maternal alcohol
    abuse during pregnancy, can cause fetal
    alcohol syndrome, producing symptoms
    including craniofacial anomalies (abnor-
    mal development of the head and face)
    and microcephaly (greatly reduced skull
    size)  Maternal cocaine abuse can lead to
    cardiovascular and brain defects.

•   Methyl mercury exposure from contami-
    nated food may be associated with central
    nervous system anomalies, abnormal den-
    tition, and mental retardation.

•   Maternal endocrine disorders such as dia-
    betes meUitus,  if  poorly controlled, also
    increase the risk of congenital anomalies

Occupational exposures to solvents (Khattak,
1999, McMartin, 1998) or glycol ethers (Knill-
Jones, 1997) just before or during pregnancy
have been associated with  increased risk of
birth defects Inhalant abuse during pregnan-
cy has been associated with craniofacial
abnormalities (Jones, 1998, Wilkins-Haug,
Birth defects have been associated with occu-
pational or environmental pesticide exposures
in some studies (Filkins,  1998).   Maternal
exposure to pesticides, either occupahonally
or during home use, has been associated with
increased risk of birth defects  (Shaw, 1999,
Garcia, 1999)  Other studies have not found
such a link, possibly because epidemic logical
studies often combine all pesticide exposures
together into a single exposure category.  This
approach increases the likelihood of missing a
true association  with a  specific pesticide
(Garcia, 1998b, Nurmmen, 1995).

Several "ecological" studies link indicators of
chemical exposure during pregnancy, usually
pesticide use, to increased risk of birth defects.
Ecological studies evaluate the relationships
between patterns of disease incidence in spe-
cific populations or  geographic areas and
indicators of potential environmental  expo-
sures, such as land use or proximity to pollu-
tion sources.   Because  exposures  are  not
directly measured, ecological studies must be
interpreted cautiously, the observed patterns
of disease incidence may actually be associat-
ed with factors not included in the analysis
Ecological studies have found, compared with
control area, elevated  rates of birth defects in
California counties with extensive agricultur-
al activities (Schwartz, 1988) and in areas with
high grain production in Norway (Kristensen,
1997).  These findings suggest a relationship
between  pesticide  exposures  and  birth
defects, but are not strong enough by  them-
selves to indicate a cause-effect relationship.
Nonetheless, these findings are consistent
with animal research showing an increase in
limb defects resulting  from exposure to cer-
tain fungicides (Chernoff, 1979; Larsson, 1976;
Maci, 1987) and organophosphate insecticides
(Byrne,  1983).   A  similar ecological study,
however, found only weak evidence for a rela-
tionship between agricultural production and
birth  defects in counties in New York State
(Lin, 1994)
                                                CRIT1CA-. PERIODS :

4.2,3 Growth Deficits During
       Pregnancy and Pre-Term
During pregnancy, the human embryo and
fetus grow rapidly, from less than a milligram
(one-thousandth of a gram or about 000004
ounces) to an average of about 3,000 grams (7
pounds)  This rapid growth is necessary to
prepare the fetus for independent existence
outside  the womb   Thus, defects  in  fetal
growth can have major impact on neonatal
health and  mortality.  Fetal growth retarda-
tion  and pre-term birth  are serious health
problems that may be related to poor mater-
nal weight gam,  substance abuse, placenta!
insufficiency, gestational hypertension,  or
other conditions  Growing evidence also links
specific environmental exposures to  fetal
growth deficits and pre-term birth

Numerous  studies have associated cigarette
smoking during pregnancy with fetal growth
retardation.  The reduction in birth weight is
dose-dependent (Center,  1995; Ellard, 1996).
Smoking one to two packs per day in the sec-
ond trimester, for example, increases the risk
of growth  deficit  by two to  five  times
(Sprauve, 1999)  Exposure to environmental
tobacco smoke also has been associated with
reduced  birth  weight   (Eskenazi,  1995,
Windham, 1999).  Smoking cessation during
pregnancy  was found to reverse the  effect
(Das, 1998)

Low-level exposure to PCBs in utero has been
associated  with  reduced birth  weight and
reduced  growth during early childhood
(Lucier, 1987, Patandin, 1998).  Other effects
include obesity in adolescence that also has
been  linked to  prior exposure to  PCBs
(Gladen, 2000)
4.2.4 Pregnancy Complications
       and  Late FetaS Death
Some types of environmental exposures  can
increase the risk of certain pregnancy compli-
cations.   These complications  then  can
increase the risk for pre-term birth, late fetal
death (stillbirth), or other adverse outcomes.
For example,  maternal smoking increases the
risk  for placenta previa (attachment of  the
placenta in  an  abnormal  position  in  the
uterus), placenta! abruption (premature sepa-
ration of the  placenta from  the  uterus), and
stillbirth (Chelmow, 1996,  DiFranza, 1995;
Shiverick, 1999, Sibai, 1995).

