Períodos Críticos en El Desarrollo

About the Paper Series
The Office of Children's Health Protection (OCHP) at the U.S. Environmental Protection Agency (EPA) has created the Paper Series on Children's Health and the Environment to share scientific, reg ulatory, and policy information about children's health and the environment with a broad audi ence. The Paper Series is comprised of papers written by EPA staff members and external researchers receiving funding from OCHP. Each paper must receive an approval from OCHP prior to accept ance in the Series and undergo technical peer reviews by experts from both in and outside EPA. All papers in the Series are distributed for purposes of information sharing and discussion only. The opinions and findings expressed in these papers are those of the authors and do not neces sarily 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 papers. For more information about the Paper Series, including submissions and questions, please contact Edward H. Chu at (202) 564-2188 or chu.ed@epa.gov.
CRITICAL PERIODS IN DEVELOPMENT
Critical Periods in Development
OCHP Paper Series on Children's Health and the Environment Paper 2003-2
Prepared by Kara Altshuler,* Michael Berg,* Linda M. Frazier,**

Jim Laurenson,* Janice Longstreth,* William Mendez,* and Craig A. Molgaard**
February 2003
* ICF Consulting, Inc. ** University of Kansas School of Medicine-Wichita
Disclaimer This paper is being distributed for purposed of information sharing and discussion only. The opinions and findings expressed in this paper are those of the authors and do not necessarily represent those of the U.S. Environmental Protection Agency or of the Office of Children's Health Protection. No official Agency endorsement should be inferred from the paper.
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Acknowledgments
This paper, the second in the Office of Children's Health Protection's Paper Series on Children's Health and the Environment, reviews crucial stages in human development from conception through adolescence and the implications of environmental insults or exposures at these differ ent stages. Many individuals and organizations assisted in preparing this paper. The authors at ICF Consulting and the colleagues who helped them relied largely on the results of a scientific litera ture review for OCHP by the University of Kansas, School of Medicine at Wichita, which was completed in early 2001. OCHP appreciates the invaluable suggestions of the following internal EPA peer reviewers: David Chen, Brenda Foos, Gary Kimmel, Amal Mahfouz, Gregory Miller, and Onyemaechi Nweke, and the following external peer reviewers: Cynthia F. Bearer of the Department of Pediatrics and Neurosciences at Case Western Reserve University School of Medicine, Ruth Etzel of the School of Public Health and Health Services at George Washington University, Daniel Goldstein of Monsanto, and Philip J. Landrigan of the Department of Community and Preventative Medicine at the Mount Sinai School of Medicine.
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Table of Contents
1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
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 2.1.2 2.1.3 2.2 Germ Cell Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Embryonic and Fetal Development During Pregnancy . . . . . . . . . . . .2
Ongoing Development During Childhood . . . . . . . . . . . . . . . . . . . . . .5
Why Certain Developmental Stages May Be Especially

Vulnerable to Environmental Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
2.2.1 2.2.2 2.2.3 2.2.4 Control of Cell Division . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Apoptosis (Programmed Cell Death) . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Cellular Metabolism and Biotransformation of
Environmental Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
2.3 3. 3.1 3.2 4.
How Are Effects During Critical Periods Identified? . . . . . . . . . . . . . . . . . . . . . .8

Environmental Agents That May Damage Germ Cells . . . . . . . . . . . . . . . . . . .10
Environmental Agents That May Cause Damage At or Just
After Conception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
General Pattern of Fetal Development and Environmental
Toxicity During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
Adverse Effects During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
4.2.1 4.2.2 4.2.3 4.2.4 Early Fetal Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
Growth Deficits During Pregnancy and Pre-Term Birth . . . . . . . . . .18
Pregnancy Complications and Late Fetal Death . . . . . . . . . . . . . . . . .18
Adverse Effects of Parental Exposures Before or Around the Time of Conception . . .10
Adverse Effects of Environmental Exposures During Pregnancy . . . . . . . . . . . . . . . . .15

4.1 4.2
5.
Adverse Effects of Exposures During Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

5.1 5.2 5.3 5.4 5.5 Neonatal Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19
Growth Deficits During Early Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20
Functional Deficits and Delayed or Impaired Functional Maturation . . . . . . .20
Effects on Puberty and Sexual Maturation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
Cancer In Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22
Cancers That Develop Later in Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
Other Effects Later in Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28
6.
Adverse Effects of Early Exposures That May Be Delayed Until Adulthood . . . . . . .27
6.1 6.2
7.
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
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Introduction
The course of human development from con ception to adulthood is extremely complex. A huge number of biochemical, physical, and organizational processes must be precisely coordinated to assure orderly development, maintain health, and avoid disease. Because of the complexity, there are numerous oppor tunities for "things to go wrong." Children at particular developmental stages may be uniquely vulnerable to influences that have little impact at other points in their develop ment or on adults. This paper reviews crucial stages in human development from conception through ado lescence and the implications of environmen tal insults or exposures at those different stages. It focuses on the developmental stages during which children may be particularly sensitive to exposures to environmental agents or may be at risk of adverse effects that would not occur if exposures occurred during adulthood. Identifying these "critical" periods is essential to developing strategies that pro tect children from adverse health effects asso ciated with environmental exposures. The remainder of this paper is divided into six chapters. Chapter 2 defines the important stages of early human development. The subsequent chapters review the evidence of adverse impacts of environmental exposures on key periods of germ cell development (Chapter 3); pregnancy (Chapter 4); and infan-
cy, early childhood, and adolescence (Chapter 5). Chapter 6 briefly discusses potential adverse effects of environmental exposures during development that may not become manifest until adulthood. Chapter 7 summa rizes the major findings and data gaps con cerning the impacts of environmental factors during key periods of development. Following Chapter 7 is a list of references used in this paper. This paper discusses a broad range of chil dren's environmental health issues, but avoids the technical details of specific studies or methods, and does not present EPA policies or positions on these issues. Interested read ers can find additional information in the pri mary literature and the more detailed review articles and textbooks cited throughout the paper and listed at the end of the document. Further, this paper discusses potential adverse effects from exposure to many toxi cants and physical agents, some of which are not environmental in origin. While EPA gen erally does not have the authority to address non-environmental exposures (e.g., drugs or medical x-rays), information regarding poten tial adverse effects from these exposures is included because many of these adverse effects are similar to the adverse effects caused by exposure to environmental contaminants.
What Are Critical Periods of Development and Why Are They Critical?
The first section of Chapter 2 briefly reviews the major stages of early human develop ment. The next section discusses the biologi cal basis for suspecting that particular stages of tissue and organ development are espe cially susceptible to environmental insult. The third and final section describes how the effects of environmental exposures are detected and why identifying specific causes of developmental impacts often is difficult.
2.1
Major Stages of Development from Conception to Adulthood
Individual development proceeds from the formation of germ cells (sperm and egg) through fertilization, embryonic and fetal development (both of which take place during pregnancy), infancy, early childhood, and adolescence. Specific events during each of these broad developmental stages may create sensitivity to environmental influences. Damage from environmental exposures may occur and manifest itself immediately or may not appear until subsequent stages of devel opment or after development is complete. 2.1.1 Germ Cell Development Germ cells are the sperm and egg cells. They carry the genetic informationDNAfrom each parent. The combination of genetic material from sperm and egg cells provide the unique genetic blueprint for each child. Environmental toxicants that harm germ cells can affect an adult's own fertility as well as the health of the offspring.
Germ cells begin development in fetal life, even though they do not mature until puber ty. In the male fetus, primordial germ cells develop in utero. From puberty throughout adulthood, these cells undergo cell division, mitosis and meiosis, to produce mature sperm. In females, primordial germ cells undergo mitosis and the first phase of meiosis during fetal life. Most of these primary numbering in the oocytesinitially millionsdegenerate naturally until, by puber ty, only about 400,000 remain as primary folli cles. During each menstrual cycle, a group of these follicles ripen, with typically only one resuming meiosis to form the egg released during ovulation. During each stage, the pri mordial germ cells in both sexes as well as pri mary oocytes in females can be damaged by environmental exposures (Anderson, 2000; Lemasters, 1993). Results of such damage may include reduced fertility later in life or offspring with congenital health problems (Loeffler, 1999; Silbergeld, 1999). 2.1.2 Embryonic and Fetal Development During Pregnancy Between conception (the union of sperm and egg) and birth, human life advances from a single-cell zygote to an infant capable of living outside the womb. Because of the complexity and speed of development and the high rate of growth through the prenatal period, this stage of development has a special set of vul nerabilities to environmental exposures that are not seen at any other time.
Figure 1. Sensitive or Critical Stages of Human Development
Reprinted with permission of W.B. Saunders Co. (Moore, 1998)
As shown in Figure 1, prenatal development is often divided into three stages: periconcep tual (generally the 2 weeks following fertiliza tion), embryonic (3 to 7 weeks), and fetal (8 to 38 weeks). During the periconceptual period, the zygote undergoes rapid cell division, implants into the wall of the uterus, and forms a simple embryo. During this period, haz ardous environmental exposures usually cause fetal death rather than injury (Sadler, 2000). Lethal effects during this period would result in a spontaneous abortion only detectable biochemically, for instance via a transiently positive serum pregnancy test (Hakim, 1995; Rowland, 1995; Wilcox, 1988). Most major organs begin to form during the embryonic period, with growth and develop ment continuing through the remainder of pregnancy and into infancy for some systems. During the early period of organ development, which varies by organ system from 3-8 weeks to 12-16 weeks, the basic structures of the organs are established, as shown in the second column of Table 1. Disruption of development
during this period can result in major disrup tions in the large-scale structure of organs or other structures (Bertollini, 1985; Omtzigt, 1992; Rodriguez-Pinilla, 2000). This type of damage may result in fetal death, but is more likely to take the form of major physical mal formations (congenital anomalies). Note that Table 1 refers predominantly to structural development and does not provide a compre hensive list of all systems. "Ear," for example, refers to the major physical structures of the auditory system, whereas auditory function is not manifest before about 28 weeks gestational age. Also, Table 1 presents only a brief sum mary of the most important developmental events. More detailed discussions of specific developmental milestones and potential envi ronmental effects on those milestones are pro vided in the following sections. Both the organ affected by exposure during this period and the resulting type of anomaly are highly dependent on both the agent and the gestational age at which the exposure occurs. For example, rubella infection before the 11th
Table 1. Stages of Prenatal and Postnatal Organ Structural Development

