Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
How Are Children Different from Adults?
Cynthia F. Bearer
Division of Neonatology, Department of Pediatrics, Rainbow Babies and
Children's Hospital, Cleveland, Ohio
Abstract
Several factors alter an individual's risk for an environmentally related
illness. A major determinant is the age of the individual. The toxicodynamic
processes that determine exposure, absorption, metabolism, excretion, and
tissue vulnerability are all age related. This paper discusses each of these
processes and their variability with age, and illustrates these points with
examples of environmentally related disease cases. -- Environ Health
Perspect 103(Suppl 6):7-12 (1995)
Key words: developmental stages, environmentally related diseases,
developmental toxicology, routes of exposure, exposure, absorption, metabolism,
excretion, preconception
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington, DC.
Address correspondence to Dr. Cynthia F. Bearer, Division
of Neonatology, Department of Pediatrics, Rainbow Babies and Children's
Hospital, 11100 Euclid Avenue, Cleveland, OH 44106. Telephone (216) 844-5249.
Fax (216) 844-3380.
Introduction
Several factors alter an individual's risk for an environmentally related
illness. These include genetic background, nutrition, age, lifestyle, etc.
These categories are not mutually exclusive but are influenced by each
other. This article will focus on age as a susceptibility factor and specifically
on how the toxicokinetic parameters of exposure, absorption, metabolism,
distribution, and target organ susceptibility change during development
(1).
Exposure
Exposure to an environmental agent is the first step in the sequence
of environmentally related health effects. Exposures differ with developmental
stage because the environments of children are different than those of adults.
When considering exposures, one must look at the exposures of an individual
over the course of a day. In general it is true that people may move through
several environments during a day, to doing errands, going home, going to
sleep. This is also true for infants and children, going to school, going
to day care, going to play. What is needed is a sum total of all the exposures
and some idea of the maximum exposure. But we are usually not able to put
monitors on people and measure them. Usually, our estimates of exposure
are from retrospective estimates. This is true not only for adults, but
for children as well. Although the total exposure in a day may be the same,
the pattern of exposure may have totally different health effects. For example,
nitrates in well water may cause methemoglobinemia. However, if they are
ingested at a rate where the methemoglobin reductase can continue to keep
the iron in hemoglobin in the reduced state, no health effect will occur.
But if the dose exceeds the capacity of methemoglobin reductase, then methemoglobinemia
will result (2). This is one mechanism that results in a threshold
effect.
Exposures that have profound health effects on an individual may occur
at periods of time that frequently are not considered, such as an exposure
that may occur to the mother before the conception of that individual which
may have a profound effect on that individual. For example, women who conceived
after eating cooking oil contaminated with polychlorinated biphenyls (PCBs)
gave birth to infants with yusho (3). The mechanism responsible is
felt to be storage of PCBs in adipose tissue during exposure, which are
then mobilized during pregnancy (4,5). Another example is that of
a woman who was inadequately treated for plumbism in childhood and who gave
birth to an infant with congenital lead poisoning (6). Storage of
the lead in bone with mobilization during pregnancy is the most logical
explanation for this result (7).
Another example of an exposure prior to conception, which may result
in effects on the individual, is a preconception exposure that directly
affects the ovum or sperm. The ovum, formed within the fetus of the future
mother, is dependent on the exposures of both the grandmother and the mother.
The ovum, therefore, is a stage of development that sums all the exposures
of the other stages of development. Studies have measured xenobiotics in
follicular fluid, showing the potential for exposure (8). Sperm,
in contrast, are created only a few hours to days prior to conception. Thus,
the exposures to the sperm are dependent on paternal exposure in the periconception
period.
In most instances, exposures to the fetus are dependent on the exposures
to the mother. However, premature infants delivered after 24 weeks have
very different exposures in the newborn intensive care unit (NICU), such
as to noise, light, compressed gases, intravenous solutions, and benzyl
alcohol (9). Not only is the NICU a unique environment, but these
infants remain in the same environment often for months.