Increased  risk of preeclampsia  (pregnancy-
induced  hypertension) has been linked to
heavy maternal coffee consumption, occupa-
tional exposure to solvents, and possibly envi-
ronmental exposure  to lead (Bogden, 1995;
Hewitt, 1998, Rabmowitz, 1987, Wergeland,
1997)   Tobacco smoking,  paradoxically,
appears to lower the risk for preeclampsia
(Zhang, 1999)

Increased risk of stillbirth also has been asso-
ciated with environmental exposures during
middle  to late pregnancy  Implicated sub-
stances include arsenic, lead, mercury, pesti-
cides, and possibly chlorinated disinfection
byproducts (Golub,  1998; Nurminen, 1995,
Pastore, 1997, Schuurs, 1999).

                             Ul~c I* f            f i"-<
                 verse  Jtttects ot exposures
           During' Criilclkoocl
Exposures to environmental agents can cause
adverse effects that are initiated  or first
become apparent in children. As discussed in
Chapter 2, major  cellular structures of the
brain and other systems continue to develop
into childhood.  For  example, neuron migra-
tion, cell proliferation, and synapse formation
occur  rapidly from birth through three years
of age, and myelination continues for about 10
years  (Rice, 2000) and potentially longer
(Benes, 1998)   Also, the  immune system
develops extensively during early childhood
as immune memory  is  established  (Dietert,
2000).   Behavioral, emotional, and  cognitive
development during  childhood also can  be
affected by environmental exposures

Adverse developmental effects seen during
this period take a wide variety of forms,
including neonatal mortality, growth deficits,
and defects or delays in functional develop-
ment   Sexual  maturation and puberty also
may be affected by environmental exposures
in utero or during childhood.  In addition,
childhood cancers occur in a pattern that is
intimately connected with  specific develop-
mental processes and is distinct from the pat-
tern in adults.

This chapter  discusses a  wide  range  of
adverse health outcomes that are manifested
during infancy, early childhood, and adoles-
cence in the following order:

•   Neonatal mortality;

•   Growth deficits during early childhood,
•   Functional  deficits  and  delayed  or
    impaired functional maturation;

•   Effects on puberty and sexual maturation;

•   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

5.1   Neonatal Mortality
Complications related to short gestation and
low birth weight (see Sections 4.2.3 and 4.2.4 in
this report) account for about one-third of
infant mortality in the United States (Sowards,
1999, US DHHS, 2000) Congenital malforma-
tions (discussed in Section 4.2.2 of this report)
also are a leading contributor to this mortality.
A number of specific environmental exposures
during  preconception,  periconception, and
pregnancy have been found to be associated
with increased risk of such effects, and as a
result, an increased risk of neonatal mortality.

In addition to the previously noted causes of
neonatal death, limited evidence links specific
environmental exposures to sudden  infant
death syndrome (SIDS) Well-controlled stud-
ies  suggest that maternal smoking  during
pregnancy, maternal smoking status  after
                                              CRITICAi. PERIODS Hi

delivery, and postnatal exposure to environ-
mental tobacco smoke (due to maternal smok-
ing or the presence of other smokers in the
household) all are associated  with elevated
risk of SIDS, and that SIDS risk is associated
with  increasing intensity  of exposure to
household   tobacco  smoke  (Blair,  1996;
Haglund, 1990; Klonoff-Cohen, 1995; Malloy,
1988,  Taylor, 1995). In 1997,  the California
Environmental Protection Agency reported
that there was sufficient evidence to  find a
causal association between environmental
tobacco smoke and SIDS (CA EPA,  1997).
Other studies have found a  higher SIDS risk
among children exposed to toxicants such as
tobacco and cocaine in  utero (Aim, 1998;
Milerad, 1998; Ostrea, 1997).  The presence of
potentially confounding  factors,  including
multiple birth, allergies, apnea, sex of child,
mother's age, and socioeconomic status, how-
ever,  suggests that these studies should be
interpreted cautiously  While  many of these
factors have been researched as primary caus-
es of SIDS, they also are relevant as confound-
ing factors when investigating  tobacco smoke
and cocaine use during pregnancy.