Sources: Benes, 1998; Dietert, 2000; Johnsen, 2000; Moore, 1977; Needleman, 2000; Rice, 2000; WorldOrtho, 2002
Organ System Central nervous system Ear Heart Immune system
Early Prenatal 3-16 weeks 4-16 weeks 3-8 weeks 8-16 weeks
Mid-Late Prenatal 17-40 weeks 17-20 weeks 17-40 weeks
Postnatal Continues into adulthood Immunocompetence: 0-1+ years Immune memory: 1-18 years Nephrons mature in outer cortical region, providing ability to concentrate urine > 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 dentition: 4 months after conception to 3 years postnatal Permanent dentition: 3 months after birth to 25 years
Kidneys
4-16 weeks
17-40 weeks
Limbs Lungs Palate Reproductive system Skeleton Teeth
4-8 weeks 3-16 weeks 6-10 weeks 7-9 weeks 1-12 weeks 12-16 weeks
17-40 weeks 10-40 weeks 17-24+ weeks
week of gestation may cause congenital heart defects and deafness (Miller, 1982). If infection occurs at 13 to 16 weeks, deafness usually occurs without heart defects. If infection occurs after 16 weeks, no structural anomalies usually occur. Another example of age-specif ic gestational damage occurs with maternal exposure to diethylstilbestrol (DES). This exposure was found to cause genital anomalies twice as often among male children of women who took the medication before the 11th week of gestation as compared to those male chil dren exposed later in gestation (Wilcox, 1995). Other effects of DES exposure are discussed in subsequent chapters. During later stages of prenatal development, environmental exposures can result in impaired growth, physiological defects, or functional deficiencies, as shown in the third
column of Table 1. As discussed in the follow ing sections, these effects may be manifested as low birth weight, prematurity, pregnancy com plications, or late fetal death (Bogden, 1995; Hewitt, 1998; Rabinowitz, 1987; Wergeland, 1997). The patterns of susceptibility summarized above are broad generalizations derived from an extensive body of medical and clinical liter ature. There are many exceptions to these patterns and many unresolved issues regarding the relationship of adverse health effects in children and environmental exposures during specific periods of development. Some of the difficulties in relating exposures during specif ic critical developmental periods to observed health impacts are discussed in Section 2.3.
2.1.3 Ongoing Development During Childhood Important development processes continue after birth. As shown in the last column of Table 1, major cellular structures of the brain and other systems continue to develop through childhood. For example, in the brain and nerv ous system, neuron migration, cell prolifera tion, and synapse formation are all very active from birth through three years of age, and myelination, the development of cellular insu lation around nerve fibers, continues for at least 10 years (Rice, 2000) and possibly well into adulthood (Benes, 1998). The immune system also develops extensively during early childhood as immune memory is established (Dietert, 2000). Improper develop ment of the immune system can cause allergies or autoimmune diseases. Exposure to environ mental agents during early childhood may affect immune system development and may contribute to the development of asthma later in life (Peden, 2000; Weiss, 1998). Physical growth and maturation of organ sys tems continues through adolescence. Puberty and sexual maturation are primary developmental milestones of adolescent development. Physiologic and hormonal changes related to puberty begin well before adolescence, at ages six to eight years. In girls, the cells of the cervix begin to mature and develop into a form and structure that will be consistent through adulthood (Moscicki, 1996). The appearance of sec ondary sexual characteristics is marked by the development of breast buds (thelarche) and is followed by the onset of menses (menarche) about two years later. Boys typically show signs of puberty two to three years later than girls. For both genders, puberty is accompa nied by a rapid increase in height (Needleman, 2000). The process of sexual maturation is accompanied by complex interactions between the central nervous system and hormonesecreting organs, which can be affected by environmental factors.
2.2
Why Certain Developmental Stages May Be Especially Vulnerable to Environmental Exposures This section briefly reviews some of the underlying biological reasons for the sensitivity of specific developmental stages to environmen tal exposures. Concepts introduced in this sec tion will be helpful in understanding the exam ples presented in later chapters.
The rapid and diverse nature of processes that occur in critical developmental periods give rise to concerns about special vulnerability during early life stages. Some processes, such as sexual maturation, occur only during cer tain periods of development. Other processes such as apoptosis, or programmed cell death, occur more widely during development and are less prominent during adulthood. Cell division in most organs occurs much faster during development than in adulthood. Finally, many complex processes need to be effectively coordinated during development, which requires the cellular and intercellular signaling systems to work correctly. The following sections of this chapter briefly discuss four important processes and instances where environmental exposures have dis turbed these processes, resulting in adverse developmental impacts: Control of cell division, Apoptosis, Gene expression, and
Cellular metabolism and biotransforma tion of environmental agents. As will be seen in the following sections, cell division and apoptosis are more active in cer tain developmental stages, resulting in vulner abilities to environmental influences that are unique to early development. Gene expression is ubiquitous throughout development and strongly modulates responses to environmen-
Table 2. Checkpoints in the Cell Cycle