Exposures of newborns, infants, toddlers, school-age children, and adolescents
can be discussed with reference to changes in physical location, breathing
zones, oxygen consumption, food consumption, types of foods consumed, and
normal behavioral development.
Physical Location
The physical location of children changes with development. The newborn
is usually near the mother or held by the mother, so exposures will be like
those experienced by the mother. The newborn frequently spends more time
in a single environment for prolonged periods of time, i.e., a crib, rather
than several different environments. Infants and toddlers are frequently
placed on the floor or carpet, or on grass. Therefore, they have much
more exposure to chemicals associated with these surfaces, such as formaldehyde
and volatile organic chemicals from synthetic carpet (10) and pesticide
residues from flea bombs (11).
Preambulatory children also may experience sustained exposure to noxious
agents because they cannot remove themselves from their environment. An
example is the infant who is badly sunburned due to the inability to protect
himself/herself. It has been shown that the risk of skin cancer is most
closely related to the amount of sun damage the skin sustains during the
first 18 years of life (12).
School-age children spend a significant period of time at school,
a very different physical environment than the house. Schools are frequently
built on relatively undesirable land for economic reasons. These sites are
frequently near highways (auto emissions and lead), under power lines (electromagnetic
fields), or on old industrial sites (benzene, arsenic). Until relatively
recently schools made frequent use of asbestos as a building material (13).
Adolescents not only have a new school environment, but begin to self-determine
physical environments, often misjudging or ignoring the risks to themselves
(14). In addition, many adolescents have part-time jobs that place
them in physical environments which may be hazardous due to occupational
exposures (15).
Breathing Zones
The breathing zone for an adult is typically 4 to 6 ft above the floor.
However, for a child, it is closer to the floor and dependent on the
height and mobility of the child. It is within these lower breathing zones
that heavier chemicals such as mercury and large respirable particulates
settle out (16) and radon accumulates (17). This is one factor
that may have accounted for the case of acrodynia in Michigan from latex
house paint (18).
Oxygen Consumption
Because of their larger surface-to-volume ratio, the metabolic rate of
children is higher, and hence their oxygen consumption is greater. Therefore,
their exposure to any air pollutant is greater. For example, if radon is
present at 2 pCi/l, an adult with an average O2 consumption rate
of 3.5 ml/kg body weight/min will receive an exposure of 48 pCi/kg in 24
hr. In contrast, a 6-month-old child with an average O2 consumption
rate of 7 ml/kg body weight/min will receive an exposure of 96 pCi/kg in
24 hr, which is twice as much (19).
Quantity and Quality of Food Consumed
Just as O2 requirement is higher for children as a function
of their surface-to-volume ratio, so is caloric requirement. Not only do
children maintain homeostasis, they also grow. Therefore, the amount of
food they consume per kg/body weight is higher than that of the adult (20).
Consider the amount of water consumed by an infant who receives formula
reconstituted in boiled tap water. Average consumption is 6 oz/kg. (In comparison,
for the average male adult, this is equivalent to drinking 35 cans of soda
pop a day.) Blood lead levels greater than 10 µg/dl have been found
in infants with exposure to tap water in formula (6). It has also
been shown that the types of food they consume differ from those of adults
(21). The diets of many newborns are limited to breast milk. Breast
milk has been documented to contain many environmental pollutants including
lead, PCBs, and dioxins (22-24). Children's diets contain more milk
products and more fruit and vegetables. When the level of exposure of children
to Alar was calculated using a child's daily consumption of apples and apple
products, an unacceptable level of risk for cancer was found (25).
Normal Behavioral Development
The normal behavioral development of a child will also influence
his environmental exposures. A preambulatory infant will not be able to
remove himself/herself from a noxious environment as mentioned earlier.