5.2    Growth Deficits  During
        Early Childhood
Early  childhood is a critical  time in develop-
ment  because many organ systems are grow-
ing and continuing to mature Many environ-
mental exposures have been associated with
early  childhood  growth retardation,  which
may in turn be associated with adverse health
outcomes (Osmond, 2000).  Growth  deficits
may be associated with high-level exposures
to toxicants,  which cause acute adverse
effects, or they may be  associated with rela-
tively low exposures, where  no other obvious
symptoms  are seen.  Sometimes, reduced
growth can be traced to a specific underlying
defect in  functional development, as  dis-
cussed in Section 5.3.

Environmental contaminants known to cause
growth retardation during childhood include
lead, PCBs, and tobacco  Chronic lead expo-
sure has been linked to decreased growth dur-
ing childhood.  In a large study of children
under  seven  years old, each increment in
average blood lead levels of 10 Hg/dL was
associated with an average decrease in height
of 1 57 cm and an average decrease in head
circumference of 0.52 cm (Ballew, 1999). In a
similar study of Greek children aged six to
nine years, height decreased 0.86 cm and head
circumference decreased 0.33 cm for every 10
Hg/dL increase  in blood lead (Kafourou,

Growth during childhood also has been stud-
ied in  individuals who  were  prenatally
exposed to marijuana  or tobacco.  Maternal
marijuana use was found to be associated
with reduced head circumference at birth, and
the effect persisted into adolescence (Fried,
1999). As noted in Section 423, prenatal PCB
exposures appears to  retard growth during
pregnancy  and into  childhood  (Patandin,

5.3   Functional Deficits and
       Delayed or impaired
       Functional Maturation
As discussed  in Chapter 2, many organ sys-
tems continue to  mature during childhood
These  developmental  processes include
myelination of  the central nervous system,
development of immune memory, maturation
of the lungs and kidney, and, later in child-
hood, sexual maturation and puberty

Many adverse effects on development in late
pregnancy and  infancy show themselves as
functional  deficits in organs or systems,
instead of  overt  malformations  or  growth
retardation (Naruse, 1995,  Rice, 2000)  The
pathologic processes leading to these defects,
which may be associated with environmental
exposures, are initiated at the time of expo-
sure, but the effects typically are not detected
until after the child is born.  For example,
exposure to neurotoxins such as lead, PCBs,
and methyl mercury during the critical period
of middle to late pregnancy has been associat-
ed with the development of neurobehavioral
effects in exposed children (Grandjean, 1999,

Stewart, 2000, Tang, 1999)  Congenital rubel-
la is a classic example in which both structur-
al birth defects and functional deficits occur,
including functional deficits involving  the
central   nervous  system   (Chess,  1978),
increased incidence of diabetes, thyroid and
other  endocrine disorders, and vascular dis-
ease (Floret, 1980; Sever, 1985).

Functional  deficits thought to  be associated
with environmental exposure are seen in the
respiratory system.  Prenatal exposure  to
tobacco  smoke  has been  associated with
deficits in respiratory function, as well as with
persistent pulmonary  hypertension  among
newborns (Bearer, 1997; Stick, 19%, US NIH,
1993)   Increased incidence of respiratory ill-
ness and reductions in lung function have
been  found to be  associated with maternal
smoking (Ware, 1984).  There is growing evi-
dence for the connection between exposures
to environmental agents and the severity and
incidence of asthma attacks (Chew, 1999,
Hajat, 1999, Kunber, 1998)

Extensive evidence also supports the relation-
ship between pre- and postnatal exposures to
lead and long-term impairments in neurologi-
cal  development.  These impairments may
translate into learning deficits and disruptive
or dangerous behavior

There is limited evidence linking children's
exposures to lead to defects in the control of
physiological processes  such as energy metab-
olism, cardiac function, and blood pressure.
In one study, adolescents with chronic lead
exposure were more likely to become obese,
even  after  adjusting for other risk factors
(Kim, 1995)  Lead poisoning  in adults  has
long been linked with increased risk of hyper-
tension, although the relationship in children
is less clear (Loghman-Adham, 1997; Todd,
1996).  Children chronically  exposed to lead
have  been  found to exhibit subclimcal alter-
ations in kidney function (Fels, 1998)  The
implications of these symptoms for the long-
term maintenance  of blood pressure control
and cardiovascular disease risk are not yet