Source: Alberts, 1994a
Phase G1 S G2 M
Activities Growth
Key Checkpoint Control Molecules G1 cyclin-dependent protein kinases Re-replication blocking factors G2 cyclin-dependent protein kinases M-phase promoting factor
Conditions Needed to Pass Checkpoint Adequate cell growth, favorable environment One copy of DNA made All DNA replicated, adequate cell growth, favorable environment All chromosomes aligned on protein spindle
Synthesis of DNA Growth
Mitosis, Cytokinesis
The cell cycle consists of four distinct phases, each regulated by specific control molecules and characterized by specific conditions required to advance to the next phase. If the conditions are not met, the cycle will not enter the next phase. However, if the checkpoint molecules have been inhibited by a toxicant, the cell cycle might advance before all conditions are met, leading to unfavorable results such as cell death.
tal stimuli. The metabolism of pollutants strongly affects the nature and magnitude of responses to environmental exposures, and patterns of metabolism and biotransformation change in important ways throughout devel opment. Other complex processes in the development of the central nervous system include cell migration, axon development (the "wiring" of the nervous system), synaptogenesis (develop ment of connections between nerve cells), and synaptic plasticity (changes in the pattern of neurological connections associated with learn ing and other developmental processes). Less is known about potential environmental influ ences on these processes, and therefore they are not covered in this paper. The reader is urged to review other literature concerning neurolog ical development including a review article regarding critical periods of vulnerability for the developing nervous system (Rice, 2000). 2.2.1 Control of Cell Division Rapid cell division is a primary driver of devel opment. The cell cycle, the process of cell divi sion and growth, involves the interaction of many metabolic and control pathways (Alberts, 1994a; Iatropoulos, 1996; Lodish,
1999). In most mammalian tissues, the cell cycle consists of four distinct phases, as shown in Table 2. The cell cycle involves continuous DNA transcription and synthesis of a wide variety of proteins. All DNA must be successfully replicated before cell division can occur. Cell growth is regulated by at least nine growth factor pro teins (Alberts, 1994a); normal cell growth requires that these proteins work properly. As indicated in Table 2, checkpoints throughout the cell cycle prevent entry into the next phase of the cycle if previous stages are not complete (Alberts, 1994a). Each of the more than 210 cell types in the human body has its own usual cell cycle length, ranging from a few hours to several months or longer. A shorter cycle, implying more rapid metabolic activity, generally makes cells more vulnerable to toxi cant effects. Embryonic cells generally have very short cell cycles. A common regulatory failure in rapidly cycling embryonic cells is for the G2 checkpoint to be bypassed. If DNA syn thesis is inhibited by a toxicant, the cell ignores the requirement that all DNA must be replicat ed and may proceed directly into a mitosis phase that results in cell death (Alberts, 1994a).
2.2.2 Apoptosis (Programmed Cell Death) Perhaps surprisingly, apoptosis, or pro grammed cell death, also is an important process during development. Cell types and numbers in specific organs are regulated not only by production of new cells through cell division, but also by removal of certain cells through apoptosis (Alberts, 1994b; Brill, 1999). In some instances, one type of cell is succeeded by another during a specific developmental period. Apoptosis is involved in removing webbing from between the fingers and in regressing the fetal zone of the adrenal gland (Alberts, 1994b; Spencer, 1999). Apoptosis is responsible for eliminating populations of cells in the immune system that, if they survived, could cause autoimmune disease (Amsen, 1998). Apoptosis also plays a critical role in the devel oping nervous system, where it occurs in waves (Naruse, 1995; Rice, 2000; Rodier, 1995). It begins in proliferative zones and recurs peri odically as the nervous system is remodeled based on the number and kind of connections each neuron has made. Apoptosis remains active during the postnatal period because of on-going nervous system development. Disruption of normal patterns of apoptosis through altered gene expression or failure of signaling mechanisms is implicated in a wide range of pathologies. These include autoim mune lymphoproliferative diseases and certain cancers (Landowski, 1997; Ramenghi, 2000). For example, the persistence of renal stem cells that are supposed to disappear four to six weeks prior to birth may make those cells vul nerable to postnatal exposures that transform them into Wilms tumor, a relatively common childhood cancer (Sharpe CR, 1995). Failure of apoptosis also is suspected as a cause of autism (Rodier, 1995). 2.2.3 Gene Expression Gene expression, which is the translation of DNA into RNA and the production of active proteins from RNA, controls not only cell divi
sion and apoptosis, but also the metabolic activity of the cell. During development, gene expression is extraordinarily active: a high proportion of genes are being expressed and a large number of genes are being "switched on" or "switched off" to control cellular activities. This high level of metabolic activity provides a wide range of opportunities for environmental agents to interfere with cell development and growth. A toxicant can interact directly with DNA to disturb gene expression. Alternatively, it may interact with the products of gene expression, such as enzymes or control molecules (Gregus, 1996). A toxicant may react directly with the "target" molecule or it may be metabolized to another compound that is the ultimate toxicant. Reactions can be random in nature if the toxic agent is highly reactive with a wide range of chemicals, or they can involve highly specific interactions between the toxicant and its target. Exposure to environmental toxicants can affect many kinds of molecular pathways. The pathways that are the most vital to continued cell survival, function, and the error-free transmis sion of genetic information are the most impor tant to children's environmental health. These pathways include the following: DNA activation and synthesis, DNA and protein repair, Signal transduction,
Cellular metabolism and biotransforma tion, and Absorption, distribution, and excretion.
For example, signaling within and between cells is key to gene expression, cell migration, and other developmental mechanisms (Hay, 1998; NRC, 2000). Researchers have identified at least 17 major pathways for developmental intercellular chemical signaling (NRC, 2000), and the number is increasing with ongoing research.
Environmental contaminants can interfere with these vital molecular processes and cause per manent damage to a child's development. Brain development may be altered when signal transduction of neurotransmitters is disrupted by toxicants such as ethanol, methyl mercury, and aluminum. Ionizing radiation and other chemical carcinogens may alter DNA synthesis. Methyl mercury and ionizing radiation may inhibit cell growth and division in the developing nervous system (Graeter, 1996), as well as affect cell survival and migration (Rodier, 1995). High levels of air pollutants containing polycyclic aromatic hydrocarbons may cause abnormal DNA formation (Whyatt, 1998). The effects of exposure to environmen tal toxicants may cause significant deficits in the developing child. 2.2.4 Cellular Metabolism and Biotransformation of Environmental Agents Metabolism and biotransformation both occur at a cellular level and their combined effects are seen throughout the body. Cellular metabo lism incorporates all chemical and energy transformations that occur in our cells as a result of the breakdown and synthesis of organic compounds (e.g., food and beverages). Biotransformation occurs when enzymes chemically alter a compound, such as a drug, in the body. Many important metabolic and biotransforma tion processes are poorly developed or are entirely absent in developing organisms. These processes are important for environmen tal health because they can affect how environ mental agents are transformed in the body after exposures. Metabolism may either increase or decrease the toxicity of a chemical agent, or make easier or harder its elimination from the body. Thus, the immaturity of bio transformation processes during development can be a disadvantage to the fetus or child when biotransformation in an adult would detoxify hazardous substances. In some situa tions, immaturity can be an advantage because biotransformation in an adult may create a
more hazardous compound through activa tion. Given their primary evolutionary func tion of detoxifying and eliminating potentially toxic chemicals, immature or underdeveloped metabolic pathways are likely, on balance, to render infants and children more sensitive to common environmental contaminants. Many instances of this vulnerability have been identi fied (AAP 1999; AAP, 1974; Adam, 1999; de Wildt, 1999; Faustman, 2000; Graeter, 1996; Leeder, 1997; Parkinson, 1996; Perera, 1999; Raunio, 1995; Strolin-Benedetti, 1998).
2.3
How Are Effects During Critical Periods Identified?
Critical periods of development are identified based on concerns such as those just discussed above and actual observations of adverse effects. Laboratory studies may identify specif ic biochemical processes that are sensitive to specific agents, and then epidemiological stud ies in humans seek to determine whether the effect noted in the laboratory is significant in the real world. In other cases, patterns of adverse effects such as premature births, birth defects, and developmental disease are seen first in a specific population and then an expla nation is sought through studies of other groups or through laboratory investigations of possible causal mechanisms. During the past three decades, the fields of epi demiology and developmental biology have worked in a complementary fashion to clarify the general patterns of sensitivity to environ mental agents during specific stages of devel opment. Knowledge about the timing of important biochemical and cellular processes and organ development provides important leads for epidemiologists studying the devel opmental impacts of environmental exposures. Findings of exposures at particular times in groups of people who later experience adverse health effects likewise indicate that particular biochemical or developmental events may be sensitive to environmental agents.
It often is difficult to determine whether specif ic stages of development are sensitive to known environmental agents. For example, it may be unclear whether developmental impacts seen in laboratory animal studies also are likely to be seen in humans. Although the general developmental patterns in laboratory animals are similar to those in humans, there may be important differences in how animals and humans absorb, metabolize, or respond to specific agents during specific developmental stages. The effect of thalidomide exposure, described below, is a case in point. Animal studies also are limited by the difficulties of determining correct doses and dosing patterns and of measuring an endpoint appropriate to the human experience. The pharmaceutical thalidomide was used suc cessfully in the 1950s to treat nausea and vom iting associated with pregnancy. Although not released for use in the United States, thalido mide was marketed in other countries for sev eral years beginning in 1956. The drug showed no apparent toxicity in adult humans or ani mals at therapeutic levels (Rogers, 1996), but caused severe limb deformities in the babies of women who had taken the drug. These defor mities were not observed in multi-generational animal toxicity studies despite the use of dose levels (per unit body weight) that were much higher than those administered to pregnant women. Worldwide, an estimated 5,850 infants were born with major limb defects after their mothers took the drug. Another difficulty with animal and epidemio logical studies is that the period of human exposure may not be precisely known, or the period of exposure in conventional animal tox icity tests may cover many different developmental stages. In the chapters that follow, we present the results of several epidemiologic studies in which the increased incidence of adverse reproductive outcomes, birth defects, or childhood diseases is linked to exposures
that may have occurred pre- or post-concep tion, during early or late pregnancy, or even postnatally. In such cases, the developmental stage affected commonly is inferred from the nature of the damage. For example, reduced fertility is taken to imply effects on germ cells or during the periconceptual period, major malformations imply effects during organ development, and growth retardation implies effects later in pregnancy. These assumptions generally are quite reasonable and may be helpful in identifying oppor tunities for exposure reduction or directions for further investigation. In the discussions that follow, however, we attempt to maintain the distinction between (1) critical periods identi fied based on inferences from limited numbers of studies or on general considerations of developmental patterns, and (2) those infer ences that have been confirmed by multiple studies in which the chain of causality is rela tively clear between the biochemical level and the observed adverse effects. The majority of examples fall into the first cate gory. Individual studies provide plausible, but not conclusive, evidence of relationships between exposures in a given developmental period and adverse health outcomes. Therefore, the reader should consider the cumulative weight of evidence concerning var ious effects, and not just individual studies. On the whole, a rapidly growing body of evidence indicates that early human development repre sents a period with its own unique set of vul nerabilities to environmental agents. Some of these vulnerabilities arise because fetuses, infants, and children are more (or occasionally, less) sensitive to the effects of specific agents than adults, because of immaturity. Other spe cial vulnerabilities arise owing to the sensitivi ty of processes that occur only during early development (e.g., organ development) or the processes that are much more prominent at this life stage (e.g., apoptosis, rapid cell division).
Adverse Effects of Parental Exposures Before or Around the Time of Conception
This chapter discusses available evidence linking adverse effects in children with parental exposures to environmental toxicants before or around the time of conception. Section 3.1 summarizes studies of parental exposures that may damage germ cells. Section 3.2 reviews studies of the adverse effects associated with exposures of parents and/or offspring during or just after concep tion.
A well-publicized example is the nemato cide dibromochloropropane (DBCP), which caused dramatic azoospermia and infertility among exposed workers (Goldsmith, 1997; Potashnik, 1995). Fewer boys than usual were born to DBCP-exposed workers who were able to conceive. Women exposed to cigarette smoke dur ing their mother's pregnancy had reduced fertility (Weinberg, 1989). Men exposed to diethylstilbestrol (DES) in utero were found to have lowered sperm count and increased frequency of abnor mal sperm, but apparently normal fertili ty (Bibbo, 1977; Wilcox, 1995).
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 follicular cells. Germ cells and their progenitors are sensitive to a wide range of environmental agents. Exposure to environmental toxicants may cause premature death of primary oocytes in the fetus through effects on discrete signaling pathways involved in apoptosis. This reduc tion in gonadal reserves, in turn, may cause reduced fertility or premature reproductive failure (Silbergeld, 1999; Tilly, 1998). Male reproductive stem cells also may be particu larly sensitive to environmental exposures due to their rapid cell cycle. Several studies have associated impaired reproductive health with damage to germ cells or their progenitors, including the fol lowing:
Fertility clearly can be harmed by hazardous exposures that affect ovarian function. Women exposed to the toxic agents in ciga rette smoke may develop menstrual disorders and altered reproductive endocrine profiles. One study shows that smoking 10 or more cig arettes per day was related to greater variabil ity in menstrual cycle length, an increased fre quency of anovulation, and short luteal phase (Windham, 1999). Many studies show that cigarette smoking reduces fertility among women (Baird, 1985; Hartz, 1987; Howe, 1985). Workplace exposures, such as high lev els of exposure to nitrous oxide or mercury, also can impair fertility (Rowland, 1995; Ovarian toxicity and Rowland, 1992). impaired fertility can be caused by drugs or radiation exposure used to treat lymphopro-
10
liferative disorders or cancer (Blumenfeld, 1998; Gonzalez-Crespo, 1995; Meirow, 1999). A substantial body of evidence from human studies demonstrates that exposures to envi ronmental agents and medical radiation can injure germ cells in such a way as to cause increased incidence of cancer, particularly leukemia, among offspring of the exposed individuals (Buckley, 1989; Gardner, 1990; McKinney, 1991; Roman, 1999). Tables 3 and 4 summarize observed relationships between preconception exposures of men and women and increased cancer rates in their children. As shown in Table 3, paternal exposures to ionizing radiation have been linked with leukemia and lymphoma in subsequent chil dren. Paternal exposures to benzene also have been linked to leukemia in children One study observed (Buckley, 1989). increased risks of leukemia in the children of fathers exposed to wood dust (McKinney, 1991). Another study found an association between paternal occupational exposure to metals and hepatoblastoma incidence in offspring (Buckley, 1989). Maternal employment in certain occupations such as the food industry or exposures to ion izing radiation have been shown to be associ ated with an increased risk of leukemia and
non-Hodgkin's lymphoma (McKinney, 1991; Draper, 1997). Maternal exposures to metals, paints, petroleum products, and pigments prior to conception have been associated with the development of hepatoblastoma in offspring (see Table 4). As noted in Section 2.3 not all studies distinguish exposures before conception from exposures during pregnancy (Buckley, 1989; McKinney, 1999). This limita tion makes it difficult to identify the precise stage at which adverse effects occur, and poses problems for women trying to understand potential reproductive risks in the workplace. These studies should not be inter preted as strong evidence for a link between parental exposures to certain toxicants and cancer in offspring because some of the stud ies investigated small numbers of affected parents or involved exposures to multiple tox icants (McKinney, 1991) or did not report a statistically significant increase in the inci dence of a particular cancer (Draper, 1997). Animal studies provide supporting evidence that exposures during prenatal life can affect future reproductive function in adult organisms. For example, prenatal exposure to cer tain highly chlorinated chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polychlorinated biphenyl-169 (PCB-169) was associated with reduced sperm produc-
Table 3. Association Between Preconception Exposures in Men and Cancer in Offspring Dose to Father Not quantified Not quantified > 100 mSv (milliSievert) > 100 mSv > 10 mSv 1-5 mSv Metalsa Wood
a
Exposure Benzenea Diagnostic X-raysb Ionizing radiationb,c
Exposure Period Preconception Preconception 6 months prior to conception Lifetime preconception 6 months prior to conception Preconception Before birth Preconception
Cancer That Developed in Child Leukemia Leukemia Leukemia/non-Hodgkin's lymphoma Leukemia Leukemia Acute lymphoblastic leukemia Hepatoblastoma Leukemia
Not quantified Not quantified