Normal children pass through a developmental stage of intense oral exploratory
behavior. Most objects grasped will be placed in the mouth. This behavior
is one common etiology of lead poisoning in environments with high levels
of lead dust (26). It also places the child at risk in environments
that have not taken the oral orientation of children into account. One example
is arsenic- and creosote-treated wood in playgrounds. Children will frequently
place their mouths on these materials in the course of normal play (27).
The ability to walk often places the child in unusual situations for play,
such as used drums, mud puddles, or empty lots, environments where adults
spend little time and which have the potential for dangerous exposures.
As children become adolescents, they gain more and more freedom from parental
authority. However, they are at a stage of development in which physical
strength and stamina are at a peak, yet they are continuing to acquire abstract
thinking (28). Therefore, they do not consider cause and effect,
particularly delayed effects, in the same way adults do. They often place
themselves in situations with greater risk due to this lack of perception.
An example is the increased incidence of farm injuries involving adolescents
as compared to adults (29).
Absorption
Absorption generally occurs by four major pathways: transplacental, percutaneous,
respiratory tract, and gastrointestinal tract. Each of these portals of
entry is dependent on the developmental stage of the child.
Transplacental
During the fetal stage, a major pathway of absorption is the placenta.
Until the late 1950s, the placenta was thought to protect the fetus from
any maternal exposure. However, the experience with thalidomide drastically
changed this paradigm (30). It is now known that several classes
of compounds readily cross the placenta. Compounds of low molecular weight
cross the placenta readily. Carbon monoxide is a good example of this type
of chemical. Because carbon monoxide has a higher affinity for fetal
compared to adult hemoglobin, the concentration of carboxyhemoglobin is
higher in the fetus than in the mother (31). Lipophilic compounds
such as polycyclic aromatic hydrocarbons and ethanol also readily gain access
to the fetal circulation. PCBs have been measured in equal concentration
in fetal and maternal blood (32). Fetal and maternal blood levels
of ethanol are equal in pregnant ewes (33). The fetal liver does
not express alcohol dehydrogenase until near term (34). Therefore,
the majority of ethanol diffuses back across the placenta and is metabolized
by the mother. There are also specific transport mechanisms in the
placenta that actively transport specific nutrients. Calcium is such
a nutrient; a 100 to 140 mg/kg/day accretion is required by the fetus in
the third trimester (35). Lead is transported via the calcium transporter.
Fetal blood lead concentration is equivalent to maternal blood lead concentration
(36).
Percutaneous
Transdermal pathways of absorption are particularly important for lipophilic
compounds. The skin undergoes enormous changes with each developmental stage,
which alters the properties of absorption.
The skin of a fetus is unkeratinized (37) and is thus without one of
the major barriers of the skin. Although xenobiotics have been described
in amniotic fluid (38), the transdermal absorption of these
compounds has not been studied. Keratinization occurs over the initial 3
to 5 days following birth and is independent of gestational age. Therefore,
the skin of a newborn remains a particularly absorptive surface. Several
epidemics have been described involving percutaneous absorption of xenobiotics,
including hypothyroidism from iodine in betadine scrub solutions (39),
neurotoxicity from hexachlorophene baths (40), and hyperbilirubinemia
from a phenolic disinfectant (41). An additional factor in the absorption
of these chemicals transdermally is the larger surface-to-volume ratio of
newborns compared to older children and adults.
Respiratory Tract
During prenatal life, the fetus makes breathing motions. Although the
net flux of fluid is from the lungs out of the trachea into the
amniotic fluid, some xenobiotics in amniotic fluid may be in contact
with the respiratory epithelium. Studies on this pathway are limited. It
has been noted that maternal smoking during pregnancy is associated with
significant reductions in forced expiratory flow rates (42).
The surface absorptive properties of the lung probably do not change
during development. However, from birth to adolescence, the lung continues
to develop alveoli (43). A consequence of this development is an
increasing surface absorptive area in the lung.
Gastrointestinal Tract
The gastrointestinal (GI) tract undergoes numerous changes during development.