5.4   Effects on Puberty and
       Sexual Maturation
There is growing concern that environmental
exposures may affect the sexual maturation of
children. This concern has focused primarily
on apparent decreases in the average age of
puberty in some ethnic groups in the United
States and other countries Decreased age at
puberty is a concern because of the increased
risk of impaired stature and earlier  onset of
risky  behaviors (Halpern, 1997; Meschke,
1997; Wilson, 1994). Changes in age at puber-
ty also might be a symptom of other impair-
ments in endocrine or reproductive function
As discussed in the next section, reduced age
at puberty  also  may  be  associated  with
increased cancer risks later in life

Some studies show that  the age at  puberty
and sexual maturation appear to be  decreas-
ing in some  populations  (Fredriks, 2000,
Freedman, 2000, Herman-Giddens, 1997).  The
apparent reduction varies across  racial  and
ethnic  groups.   In the United States  as  a
whole, evidence suggests that girls are begin-
ning to develop secondary sexual characteris-
tics at  a  younger  age, although the average
age at  menarche,  the beginning of the men-
strual  function, is generally stable While
some of the observed changes in sexual devel-
opment may be due to improved children's
health    and   nutrition   (Baker,   1985,
Georgopoulos, 1999), exposures to  environ-
mental agents also may play a role (Herman-
Giddens, 1997)

Effects on puberty and  sexual development
are seen most clearly in  children who  have
received cytotoxic drugs or high-dose radia-
tion  therapy  as  treatment  for   cancer
Chemotherapy  with  alky la ting agents  and
other  cancer  drugs  causes  pathological
changes in the reproductive systems in both
adolescent females (Nocosia,  1985,  Quigley,
                                               CRITICAL PERIODS sK BfVf-.OPMf.NT   21

1989) and males (Matus-Ridley, 1985; Quigley,
1989).  Irradiating the head to treat leukemia
has been shown to induce premature puberty
among both girls and boys (Mills, 1997;
Oberfield, 19%; Olgilvy-Stuart, 1994)  While
the severity of the effect depends on the age at
which  radiation occurs,  sexual  maturation
may be advanced  by 1.5 years or more
(Oberfield, 1996) and  the risk of premature
menarche may be increased up  to two-fold
(Mills,  1997).  Direct irradiation to the gonads
has  been  associated  with delayed  puberty
(Mills,  1997), which  is consistent with  the
known cytotoxic effects of  radiabon on  the
ovary and testes. Whether the much lower
levels  of radiation experienced in everyday
life affect the onset of puberty  is unknown.

Specific evidence regarding the effects of envi-
ronmental chemical pollution on the age of
puberty in humans is limited and has been
difficult to acquire.   Epidemiological tech-
niques for detecting changes  in  populations
such as earlier onset  of puberty generally
depend on large sample sizes. The studies to
date provide only limited  evidence for an
association between exposure  to environmen-
tal toxicants and decreased age of puberty

•   One study has linked precocious sexual
    development  in children  with a higher
    frequency of exposure to certain hair care
    and cosmetics products  (Zimmerman,
    1995)  The authors speculated that expo-
    sures  to  estrogenic compounds in  the
    products may have increased the risk of
    premature puberty

•   Another study attempted to link pubertal
    development in offspring  to estimates of
    perinatal  maternal   PCB  exposures
    (Gladen, 2000)  The mothers' PCB body
    burdens  (measured  during  pregnancy
    and lactation) were found  to be positively
    associated with the weight of their daugh-
    ters as they approached puberty, but the
    daughters' age at menarche was found to
    be unaffected at the relatively low expo-
    sure levels seen in the study
•   No significant connection to environmen-
    tal pollution could be confirmed  in an
    industrialized area of Puerto Rico with a
    well-documented increase in rates of pre-
    mature  puberty (Freni-Titulaer,  1986;
    Saenz de Rodriguez, 1985).

A large number of laboratory animal studies
have shown that chemical exposures can have
profound effects on sexual development For
example, female and male animals exposed
prenatally and perinatally to PCBs experi-
enced delayed puberty and  reduced sperm
counts, respectively (Faqi, 1998; Gray, 1998;
Restum,  1998)   Other chemicals showing
effects on   sexual  maturation  in animals
include TCDD, bisphenol A, 4-nonylphenol,
vinclozolin,  p,p'-DDE, phthalates, gemstem,
and others (Ashby, 1998; Chapin, 1999; Gray,
1998; Hurst, 2000; Levy, 1995;  Monosson,
1999; Mucignat-Caretta, 1995, Sumpter, 1995;
Yu, 1996). Effects on puberty have been seen
in both male and female animals, and the bio-
chemical mechanisms for the effects seem to
vary with the agent involved.