b
dustb
Buckley, 1989;
McKinney, 1991; c Roman, 1999.
11
Table 4. Association Between Preconception Exposures in Women and Cancer in Offspring Dose to Mother Not quantified Cancer That Developed in Child Leukemia/non-Hodgkin's lymphoma
Exposure Food industrya Metal dusts, petroleum products, paints, pigmentsb Radiationc
a
Exposure Period Preconception or prenatal
Preconception or prenatal Preconception
Hepatoblastoma Leukemia/non-Hodgkin's lymphoma
McKinney, 1991;
Buckley, 1989; c Draper, 1997
tion in male rats (Gray, 1998; Loeffler, 1999). This effect occurred after a single dose of TCDD (Gray, 1997). In another example, reduced sperm production was seen in rats that were exposed to DES during gestation (Sharpe RM, 1995). Ovarian toxicity has been demonstrated in experimental animals after exposures to lead, 1,3-butadiene epoxides, 4vinylcyclohexene, cyclophosphamide, hexa chlorobenzene, and other compounds (Doerr, 1996; Doerr, 1995; Foster, 1992; Junaid, 1997; Plowchalk, 1992). As with humans, exposures of test animals during germ cell development are associated with increased risk of cancer in offspring. An excellent review of the literature on this sub ject can be found in an article by Anderson (2000). Among the agents causing increased cancer incidence in offspring after paternal exposures are x-rays, DES, urethane, and drugs such as some chemotherapy agents. Exposure to these agents has been associated with development of lung cancer, leukemia, lymphoma, and liver tumors in offspring. Preconception exposures of female laboratory animals to x-rays, DES, 7,12-dimethyl benz[a]anthracene, N-nitrosodiethylamine, or urethane have been associated with develop
ment of lung cancer and uterine adenocarci nomas in the offspring. Genetic research has suggested mechanisms by which some of these adverse effects may occur. Studies have shown that both smoking and pesticide exposure can increase aneu ploidy (an abnormal number of chromo somes) in sperm cells (Harkonen, 1999; Padungtod, 1999). Other studies illustrate how exposure to combustion byproducts may directly damage DNA in sperm cells. For example, benzo[a]pyrene, a common product of tobacco and other combustion, can react with DNA to form adducts, which are DNA bases that have been chemically changed so that they do not resemble normal DNA (Zenzes, 1999). The studies reported that the frequency of DNA adducts is highest in the sperm of smokers, with lower but still Such detectible levels in non-smokers. adducts may be a potential cause of mutations that could affect fertility and the health of any offspring. Research on female germ cells also has shown that oocyte (egg cell) DNA can be altered by toxic exposures in the preconception period. For example, alcohol exposure can disrupt chromosome duplication, resulting in aneu-
12
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 microenvironment of the conceptus (the cell mass at conception), disruption of checkpoint control mechanisms (discussed in Section 2.2.1), or other unknown mechanisms (Alberts, 1994a; Olshan, 1993). Disruption of checkpoint control mechanisms could explain, in part, the ability of certain toxicants to cause the embryo to die following exposures that occur shortly after conception. As discussed in Section 2.3, it often is difficult to distinguish effects caused by exposures in the more distant past from exposures in the period around conception. Despite these technical difficulties, a number of studies have linked paternal periconceptu al exposures to adverse outcomes during pregnancy and childhood. For example, increases in spontaneous abortions and other types of fetal death have been observed in populations in which the father was exposed to anesthetic gases, lead, mercury, organic solvents, pesticides, or welding fumes (Anttila, 1995; Arbuckle, 1999; Arbuckle, 1998; Cohen, 1980; Kristensen, 1993; Lindbohm, 1991a; Lindbohm, 1991b; Olshan, 1993; Savitz, 1997; Savitz, 1994; Taskinen, 1989). Congenital mal formations have been linked with paternal exposure to anesthetic gases, marijuana, pesti cides, tobacco, welding fumes, and possibly
lead (Blatter, 1997; Garcia, 1998a; Kristensen, 1997; Olshan, 1993; Sallmen, 1992; Savitz, 1994; Wilson, 1998; Zhang, 1992). Pre-term delivery and low birth weight have been asso ciated with exposure of the father to lead, pes ticides, or solvents (Kristensen, 1993; Lin, 1998; Min, 1996; Savitz, 1997). Periconceptual exposures as well as paternal preconception exposures also may have contributed to the elevated cancer risks in children shown in Table 3. Other studies have demonstrated the presence of a wide variety of environmental toxicants in semen (Arbuckle, 1999; Pacifici, 1995; Schecter, 1996; Stachel, 1989). These findings may be significant given the evidence that tox icant exposures can affect sperm count, motil ity, and morphology (Lemasters, 1998; Vine, 1994). A few studies distinguish between the effects of women's pre-conception and periconceptu al exposures on reproductive outcomes. Studies of Yusho and Yu-Cheng disease describe the effects of food contaminated with polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans, including in utero and lactational exposure to infants (Aoki, 2001; Lucier, 1987). PCBs and other endocrine disruptors may be transferred to children through the placenta four to five years after the maternal exposure occurred and contribute to decreased birth weight (Lucier, 1987). Alterations in neural function, devel opmental delays, and intellectual impair ments have been observed in children exposed to PCBs, but the particular period of exposure was not described (Aoki, 2001). Isotopic studies indicate that maternal exposure to lead may occur prior to conception; during a subsequent pregnancy, lead from skeletal stores can be mobilized and trans ferred to the fetus through the bloodstream, resulting in exposure during a critical period of prenatal development (Gulson, 1998;
13
Gulson, 1997; Han, 2000). Most women expe rience limited lead exposure during pregnan cy and the postnatal period, but their longterm skeletal stores may contain large quanti ties of lead that can become mobilized at an accelerated rate and impact the development of their offspring. In addition, greater mobi lization of skeletal lead occurs during the postnatal period than during pregnancy, resulting in increased exposure to breast-feed ing infants (Gulson, 1998). As with men's exposures, it is likely that some of the effects attributed to preconception exposures may in fact be due to exposures near conception.
14
Adverse Effects of Environmental Exposures During Pregnancy
This chapter summarizes available informa tion linking adverse effects in children with environmental exposures during pregnancy. The exposure period addressed in this chapter occurs after the period addressed in Chapter 3 (before or around the time of conception) and before the period addressed in Chapter 5 (childhood). Section 4.1 describes the general pattern of fetal development and environmen tal toxicity during pregnancy. Section 4.2 describes a range of adverse effects that can occur during pregnancy.
ronmental toxicants also may increase the risk for cancers in adults and may be responsible for childhood cancers that have been linked to preconception exposures (Hoover, 2000; Lichtenstein, 2000). Interference with repair or defense pathways is one mechanism by which environmental exposures may produce adverse health effects in children. Experimental studies suggest that defects in DNA repair may result in vulnera bility to specific toxicants during develop ment. For example, the effects of benzo[a]pyrene on the developing fetus have been studied in transgenic mice that are miss ing p53, a tumor suppressor gene important for DNA repair (Nicol, 1995). These animals an increased sensitivity to show benzo[a]pyrene exposure and an increased death rate when exposed to the chemical dur ing gestation. Damage to related genes in humans likewise could increase sensitivity to agents that damage genetic material. Environmental agents also can affect cell migration during fetal development. Exposures to ionizing radiation and methyl mercury, for example, have been shown to affect the migration of neurons (cells that will form the nervous system and brain) during development (Rodier, 1995). Schizophrenia is thought to result, in part, from abnormal neu ronal migration (Beckmann, 1999; Bunney, 1995; Bracha, 1991), but the role of prenatal exposures to environmental agents in causing this disease is not clear. During the course of embryonic and fetal development, individual cells also differenti-
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
15
ate, assuming the specific form and function associated with their final role in the body. This process is under the control of inter- and intra-cellular signaling processes. If cells fail to differentiate properly, organ function may be compromised and fetal survival may be endangered. Many cancers disrupt proper cell differentiation or cause differentiated cells to revert to more primitive forms (Bisogno, 2002; Shimada, 2001). Exposures to environ mental agents may disrupt proper cell differ entiation either by damaging genetic material or by interfering with normal cell signaling (Anderson, 2000). Undifferentiated cells also may be more vul nerable than differentiated cells to toxic effects. Chemicals shown to affect specific types of undifferentiated cells include ethanol (Mullikin-Kilpatrick, 1995), manganese (Di Lorenzo, 1996), nicotine (Berger, 1998), and TCDD (Murante, 2000).
spontaneous abortion during early pregnan cy. A wide variety of compounds have been shown to cause early fetal death. Heavy caf feine intake, smoking, and cocaine use by pregnant women, for example, can cause increased rates of spontaneous abortion (Infante-Rivard, 1993; Ness, 1999). Workplace exposure to antineoplastic drugs or to solvents in the periconception and/or prenatal period also has been linked to an increased risk of miscarriage (Lindbohm, 1990; Lipscomb, 1991; Taskinen, 1994; Valanis, 1999). Some studies have associated spontaneous abortion with women's exposure to environ mental contaminants at relatively low levels. One study noted this effect for chlorination byproducts found in drinking water (Waller, 1998), although another study did not (Savitz, 1995). Indicators of maternal pesticide exposure during pregnancy also have been associ ated with increased risk of miscarriage (Arbuckle, 1998; Nurminen, 1995). Animal studies also have associated fetal death with pesticide exposure (Leoni, 1989; Perreault, 1992; Varma, 1987). 4.2.2 Congenital Malformations Congenital malformations arise from the fail ure of specific organ systems or structures to form and develop properly. As discussed in Chapter 2, the bulk of major malformations are thought to arise from developmental defects during the early stages of organ devel opment in the first trimester of pregnancy. Both the type of anomaly and the specific organ affected by exposure during organ development are highly dependent on the agent and the gestational age at which the exposure occurs. Well-studied examples of the variability and specificity of such effects include rubella (Miller, 1982) and diethyl stilbestrol (DES) (Wilcox, 1995). Rapid cell division during organ development has been suggested to account for some of the increased sensitivity to environmental exposures during this period (Rogers, 1996).
4.2
Adverse Effects During Pregnancy
This section summarizes the literature supporting the sensitivity of prenatal develop ment to insult by environmental exposures. As noted in Section 2.3, attributing specific adverse effects to exposures during specific time periods is not always possible. For this reason, we concentrate on several effects that are detected during pregnancy or at birth and therefore can be attributed to prenatal expo sures with a high degree of confidence. These include early fetal death, congenital malfor mations, growth deficits during pregnancy and pre-term birth, and pregnancy complica tions and late fetal death. Subsequent chap ters address effects seen during childhood and adulthood that may arise from exposures during sensitive time periods. 4.2.1 Early Fetal Death Early fetal death can be caused by exposure to environmental agents in the periconception period (approximately the first two weeks after fertilization) or in later prenatal develop ment. Clinically, this effect is manifested as a
16
Birth defects are a leading cause of infant mor tality. The relationship between exposures to environmental agents and specific types of abnormalities has been studied extensively. Texts by Schardein (2000) and Shepard (2001) provide useful overviews of the current state of knowledge, including the following wellestablished examples of human teratogens (chemicals that cause birth defects): Pharmaceuticals such as anticancer agents, sex hormones, certain anticonvulsants, and certain psychotropics may cause abnormalities of the nervous system and other organs. Infectious agents such as cytomegalovirus, syphilis, and toxoplasma gondii produce a wide range of malformations. Intensive ionizing radiation administered for diagnostic or therapeutic purposes can affect fetal development. Substance abuse, such as maternal alcohol abuse during pregnancy, can cause fetal alcohol syndrome, producing symptoms including craniofacial anomalies (abnor mal development of the head and face) and microcephaly (greatly reduced skull size). Maternal cocaine abuse can lead to cardiovascular and brain defects. Methyl mercury exposure from contami nated food may be associated with central nervous system anomalies, abnormal den tition, and mental retardation. Maternal endocrine disorders such as dia betes mellitus, if poorly controlled, also increase the risk of congenital anomalies. Occupational exposures to solvents (Khattak, 1999; McMartin, 1998) or glycol ethers (KnillJones, 1997) just before or during pregnancy have been associated with increased risk of birth defects. Inhalant abuse during pregnan cy has been associated with craniofacial abnormalities (Jones, 1998; Wilkins-Haug, 1997).