The fetus actively swallows amniotic fluid (44). Xenobiotics
are known to be present in amniotic fluid, but prenatal absorption
from the GI tract has not been investigated.
Following delivery, the gastric pH is relatively high and does not achieve
adult levels of acidity until several months of age (45). The difference
in pH will markedly affect xenobiotic absorption from the stomach, as it
will change the ionization status of these chemicals (46). In addition,
under low levels of acidity, bacterial overgrowth in the small bowel and
stomach may result. The absorption of nitrites formed by bacteria from ingestion
of formula reconstituted with well water with nitrate contamination resulted
in several cases of methemoglobinemia in Iowa (47).
The small bowel is felt to express specific transport mechanisms
in the newborn. In the newborn mouse and rat, maternal IgM and IgG present
in colostrum are specifically transported across the small bowel and
into the blood. Whether these mechanisms are present in humans has not been
proved (48). The bowel also responds to increased nutritional needs
by increasing absorption of the particular nutrient. For example, growing
children require more calcium than adults for continued bone growth. Thus,
they absorb more calcium from intraluminal contents than adults. However,
they also absorb more lead from the GI tract than adults because of this
enhanced absorption. It is estimated that an adult will absorb 10% of ingested
lead, whereas a 1- to 2-year-old child will absorb 50% of ingested lead
(49).
Distribution
The tissue distribution of chemicals varies with developmental stage
of the child. For example, many drugs in the newborn have higher apparent
volumes of distribution (50). In animal models, it has been shown
that lead is retained to a larger degree in the infant animal brain than
in the adult (51). Lead also accumulates more rapidly in children's
bones, doubling between infancy and the late teen years (52).
Metabolism
Metabolism of chemicals may result in their activation or deactivation.
These enzymes involved in the biotransformation of chemicals can be categorized
into two groups, Phase I and Phase II enzymes. Phase I enzymes promote formation
of a conjugable group, and phase II enzymes catalyze the conjugation of
a more polar compound to the conjugable group such that the resulting conjugate
is more polar and therefore more easily excreted. Not only does developmental
stage determine the activity of these metabolic pathways, but also the genetic
polymorphisms of each locus determine the activity of each component enzyme.
The family of glutathione S-transferases, phase II enzymes, illustrates
both of these points. The glutathione S-transferases (GST) are a
large and complex family of enzymes which share the catalytic activity of
glutathione conjugation to a second substrate with a conjugable group (53).
They can be separated into four families of enzymes: 
, µ, ¼,
and microsomal. The µ family is lacking in 50% of individuals (54).
Smokers with lung cancer have a higher incidence of lacking the µ
glutathione transferases (55). Thus, these individuals have a genetic
susceptibility to carcinogenesis from cigarette smoke. The expression of
the families of GST show a marked tissue specificity. GST ¼ is
only found in placenta (56,57); the Yc isozyme of GST is not expressed
in brain, but the Yb3 isozyme of GST µ is only expressed
in brain (58,59). Developmental regulation is evident in that 50%
of GST activity in fetal liver is GST ¼, which is not expressed in
adult liver (60).
Developmental regulation is more complex in the P450 cytochrome family.
[Nebert and Gonzales (61) present a complete review.] Clinically
this is important for the pediatrician to know in order to prescribe medications
accurately. Theophylline is metabolized by the P450 cytochrome system. Initially,
during the newborn period, the half-life of theophylline is prolonged, requiring
dosing twice a day. However, P450 cytochrome expression increases over the
first few months of life, decreasing drug half-life and necessitating
more frequent dosing. If one examines urinary metabolites of theophylline
during this period, one sees a difference in the pattern of metabolites
denoting complex developmental stages in the expression and activity of
the P450 cytochromes (61). The half-life of theophylline is again
prolonged during adolescence, possibly as a consequence of competition with
steroid hormones (62). Dosing interval must again be prolonged to
avoid toxicity.