5.5   Cancer In Children
Childhood  cancers tend  to be qualitatively
different from cancers in adults, involving dif-
ferent organs and cell types. Researchers have
questioned  whether exposures  to  specific
agents might increase the rates of cancers in
children through mechanisms different from
those causing adult cancers   Another key
question is whether sensitivity to carcinogens
is  greater during  the  prenatal period and
childhood than during adulthood   Human
and animal studies provide only partial
answers to these questions.

There is general agreement that a small num-
ber of agents may cause cancer  in children
after prenatal exposures,  apparently through
mechanisms that are unique to those develop-
mental stages (Anderson, 2000).  The scientif-
ic evidence is strong for the induction of clear-
cell carcinoma in  the daughters of women
exposed to DES and for the development of
increased risk of leukemia in children exposed

prenatally or during early childhood to high
levels of ionizing  radiation (Olshan,  2000).
There also is a wide range of agents for which
the evidence of human cancer causation due
to prenatal exposures is suggestive, but not
confirmed.  Table 5 lists a number of studies
that suggest a  relationship between prenatal
exposures and childhood cancer

A wider range of agents has been proven to be
carcinogenic in laboratory animals after pre-
natal  exposures.  Table 6 lists examples of
studies illustrating the  association in experi-
mental animals between the development of
cancer in offspring andprenatal exposure of
pregnant females to x-rays, ethylnitrosourea
(ENU),     7,12-dimethylbenz[a]anthracene
(DMBA), and  5-azacytidine   The  cancers
range from skin and nervous system tumors
to ovarian and  lymphoid tumors

Some epidemic logical evidence suggests that
children may be more sensitive to the carcino-
genic effects of certain chemicals than  adults
are   Children exposed  to trichloroethene
(TCE) in drinking water appear  to  exhibit
risks of leukemia greater than those predicted
based on adult experience (Plon, 1997) The
results of case-controlled  investigations con-
ducted in Woburn, Massachusetts, and Dover
Township, New Jersey, suggested that prena-
tal exposure to chemicals in drinking water
may lead to an elevated  risk of leukemia or
central  nervous system  cancer in  children
(MDPH, 1997, NJDHSS, 2001)  The Woburn
study observed a  significant  trend  between
maternal consumption of drinking water con-
taminated with organic agents, namely TCE,
and increased incidence of childhood cancer
in their offspring during the  period 1969
through 1989 (MDPH, 1997).  Despite a high-
er-than-ex pec ted overall  incidence of child-
hood  cancer  from 1979  through 1991, the
Dover Township report found a statistically
significant association only  between con-
sumption of well  water  contaminated with
TCE,  tetrachloroethylene, and styrene-acry-
lonitrile, and elevated  risk of leukemia and
central nervous system cancer in female chil-
dren  under  age  five   (NJDHSS,  2001)
Exposure to the ultraviolet radiation in sun-
light during childhood also has been associat-
ed with a greater risk for melanoma skin can-
cer than the same exposure during adulthood
(Autier, 1998)    Children  who   receive
chemotherapy or radiation for a primary can-
cer also are at increased risk of developing
additional malignancies (Plon, 1997).
                                               CRITICAL PERIODS SI* DEVELOPMENT   23

                 Table 5.  Exposures During Pregnancy and Childhood Cancer
Cancer That
(employment in
metal refining and
Not quantified
 Acute nonlymphocytic
Shu, 1988
Cigarette smoke
 10 cigarettes
 Any childhood cancer
 (50 percent increased risk),
 non-Hodgkm's lymphoma,
 acute lymphoblastic
 leukemia, and Wilms
 tumor (doubled risk)	
Stiemfeldt, 1986
Not quantified
 Vaginal adenocarcmoma
 in female children
Waggoner, 1994
Not quantified
 Acute nonlymphocytic
 leukemia, acute
Shu, 1988
Ionizing radiation
   2 mSv
Petridou, 1996
Ionizing radiation
Not quantified
 Thyroid cancer
Antonelli, 1996,
Lund, 1999
Personal services
industry (beauty
shop workers,
laundry or catering
workers, domestics)
Not quantified
Lowengart, 1987
Not quantified
 Acute lymphocytic
Shu, 1988
Phenytom (drug)
Not quantified
Keren, 1989,
Murray, 1996
and styrene-
acrylomtnle tnmer
Not quantified
 Acute lymphocytic
 leukemia, brain
 and central nervous
 system cancers in
 female children
 under age five	
NJDHSS, 2001
Tnchloroethylene (TCE)
Not quantified
 Childhood leukemia
MDPH, 1997