Birth defects have been associated with occu pational or environmental pesticide exposures Maternal in some studies (Filkins, 1998). exposure to pesticides, either occupationally or during home use, has been associated with increased risk of birth defects (Shaw, 1999; Garcia, 1999). Other studies have not found such a link, possibly because epidemiological studies often combine all pesticide exposures together into a single exposure category. This approach increases the likelihood of missing a true association with a specific pesticide (Garcia, 1998b; Nurminen, 1995). Several "ecological" studies link indicators of chemical exposure during pregnancy, usually pesticide use, to increased risk of birth defects. Ecological studies evaluate the relationships between patterns of disease incidence in spe cific populations or geographic areas and indicators of potential environmental expo sures, such as land use or proximity to pollu tion sources. Because exposures are not directly measured, ecological studies must be interpreted cautiously; the observed patterns of disease incidence may actually be associat ed with factors not included in the analysis. Ecological studies have found, compared with control area, elevated rates of birth defects in California counties with extensive agricultur al activities (Schwartz, 1988) and in areas with high grain production in Norway (Kristensen, 1997). These findings suggest a relationship between pesticide exposures and birth defects, but are not strong enough by themselves to indicate a cause-effect relationship. Nonetheless, these findings are consistent with animal research showing an increase in limb defects resulting from exposure to cer tain fungicides (Chernoff, 1979; Larsson, 1976; Maci, 1987) and organophosphate insecticides (Byrne, 1983). A similar ecological study, however, found only weak evidence for a rela tionship between agricultural production and birth defects in counties in New York State (Lin, 1994).
17
4.2.3 Growth Deficits During Pregnancy and Pre-Term Birth During pregnancy, the human embryo and
fetus grow rapidly, from less than a milligram
(one-thousandth of a gram or about 0.00004
ounces) to an average of about 3,000 grams (7
pounds). This rapid growth is necessary to
prepare the fetus for independent existence
outside the womb. Thus, defects in fetal
growth can have major impact on neonatal
health and mortality. Fetal growth retarda tion and pre-term birth are serious health problems that may be related to poor mater nal weight gain, substance abuse, placental insufficiency, gestational hypertension, or other conditions. Growing evidence also links specific environmental exposures to fetal growth deficits and pre-term birth. Numerous studies have associated cigarette smoking during pregnancy with fetal growth retardation. The reduction in birth weight is dose-dependent (Conter, 1995; Ellard, 1996). Smoking one to two packs per day in the sec ond trimester, for example, increases the risk of growth deficit by two to five times (Sprauve, 1999). Exposure to environmental tobacco smoke also has been associated with reduced birth weight (Eskenazi, 1995; Windham, 1999). Smoking cessation during pregnancy was found to reverse the effect (Das, 1998). Low-level exposure to PCBs in utero has been associated with reduced birth weight and reduced growth during early childhood (Lucier, 1987; Patandin, 1998). Other effects include obesity in adolescence that also has been linked to prior exposure to PCBs (Gladen, 2000).
4.2.4 Pregnancy Complications and Late Fetal Death Some types of environmental exposures can increase the risk of certain pregnancy compli cations. These complications then can increase the risk for pre-term birth, late fetal death (stillbirth), or other adverse outcomes. For example, maternal smoking increases the risk for placenta previa (attachment of the placenta in an abnormal position in the uterus), placental abruption (premature sepa ration of the placenta from the uterus), and stillbirth (Chelmow, 1996; DiFranza, 1995; Shiverick, 1999; Sibai, 1995). Increased risk of preeclampsia (pregnancyinduced hypertension) has been linked to heavy maternal coffee consumption, occupa tional exposure to solvents, and possibly envi ronmental exposure to lead (Bogden, 1995; Hewitt, 1998; Rabinowitz, 1987; Wergeland, 1997). Tobacco smoking, paradoxically, appears to lower the risk for preeclampsia (Zhang, 1999). Increased risk of stillbirth also has been asso ciated with environmental exposures during middle to late pregnancy. Implicated substances include arsenic, lead, mercury, pesti cides, and possibly chlorinated disinfection byproducts (Golub, 1998; Nurminen, 1995; Pastore, 1997; Schuurs, 1999).
18
Adverse Effects of Exposures During Childhood
Exposures to environmental agents can cause adverse effects that are initiated or first become apparent in children. As discussed in Chapter 2, major cellular structures of the brain and other systems continue to develop into childhood. For example, neuron migra tion, cell proliferation, and synapse formation occur rapidly from birth through three years of age, and myelination continues for about 10 years (Rice, 2000) and potentially longer (Benes, 1998). Also, the immune system develops extensively during early childhood as immune memory is established (Dietert, 2000). Behavioral, emotional, and cognitive development during childhood also can be affected by environmental exposures. Adverse developmental effects seen during this period take a wide variety of forms, including neonatal mortality, growth deficits, and defects or delays in functional develop ment. Sexual maturation and puberty also may be affected by environmental exposures in utero or during childhood. In addition, childhood cancers occur in a pattern that is intimately connected with specific developmental processes and is distinct from the pattern in adults. This chapter discusses a wide range of adverse health outcomes that are manifested during infancy, early childhood, and adoles cence in the following order: Neonatal mortality; Growth deficits during early childhood;
Functional deficits and delayed or impaired functional maturation; Effects on puberty and sexual maturation; and Childhood cancer.
As noted previously, the precise timing of the exposures responsible for the observed effect may not be clear in all cases. For example, studies of maternal occupation may involve exposures occurring both before and after conception. In the following discussion, we take care to indicate the strength of evidence for the relationship between exposures during particular developmental periods and adverse effects.
5.1
Neonatal Mortality
Complications related to short gestation and low birth weight (see Sections 4.2.3 and 4.2.4 in this report) account for about one-third of infant mortality in the United States (Sowards, 1999; US DHHS, 2000). Congenital malforma tions (discussed in Section 4.2.2 of this report) also are a leading contributor to this mortality. A number of specific environmental exposures during preconception, periconception, and pregnancy have been found to be associated with increased risk of such effects, and as a result, an increased risk of neonatal mortality. In addition to the previously noted causes of neonatal death, limited evidence links specific environmental exposures to sudden infant death syndrome (SIDS). Well-controlled stud ies suggest that maternal smoking during pregnancy, maternal smoking status after
19
delivery, and postnatal exposure to environ mental tobacco smoke (due to maternal smok ing or the presence of other smokers in the household) all are associated with elevated risk of SIDS, and that SIDS risk is associated with increasing intensity of exposure to household tobacco smoke (Blair, 1996; Haglund, 1990; Klonoff-Cohen, 1995; Malloy, 1988; Taylor, 1995). In 1997, the California Environmental Protection Agency reported that there was sufficient evidence to find a causal association between environmental tobacco smoke and SIDS (CA EPA, 1997). Other studies have found a higher SIDS risk among children exposed to toxicants such as tobacco and cocaine in utero (Alm, 1998; Milerad, 1998; Ostrea, 1997). The presence of potentially confounding factors, including multiple birth, allergies, apnea, sex of child, mother's age, and socioeconomic status, however, suggests that these studies should be interpreted cautiously. While many of these factors have been researched as primary caus es of SIDS, they also are relevant as confound ing factors when investigating tobacco smoke and cocaine use during pregnancy.
ing childhood. In a large study of children under seven years old, each increment in average blood lead levels of 10 g/dL was associated with an average decrease in height of 1.57 cm and an average decrease in head circumference of 0.52 cm (Ballew, 1999). In a similar study of Greek children aged six to nine years, height decreased 0.86 cm and head circumference decreased 0.33 cm for every 10 g/dL increase in blood lead (Kafourou, 1997). Growth during childhood also has been stud ied in individuals who were prenatally exposed to marijuana or tobacco. Maternal marijuana use was found to be associated with reduced head circumference at birth, and the effect persisted into adolescence (Fried, 1999). As noted in Section 4.2.3, prenatal PCB exposures appears to retard growth during pregnancy and into childhood (Patandin, 1998).
5.3
Functional Deficits and Delayed or Impaired Functional Maturation
5.2
Growth Deficits During Early Childhood
Early childhood is a critical time in develop ment because many organ systems are grow ing and continuing to mature. Many environ mental exposures have been associated with early childhood growth retardation, which may in turn be associated with adverse health outcomes (Osmond, 2000). Growth deficits may be associated with high-level exposures to toxicants, which cause acute adverse effects, or they may be associated with rela tively low exposures, where no other obvious symptoms are seen. Sometimes, reduced growth can be traced to a specific underlying defect in functional development, as discussed in Section 5.3. Environmental contaminants known to cause growth retardation during childhood include lead, PCBs, and tobacco. Chronic lead exposure has been linked to decreased growth dur
As discussed in Chapter 2, many organ sys tems continue to mature during childhood. These developmental processes include myelination of the central nervous system, development of immune memory, maturation of the lungs and kidney, and, later in childhood, sexual maturation and puberty. Many adverse effects on development in late pregnancy and infancy show themselves as functional deficits in organs or systems, instead of overt malformations or growth retardation (Naruse, 1995; Rice, 2000). The pathologic processes leading to these defects, which may be associated with environmental exposures, are initiated at the time of exposure, but the effects typically are not detected until after the child is born. For example, exposure to neurotoxins such as lead, PCBs, and methyl mercury during the critical period of middle to late pregnancy has been associat ed with the development of neurobehavioral effects in exposed children (Grandjean, 1999;
20
Stewart, 2000; Tang, 1999). Congenital rubel la is a classic example in which both structur al birth defects and functional deficits occur, including functional deficits involving the central nervous system (Chess, 1978), increased incidence of diabetes, thyroid and other endocrine disorders, and vascular dis ease (Floret, 1980; Sever, 1985). Functional deficits thought to be associated with environmental exposure are seen in the respiratory system. Prenatal exposure to tobacco smoke has been associated with deficits in respiratory function, as well as with persistent pulmonary hypertension among newborns (Bearer, 1997; Stick, 1996; US NIH, 1993). Increased incidence of respiratory ill ness and reductions in lung function have been found to be associated with maternal smoking (Ware, 1984). There is growing evi dence for the connection between exposures to environmental agents and the severity and incidence of asthma attacks (Chew, 1999; Hajat, 1999; Kimber, 1998). Extensive evidence also supports the relationship between pre- and postnatal exposures to lead and long-term impairments in neurologi cal development. These impairments may translate into learning deficits and disruptive or dangerous behavior. There is limited evidence linking children's exposures to lead to defects in the control of physiological processes such as energy metab olism, cardiac function, and blood pressure. In one study, adolescents with chronic lead exposure were more likely to become obese, even after adjusting for other risk factors (Kim, 1995). Lead poisoning in adults has long been linked with increased risk of hypertension, although the relationship in children is less clear (Loghman-Adham, 1997; Todd, 1996). Children chronically exposed to lead have been found to exhibit subclinical alter ations in kidney function (Fels, 1998). The implications of these symptoms for the longterm maintenance of blood pressure control
and cardiovascular disease risk are not yet known.
5.4 Effects on Puberty and Sexual Maturation