Type of Exposure
A »f ma! Exposure* Dose
6: Associations Between Prenatal Exposures jjrtd
Cancer In Laboratory Animals
Source Asiderssrs, 2000
Prenatal Exposures Resulting in Cancer
Gestations! Sensitive
Exposure Exposure
Periad(s)1" PeriodCs)"
Hamster/SG ENU 0 2 or 0 5 mmol/kg 7-14
Mouse/B6WHT X-ray 200 Radd
Mouse/A/C5 Urethane 25 mg/mouse
Mouse/86 ENU 0 5 mmol/kg
Mouse/B6C3 ENU 0 5 mmol/kg
60 mg/kg
12, 16-18
12, 16-18
17-21, 1x
14,15,17 -
12-18, 1x
12, 14,16,18
12, 14,16, 18
Mouse/C3HeB/FeJ ENU 1 0, 25. or 50 mg/kg 1 0. 1 3, 1 5. adult
Mouse/C3HneNC ENU 0 4 mmol/kg
Mouse C57L/J ENU 0 5 mmol/kg
Mouse DBA/2J ENU 0 5 mmol/kg

16, 19
12, 14,16,18

9-1 4 (05 mmol/kg)
All groups
All groups
All groups
Both groups

Period of
1 6-1 8,
fewer lung tumors
in male offspring
from GD 1 2
< 8 hr before birth
No significant difference
16, 18

Skin tumors
Skin tumors
Lung tumors
Ovarian tumors
Lung tumors
Lung tumors
Nervous system
Kidney tumors
Lung tumors
Lung tumors
Nervous system
Lymphoid tumors
Lymphoid tumors







Table 6 (continued)
Prenatal Exposures Re&uiiing in Cancer
Type of
Animal Exposure*
Mouse /NMRI 5-Azacytdine
Mouse/NMRI X-ray
Rabbit ENU
1 or 2 mg/mouse
60 mg/kg
0 88-1 2 Gray
60 mg/kg
0 5 mmol/kg
50 mg/kg
60 mg/kg
12-16, 1x
12, 14,16
6-20, 1 x
6-20, 1 x
11-13, 14-16
6-20, 1 x
12. 14, 16, 18
1 0-1 9, 1 5-24
14(2mgonly), 16
1 2 1 mg/kg,
1 6 both doses
All groups
All groups
All groups
Period of
Increase GD 16,
1 mg/kg Decrease
GD 1 4, 2 mg/kg
11 (males) 6-11 (females)
All similar
Lung tumors
Lymphoid tumors
Lymphoid tumors
Lung tumors
Ovanan tumors
Ovanan tumors
Lymphoid tumors
Nervous system
Nervous system
• Abbreviations used DMBA (7.1 2-dimethylbenz[a]anthracene) and ENU (ethylnitrosourea)
" Provided in gestatonal days (GD)
c 1 x indicates a single exposure on each of the days indicated
" Rad = Radiation absorbed dose, basic unit of measurement for absorbed radiant energy
NA, not applicable (sensitive range indicated in previous column)

           Adverse Effects  ot  Early
           Hxposurcs 1  oat May  Be  Delayed
           Until Adulthood
The studies reviewed in Chapters 3 and 4
focused primarily on the effects of environ-
mental  exposures  during early  stages of
development that are manifested during these
periods. As discussed in Chapter 5, however,
many effects of prenatal exposures become
clinically significant only  at later stages in
infancy or later in childhood In this chapter,
we briefly discuss  effects of environmental
exposures during early development that do
not develop until adulthood  Sections 6.1 and
6 2 describe cancers and other effects, respec-
tively, that develop later in life.

Detecting long-term or latent impacts of early
exposure in humans is difficult, because large
populations may need to be studied for long
periods.   Nonetheless,  both  animal  and
human studies clearly support the existence of
delayed effects of exposures early in develop-
ment   In  many cases,  agents  that cause
adverse effects after exposures in adults cause
similar effects after exposures occurring early
in  development The challenge is to identify
instances in which early  exposures cause
effects in adults that are qualitatively different
or quantitatively  greater  than  those  that
would  be seen after adult exposures.  Such
studies  are difficult to perform,  and as a
result,  definitive identification of delayed
effects is challenging.