There is growing concern that environmental
exposures may affect the sexual maturation of
children. This concern has focused primarily
on apparent decreases in the average age of
puberty in some ethnic groups in the United
States and other countries.
Decreased age at puberty is a concern because of the increased
risk of impaired stature and earlier onset of
risky behaviors (Halpern, 1997; Meschke,
1997; Wilson, 1994). Changes in age at puber
ty also might be a symptom of other impair
ments in endocrine or reproductive function.
As discussed in the next section, reduced age
at puberty also may be associated with
increased cancer risks later in life.
Some studies show that the age at puberty
and sexual maturation appear to be decreas
ing in some populations (Fredriks, 2000;
Freedman, 2000; Herman-Giddens, 1997). The
apparent reduction varies across racial and
ethnic groups. In the United States as a
whole, evidence suggests that girls are begin
ning to develop secondary sexual characteris
tics at a younger age, although the average
age at menarche, the beginning of the men
strual function, is generally stable. While
some of the observed changes in sexual devel
opment may be due to improved children's
(Baker, 1985; health and nutrition
Georgopoulos, 1999), exposures to environ
mental agents also may play a role (Herman-
Giddens, 1997).
Effects on puberty and sexual development
are seen most clearly in children who have
received cytotoxic drugs or high-dose radia
tion therapy as treatment
for cancer. Chemotherapy with alkylating agents and
other cancer drugs
causes pathological changes in the reproductive systems in both
adolescent females (Nocosia, 1985; Quigley,
21
1989) and males (Matus-Ridley, 1985; Quigley, 1989). Irradiating the head to treat leukemia has been shown to induce premature puberty among both girls and boys (Mills, 1997; Oberfield, 1996; Olgilvy-Stuart, 1994). While the severity of the effect depends on the age at which radiation occurs, sexual maturation may be advanced by 1.5 years or more (Oberfield, 1996) and the risk of premature menarche may be increased up to two-fold (Mills, 1997). Direct irradiation to the gonads has been associated with delayed puberty (Mills, 1997), which is consistent with the known cytotoxic effects of radiation on the ovary and testes. Whether the much lower levels of radiation experienced in everyday life affect the onset of puberty is unknown. Specific evidence regarding the effects of envi ronmental chemical pollution on the age of puberty in humans is limited and has been difficult to acquire. Epidemiological tech niques for detecting changes in populations such as earlier onset of puberty generally depend on large sample sizes. The studies to date provide only limited evidence for an association between exposure to environmen tal toxicants and decreased age of puberty: One study has linked precocious sexual development in children with a higher frequency of exposure to certain hair care and cosmetics products (Zimmerman, 1995). The authors speculated that expo sures to estrogenic compounds in the products may have increased the risk of premature puberty. Another study attempted to link pubertal development in offspring to estimates of perinatal maternal PCB exposures (Gladen, 2000). The mothers' PCB body burdens (measured during pregnancy and lactation) were found to be positively associated with the weight of their daugh ters as they approached puberty, but the daughters' age at menarche was found to be unaffected at the relatively low exposure levels seen in the study.
No significant connection to environmen tal pollution could be confirmed in an industrialized area of Puerto Rico with a well-documented increase in rates of premature puberty (Freni-Titulaer, 1986; Saenz de Rodriguez, 1985). A large number of laboratory animal studies have shown that chemical exposures can have profound effects on sexual development. For example, female and male animals exposed prenatally and perinatally to PCBs experi enced delayed puberty and reduced sperm counts, respectively (Faqi, 1998; Gray, 1998; Restum, 1998). Other chemicals showing effects on sexual maturation in animals include TCDD, bisphenol A, 4-nonylphenol, vinclozolin, p,p'-DDE, phthalates, genistein, and others (Ashby, 1998; Chapin, 1999; Gray, 1998; Hurst, 2000; Levy, 1995; Monosson, 1999; Mucignat-Caretta, 1995; Sumpter, 1995; Yu, 1996). Effects on puberty have been seen in both male and female animals, and the bio chemical mechanisms for the effects seem to vary with the agent involved.
5.5
Cancer In Children
Childhood cancers tend to be qualitatively different from cancers in adults, involving dif ferent organs and cell types. Researchers have questioned whether exposures to specific agents might increase the rates of cancers in children through mechanisms different from those causing adult cancers. Another key question is whether sensitivity to carcinogens is greater during the prenatal period and childhood than during adulthood. Human and animal studies provide only partial answers to these questions. There is general agreement that a small num ber of agents may cause cancer in children after prenatal exposures, apparently through mechanisms that are unique to those developmental stages (Anderson, 2000). The scientif ic evidence is strong for the induction of clearcell carcinoma in the daughters of women exposed to DES and for the development of increased risk of leukemia in children exposed
22
prenatally or during early childhood to high levels of ionizing radiation (Olshan, 2000). There also is a wide range of agents for which the evidence of human cancer causation due to prenatal exposures is suggestive, but not confirmed. Table 5 lists a number of studies that suggest a relationship between prenatal exposures and childhood cancer. A wider range of agents has been proven to be carcinogenic in laboratory animals after prenatal exposures. Table 6 lists examples of studies illustrating the association in experi mental animals between the development of cancer in offspring andprenatal exposure of pregnant females to x-rays, ethylnitrosourea (ENU), 7,12-dimethylbenz[a]anthracene (DMBA), and 5-azacytidine. The cancers range from skin and nervous system tumors to ovarian and lymphoid tumors. Some epidemiological evidence suggests that children may be more sensitive to the carcino genic effects of certain chemicals than adults are. Children exposed to trichloroethene (TCE) in drinking water appear to exhibit risks of leukemia greater than those predicted based on adult experience (Plon, 1997). The results of case-controlled investigations con
ducted in Woburn, Massachusetts, and Dover Township, New Jersey, suggested that prena tal exposure to chemicals in drinking water may lead to an elevated risk of leukemia or central nervous system cancer in children (MDPH, 1997; NJDHSS, 2001). The Woburn study observed a significant trend between maternal consumption of drinking water con taminated with organic agents, namely TCE, and increased incidence of childhood cancer in their offspring during the period 1969 through 1989 (MDPH, 1997). Despite a high er-than-expected overall incidence of childhood cancer from 1979 through 1991, the Dover Township report found a statistically significant association only between con sumption of well water contaminated with TCE, tetrachloroethylene, and styrene-acry lonitrile, and elevated risk of leukemia and central nervous system cancer in female chil dren under age five (NJDHSS, 2001). Exposure to the ultraviolet radiation in sunlight during childhood also has been associat ed with a greater risk for melanoma skin can cer than the same exposure during adulthood (Autier, 1998). Children who receive chemotherapy or radiation for a primary can cer also are at increased risk of developing additional malignancies (Plon, 1997).
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Table 5. Exposures During Pregnancy and Childhood Cancer Exposure Benzene (employment in metal refining and processing) Cigarette smoke Dose Not quantified Cancer That Developed Acute nonlymphocytic leukemia References Shu, 1988
10 cigarettes daily
Any childhood cancer (50 percent increased risk); non-Hodgkins lymphoma, acute lymphoblastic leukemia, and Wilms tumor (doubled risk) Vaginal adenocarcinoma in female children Acute nonlymphocytic leukemia, acute lymphocytic leukemia Leukemia Thyroid cancer Leukemia
Stjernfeldt, 1986
Diethylstilbestrol Gasoline
Waggoner, 1994 Shu, 1988
Ionizing radiation Ionizing radiation Personal services industry (beauty shop workers, laundry or catering workers, domestics) Pesticides (occupational exposure) Phenytoin (drug)
2 mSv (milliSievert) Not quantified Not quantified
Petridou, 1996 Antonelli, 1996; Lund, 1999 Lowengart, 1987
Not quantified
Acute lymphocytic leukemia Neuroblastoma, lymphoblastic lymphoma Acute lymphocytic leukemia, brain and central nervous system cancers in female children under age five Childhood leukemia
Shu, 1988
Not quantified
Koren, 1989; Murray, 1996 NJDHSS, 2001
TCE, tetrachloroethylene, and styreneacrylonitrile trimer
Not quantified
Trichloroethylene (TCE)
Not quantified
MDPH, 1997
24
Table 6: Associations Between Prenatal Exposures and Cancer in Laboratory Animals Source: Anderson, 2000 Prenatal Exposures Resulting in Cancer Exposure Dose 0.2 or 0.5 mmol/kg 200 Radd 12, 16-18 12, 16-18 16-18 16-18 7-14 9-14 (0.5 mmol/kg) 12-13 Gestational Exposure Period(s)b,c Cancer Type Skin tumors Skin tumors Lung tumors Sensitive Exposure Period(s)b Period of Highest Sensitivityb
Animal
Type of Exposurea
Hamster/SG
ENU
Mouse/B6WHT
X-ray
12, 16-18 25 mg/mouse 0.5 mmol/kg 0.5 mmol/kg 60 mg/kg 12, 14, 16, 18 12, 14, 16, 18 10, 13, 15, adult 16, 19 10-15 Both groups All groups All groups 12-18, 1x 12-18 14, 15, 17 All groups 17-21, 1x 17-21
16-18
NA 16-18; fewer lung tumors in male offspring from GD 12 NA < 8 hr before birth 15 12-14 No significant difference 16 15 19
Ovarian tumors Lung tumors Lung tumors Nervous system Kidney tumors Lung tumors Lung tumors Nervous system
Mouse/A/C5
Urethane
Mouse/B6
ENU
Mouse/B6C3 tumors
ENU
Mouse/C3HeB/FeJ 0.4 mmol/kg
ENU
10, 25, or 50 mg/kg
Mouse/C3HneNC tumors 0.5 mmol/kg 0.5 mmol/kg 12, 14, 16, 18 12, 14, 16, 18
ENU
Mouse C57L/J
ENU
14-18 14-18
16, 18 16
Lymphoid tumors Lymphoid tumors
Mouse DBA/2J
ENU
25
Table 6 (continued) Prenatal Exposures Resulting in Cancer Exposure Dose 1 or 2 mg/mouse 12-16, 1x 12, 14,16 14 (2 mg only), 16 12: 1 mg/kg; 16: both doses Gestational Exposure Period(s)b,c Sensitive Exposure Period(s)b Period of Highest Sensitivityb 16 Increase: GD 16, 1 mg/kg Decrease: GD 14, 2 mg/kg Cancer Type Lung tumors Lymphoid tumors