6.1   Cancers That Develop
       Later in Life
Table 5 above identifies childhood cancers
that have been linked to prenatal or early
postnatal exposures in human studies   In
these cases, observable increases in risk clear-
ly occur soon after exposures. In contrast, rel-
atively little information is available to make
judgments about the relative risk of cancers
occurring with  longer latency  periods   It
seems likely, however, that increased risks of
some tumor types may persist past adoles-
cence  Several studies of children of fathers
occupahonally exposed to ionizing radiation,
for example, have found that increased risks
of leukemia  seem  to  persist  to  age 25
(Anderson, 2000)  Similarly, elevated cancer
risks from prenatal exposure to DES, although
concentrated in late adolescence, also persist
into early adulthood (Waggoner, 1994).

Breast cancer risk is increased by x-ray thera-
py, and the risk is greatest if exposure occurs
during ages 10 to 14 (Hoffman-Goetz, 1998;
Miller, 1989; Tinger, 1997), which is a critical
period of breast development.   This finding
raises the question whether studies that inves-
tigate exposure in the years of adulthood just
before  breast  cancer develops are capturing
the important window of exposure in adoles-
cence (Ardies, 1998; Hoyer, 2000)  In addition,
studies suggest that exposure  to low-level
diagnostic radiation during infancy or child-
hood may increase the risk of breast cancer,
young girls appear to be particularly suscepti-
ble to radiation injury that can result in long-
term effects  (Hoffman-Goetz, 1998).   These
considerations also may be important in stud-
ies of the potential increase in breast cancer
risk  through  exposure to exogenous  estro-
genic compounds such as certain pesticides
and PCBs (Dich, 1997; Wolff, 1995).

Lung cancer research suggests that exposures
to environmental agents during adolescence
may have greater risks than the same expo-
                                             CRITICA:. PSRIODS !N DEVPLOPMENT

sures  later in  life.  Among a  group of
Norwegian men, those who began smoking as
teenagers had a 50 percent greater lung cancer
risk than those who took up smoking at ages
20 to 29  (Engeland, 19%).   The effect was
smaller but still significant among women and
persisted even when controlling for age-spe-
cific background cancer risks and years of fol-
low-up. Increased risk from early exposures
to tobacco smoke  could be associated with
increased  levels  of persistent chemical  dam-
age  to DNA  ("DNA  adducts")  (Wiencke,

The  increased levels of exogenous hormone
exposure associated with early puberty could
be a  risk factor for cancer later in life (Wolff,
1997).  A recent study has demonstrated that
women who attain their adult height at a
younger age,  which  is  indicative  of  early
puberty, have an increased risk of breast can-
cer (Li, 1997)  Breast cancer risk also increases
with early age at menarche (Hoffman-Goetz,
1998; Kumar, 1995; Russo, 1998).  Behavioral
changes associated with early puberty also
may   increase  cancer  risks  in  women.
Decreases in the age of first intercourse and
early use of oral  contraceptives  have been
found to increase  the risk of cervical cancer
significantly (Daling, 1996)  Boys who under-
go puberty early  will have more  years of
exposure  to endogenous androgen produc-
tion, and the incidence of prostate cancer has
been increasing  in parallel with reduced age
at puberty (Garnick, 1996).

Table 6 summarizes data from a small portion
of the many laboratory studies that link pre-
natal exposures  in animals to the  develop-
ment of cancer  in offspring   These studies
show that such exposures cause tumors that
occur early in development and are manifest-
ed throughout life.  Thus, increased cancer
risks m animals due to prenatal exposures
clearly are not limited to the immediate post-
natal period.  The authors of the review from
which these data are taken (Anderson, 2000)
do not, however,  indicate  how cancer risks
differ through different life stages, so it is not
possible to conclude whether prenatal expo-
sures result in higher risks than exposures
after birth. Technical issues, such as compar-
ing dose levels resulting from exposures of
differing  duration  in different  life stages,
make such comparisons difficult.

6.2   Other Effects Later in
In Chapters 4 and 5, we  discussed health
impacts of early environmental exposures that
could persist into adulthood.  Malformations
of major organs, delays in development, or
defects in function associated with these expo-
sures may have lifelong consequences.  There
also is limited evidence for a number of non-
cancer effects  of early exposures that might
not become apparent until late in life. Even
though most of these effects have not been
linked directly to environmental agents, the
observed patterns of occurrence demonstrate
the possibility that such exposures may con-
tribute to adverse health outcomes in later life.