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60 mg/kg 6-20, 1x 6-20, 1x 11-13, 14-16 6-20, 1x 12, 14, 16, 18 8, 10 10-19, 15-24 14-16 All groups 12-18 All groups All groups 6-15 10-20 0.88-1.2 Gray 60 mg/kg 0.5 mmol/kg 50 mg/kg 60 mg/kg NA 8-13 All similar 8 NA
Animal
Type of Exposurea
Mouse/NMRI
5-Azacytidine
DMBA
11 (males) 6-11 (females) Lymphoid tumors 15-20 Lung tumors Ovarian tumors Ovarian tumors Lymphoid tumors Nervous system tumors Nervous system tumors
Mouse/NMRI
X-ray DMBA
Mouse SWR/J
ENU
Rabbit
ENU
Abbreviations used: DMBA (7,12-dimethylbenz[a]anthracene) and ENU (ethylnitrosourea) Provided in gestational days (GD) 1x indicates a single exposure on each of the days indicated Rad = Radiation absorbed dose, basic unit of measurement for absorbed radiant energy
NA, not applicable (sensitive range indicated in previous column)
Adverse Effects of Early Exposures That May Be Delayed Until Adulthood
The studies reviewed in Chapters 3 and 4 focused primarily on the effects of environ mental exposures during early stages of development that are manifested during these periods. As discussed in Chapter 5, however, many effects of prenatal exposures become clinically significant only at later stages in infancy or later in childhood. In this chapter, we briefly discuss effects of environmental exposures during early development that do not develop until adulthood. Sections 6.1 and 6.2 describe cancers and other effects, respec tively, that develop later in life. 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.
atively little information is available to make judgments about the relative risk of cancers occurring with longer latency periods. It seems likely, however, that increased risks of some tumor types may persist past adoles cence. Several studies of children of fathers occupationally exposed to ionizing radiation, for example, have found that increased risks of leukemia seem to persist to age 25 (Anderson, 2000). Similarly, elevated cancer risks from prenatal exposure to DES, although concentrated in late adolescence, also persist into early adulthood (Waggoner, 1994). Breast cancer risk is increased by x-ray thera py, and the risk is greatest if exposure occurs during ages 10 to 14 (Hoffman-Goetz, 1998; Miller, 1989; Tinger, 1997), which is a critical period of breast development. This finding raises the question whether studies that inves tigate exposure in the years of adulthood just before breast cancer develops are capturing the important window of exposure in adoles cence (Ardies, 1998; Hoyer, 2000). In addition, studies suggest that exposure to low-level diagnostic radiation during infancy or childhood may increase the risk of breast cancer; young girls appear to be particularly suscepti ble to radiation injury that can result in longterm effects (Hoffman-Goetz, 1998). These considerations also may be important in stud ies of the potential increase in breast cancer risk through exposure to exogenous estro genic compounds such as certain pesticides and PCBs (Dich, 1997; Wolff, 1995). Lung cancer research suggests that exposures to environmental agents during adolescence may have greater risks than the same expo-
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
27
sures later in life. Among a group of Norwegian men, those who began smoking as teenagers had a 50 percent greater lung cancer risk than those who took up smoking at ages 20 to 29 (Engeland, 1996). The effect was smaller but still significant among women and persisted even when controlling for age-spe cific background cancer risks and years of fol low-up. Increased risk from early exposures to tobacco smoke could be associated with increased levels of persistent chemical damage to DNA ("DNA adducts") (Wiencke, 1999). The increased levels of exogenous hormone exposure associated with early puberty could be a risk factor for cancer later in life (Wolff, 1997). A recent study has demonstrated that women who attain their adult height at a younger age, which is indicative of early puberty, have an increased risk of breast can cer (Li, 1997). Breast cancer risk also increases with early age at menarche (Hoffman-Goetz, 1998; Kumar, 1995; Russo, 1998). Behavioral changes associated with early puberty also may increase cancer risks in women. Decreases in the age of first intercourse and early use of oral contraceptives have been found to increase the risk of cervical cancer significantly (Daling, 1996). Boys who undergo puberty early will have more years of exposure to endogenous androgen produc tion, and the incidence of prostate cancer has been increasing in parallel with reduced age at puberty (Garnick, 1996). Table 6 summarizes data from a small portion of the many laboratory studies that link prenatal exposures in animals to the develop ment of cancer in offspring. These studies show that such exposures cause tumors that occur early in development and are manifested throughout life. Thus, increased cancer risks in animals due to prenatal exposures clearly are not limited to the immediate postnatal period. The authors of the review from which these data are taken (Anderson, 2000) do not, however, indicate how cancer risks differ through different life stages, so it is not
possible to conclude whether prenatal expo sures result in higher risks than exposures after birth. Technical issues, such as compar ing dose levels resulting from exposures of differing duration in different life stages, make such comparisons difficult.
6.2
Other Effects Later in Life
In Chapters 4 and 5, we discussed health impacts of early environmental exposures that could persist into adulthood. Malformations of major organs, delays in development, or defects in function associated with these expo sures may have lifelong consequences. There also is limited evidence for a number of noncancer effects of early exposures that might not become apparent until late in life. Even though most of these effects have not been linked directly to environmental agents, the observed patterns of occurrence demonstrate the possibility that such exposures may contribute to adverse health outcomes in later life. One area of concern is neurological and neu rodegenerative disease. Laboratory studies suggest that exposures to specific organometallic compounds early in life may result in a loss of neurons, causing impair ments in behavioral function in older animals (Barone, 1995). Multiple sclerosis is a poten tially fatal disease whose symptoms generally begin to occur around age 40. The disease shows a geographic pattern of occurrence and other features suggesting that environmental exposures, perhaps infection, prior to age 10 may be important risk factors (Kurtzke, 2000; Rice 2000). Also, early environmental expo sures to lead may contribute to the develop ment of Alzheimer's disease. This suggestion is based on the finding that the functions of several genes thought to be associated with high risk of Alzheimer's disease also are affected by lead exposures (Claudio, 1997; Onalaja, 2000; Prince, 1998). Epidemiologic studies are needed to confirm this association. Reproductive health in adults also can be affected by exposures to environmental
28
agents in childhood. Early menopause can be caused by exposure to chemotherapeutic agents during adolescence (Meirow, 1999). This effect is thought to be associated with depletion of the viable oocytes. Cigarette smoking also can result in early menopause (Cramer, 1996), although no studies separate the impacts of smoking during adolescence from those of smoking in adulthood. The impact of exposures to environmental pollu tants on menopause has not yet been estab lished. Osteoporosis is a major public health problem in the elderly. Bone density in children and adolescents can be strongly affected by envi ronmental agents including aluminum, cad mium, hexachlorobenzene, and lead (Andrews, 1988; Capdevielle, 1998; Katsuta, 1994; Long, 1992; Mason, 1990; Rosen, 1997; Rosen, 1989). Because bone density in adults is highly correlated with peak bone density
achieved during adolescence, long-term fol lowup of lead-exposed children has been sug gested to determine if early exposures have any long-term impacts on bone density and osteoporosis (Rosen, 1997). Early exposures to environmental agents may have other impacts on the generalized aging process. While the biochemical and physio logical processes associated with aging are not well understood, exposures to environmental toxicants during critical life stages could reduce the number of healthy cells available to maintain important physiological activities (Barone, 2000; Rice, 2000). Further, the aging process involves programmed cell death, or apoptosis. Exposures to environmental agents can cause disordered apoptosis during embryonic development, which may increase the risk for neurodegenerative illnesses such as Alzheimer's and Parkinson's disease (Brill, 1999).
29
Summary
There are strong biological reasons for believ ing that humans at specific periods in their early development may be especially sensitive to exposures to environmental agents. The fragility, speed, and complexity of early development clearly provide many targets for specific interactions with environmental agents that are not present at later life stages. Development is a continuum, progressing from germ cells through embryo, fetus, infant, child, adolescent, and adult. It is not always possible to identify exactly when a damaging exposure occurred or which stage of develop ment has been affected. Sufficient knowledge is available, however, to identify many key events and processes and to delineate general patterns in sensitivity. The current state of knowledge is insufficient to definitively rank or quantitatively compare vulnerability to environmental agents across developmental stages, except for a few envi ronmental agents. Identifying certain periods as "critical" therefore is primarily qualitative, based on the observed patterns of effect and the cumulative weight of evidence. Using these criteria, germ cell development, fertil ization, embryonic and fetal growth, childhood, and adulthood all qualify as "critical" stages. Each stage is affected by known and varying sets of environmental agents in ways that can result in serious adverse effects on health. The response to a given level of envi
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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CRITICAL PERIODS IN DEVELOPMENT

Critical Periods in Development

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

* ICF Consulting, Inc. ** University of Kansas School of Medicine-Wichita

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

Why Certain Developmental Stages May Be Especially

2.3 3. 3.1 3.2 4.

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

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

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

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

Major Stages of Development from Conception to Adulthood

CRITICAL PERIODS IN DEVELOPMENT

Figure 1. Sensitive or Critical Stages of Human Development

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

CRITICAL PERIODS IN DEVELOPMENT

Table 1. Stages of Prenatal and Postnatal Organ Structural Development

Organ System Central nervous system Ear Heart Immune system

Mid-Late Prenatal 17-40 weeks 17-20 weeks 17-40 weeks

Limbs Lungs Palate Reproductive system Skeleton Teeth

17-40 weeks 10-40 weeks 17-24+ weeks

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

Table 2. Checkpoints in the Cell Cycle

Synthesis of DNA Growth

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

How Are Effects During Critical Periods Identified?

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

Adverse Effects of Parental Exposures Before or Around the Time of Conception

Environmental Agents That May Damage Germ Cells

CRITICAL PERIODS IN DEVELOPMENT

Exposure Benzenea Diagnostic X-raysb Ionizing radiationb,c

Not quantified Not quantified

McKinney, 1991; c Roman, 1999.

CRITICAL PERIODS IN DEVELOPMENT

Exposure Period Preconception or prenatal

Not quantified Not quantified

Preconception or prenatal Preconception

Hepatoblastoma Leukemia/non-Hodgkin's lymphoma

Buckley, 1989; c Draper, 1997

CRITICAL PERIODS IN DEVELOPMENT

Environmental Agents That May Cause Damage At or Just After Conception

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

Adverse Effects of Environmental Exposures During Pregnancy

General Pattern of Fetal Development and Environmental Toxicity During Pregnancy

CRITICAL PERIODS IN DEVELOPMENT

Adverse Effects During Pregnancy

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

CRITICAL PERIODS IN DEVELOPMENT

Adverse Effects of Exposures During Childhood

CRITICAL PERIODS IN DEVELOPMENT

Functional Deficits and Delayed or Impaired Functional Maturation

Growth Deficits During Early Childhood

CRITICAL PERIODS IN DEVELOPMENT

and cardiovascular disease risk are not yet known.