One area of concern is neurological and neu-
rodegenerative disease.  Laboratory studies
suggest    that   exposures   to   specific
organometallic compounds early in life may
result in a loss of neurons, causing impair-
ments in behavioral function in older animals
(Barone, 1995). Multiple sclerosis is a poten-
tially fatal disease whose symptoms generally
begin to occur around age 40.   The disease
shows a geographic pattern of occurrence and
other features suggesting that environmental
exposures, perhaps infection, prior to age 10
may be important risk factors (Kurtzke, 2000,
Rice 2000)  Also, early environmental expo-
sures to lead may contribute to the develop-
ment of Alzheimer's disease  This suggestion
is based on the finding that the  functions of
several genes  thought to be associated with
high  risk  of  Alzheimer's  disease  also are
affected by lead exposures (Claudio, 1997;
Onalaja, 2000, Prince, 1998)  Epidemiologic
studies are needed to confirm this association.

Reproductive  health  in adults also can be
affected   by   exposures to environmental

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-

Osteoporosis is a major public health problem
in the elderly  Bone density in children and
adolescents can be strongly affected by envi-
ronmental agents including aluminum, cad-
mium,   hexachlorobenzene,   and   lead
(Andrews, 1988, Capdevielle, 1998, Katsuta,
1994,  Long, 1992, Mason, 1990;  Rosen, 1997,
Rosen, 1989)  Because bone density in adults
is highly correlated with peak bone density
achieved during adolescence, long-term fol-
low up of lead-exposed children has been sug-
gested to determine if early exposures have
any long-term impacts on bone density and
osteoporosis (Rosen, 1997)

Early exposures to environmental agents may
have other impacts on the generalized aging
process While the  biochemical and physio-
logical processes associated with aging are not
well understood, exposures to environmental
toxicants  during critical  life stages  could
reduce the number of healthy cells available to
maintain important physiological activities
(Barone, 2000, Rice, 2000)  Further, the aging
process involves programmed cell death, or
apoptosis    Exposures  to environmental
agents can cause disordered apoptosis during
embryonic development, which may increase
the risk for neurodegenerative illnesses such
as Alzheimer's and Parkinson's disease (Brill,
                                                CRITICAL PERIODS :N DEVELOPMENT   29

There are strong biological reasons for believ-
ing that  humans at specific periods in their
early development may be especially sensitive
to exposures to environmental agents  The
fragility, speed, and  complexity  of early
development clearly provide many targets for
specific  interactions  with  environmental
agents that are not present at later life stages

Development is a  continuum,  progressing
from germ cells through embryo, fetus, infant,
child, adolescent, and adult It is not always
possible to  identify exactly when a damaging
exposure occurred or which stage of develop-
ment has been affected. Sufficient knowledge
is available,  however,  to identify many key
events and processes and to delineate general
patterns in sensitivity.

The current state of knowledge is insufficient
to definitively rank or quantitatively compare
vulnerability to environmental agents across
developmental stages, except for a few envi-
ronmental agents Identifying certain periods
as "critical" therefore is primarily qualitative,
based on the observed patterns of effect and
the cumulative  weight of  evidence  Using
these criteria, germ cell development, fertil-
ization, embryonic  and fetal  growth, child-
hood, and  adulthood all qualify as "critical"
stages Each stage is affected  by known and
varying sets of environmental agents in ways
that can  result in serious adverse effects on
health The response to a given level of envi-
ronmental exposure may vary greatly during
development, as measured in laboratory stud-
ies. Differences in sensitivity to environmental
agents are often difficult to measure, because
different life stages imply different patterns of
uptake, metabolism, and excretion  of toxi-
cants and different repair and compensatory
mechanisms Each stage of development also
may be uniquely sensitive to environmental
agents and the accelerated  rates  of  some
processes (e.g, cell division) and the complex
processes  occurring during  maturation (cell
signaling,  migration,  differentiation)  This
combination of factors gives rise to concerns
over early environmental exposures. This
paper focused on the particular sensitivities of
children to environmental effects. Each devel-
opmental stage, including adulthood, howev-
er, possesses specific characteristics that create
additional sets of sensitivities, making them
"critical" for certain kinds of effects.

The current challenge is to interpret and apply
the available data to  improve the health of
children and the general population, and to
establish priorities for additional research that
can  better support  risk reduction efforts
Several new laws, regulations, programs, and
policies have been developed in recent years
for assessing and managing the risk of repro-
ductive and developmental environmental
agents (US EPA, 2000, US  EPA, 1998a; US
EPA, 1998b).
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