Another clinical example of developmental changes in metabolism is the
case of acetaminophen. In the adult, as well as the pregnant adult, high
levels of acetaminophen may cause fatal hepatotoxicity. However, infants
delivered to mothers with high acetaminophen levels will also have elevated
acetaminophen levels in blood, but will not sustain liver damage. It is
thought that the lack of the fetus's ability to metabolize the acetaminophen
protects the fetus from end-organ damage (63,64).
From these two examples, one can conclude that biotransformation of xenobiotics
is developmentally regulated and may either protect or harm the individual.
Excretion
Kidney function is also developmentally regulated. At birth, glomerular
filtration rate is a fraction of normal adult values. It gradually
increases to adult values by approximately 1 year of age. The ability to
concentrate urine is also developmentally regulated, the newborn being relatively
poor at concentrating urine. By 16 months of age, renal function has reached
adult capabilities (65).
Target Organ Susceptibility
Children are also different than adults because their organs are undergoing
growth and differentiation. Both of these processes may be affected by xenobiotics.
The result of exposure to xenobiotics may be different in children than
adults, both in the degree of severity of effect and also in the nature
of the effect. Since children's bodies are growing and developing, these
processes may be disrupted as a result of environmental exposures, leading
to different outcomes. Examples of such outcomes are prenatal and postnatal
growth retardation, diminished IQ, precocious puberty, microcephaly, and
diminished lung volume.
Growth occurs by three mechanisms: auxelic, where growth occurs by cells
becoming larger; multiplicative, where growth occurs by cells dividing;
and accretionary, where ground substance and nonliving structural components
accumulate (66). Multiplicative growth is felt to be complete at
6 months of gestation for those tissues not undergoing continual turnover
such as epithelial cells. All subsequent growth is accretionary or auxelic.
Cells undergo two further processes to become the adult organism, differentiation
and migration. Differentiation is the process by which cells take on their
particular chemical operations and lose the ability to divide. These events
may be triggered by hormone-receptor interactions. Some environmental agents
may mimic hormones and alter the differentiation of some tissues. Chlorinated
insecticides are an example of this mechanism. Recent studies have shown
effects on the reproductive system from exposure to chlordecone (67).
Cell migration is necessary for certain cells to reach their destination
for function. Neurons, for example, originate in the germinal matrix, then
migrate out along radial glia to a predestined location in one of the many
layers of the brain (68). Xenobiotics may have a profound effect
on this process, as shown in children with fetal alcohol syndrome. Prenatal
exposure to ethanol may result in interruption in this process severe enough
to cause lissencephaly (69).
Examples of organs that have a prolonged period of postnatal development
are the brain and the lungs. Myelination of the brain is not complete until
adolescence (70). Alveolarization is not complete until adolescence
(43). This protracted period of growth and development increases
the vulnerability of these organs. For example, intracranial tumors are
frequently treated by radiation therapy in adults, with uncomfortable but
reversible side effects (71). However, in infants, radiation therapy
is avoided because of the profound and permanent effects on the developing
central nervous system.
Another example of the unique vulnerability of children is the neurotoxic
effects of lead. The current blood lead concentration of concern for children
is 10 µg/dl (72). This level is based on studies by numerous
investigators (73) that show that children with blood lead concentrations
greater than 10 µg/dl have measurable decreases in intelligence quotient.
The occupational limit for adults is 60 µg/dl, at which no encephalopathy
is noted, but may impair kidney function, fertility, and peripheral nerves
(49).
That the developing lung may also be compromised by exposure to environmental
agents is illustrated by studies of the effects of environmental tobacco
smoke on children. It has been shown that the FEV1's of children exposed
to environmental tobacco smoke (ETS) are measurably slower than children
with no exposure (74).
Tissues undergoing proliferation and terminal differentiation are particularly
susceptible to carcinogenesis (75). This increased susceptibility
is due to the shortened time period for DNA repair and the multiple changes
that are occurring within the DNA, such as interaction with growth factors,
the switching on of genes as well as the switching off of genes. All are
likely sites for interaction with chemicals that will interrupt the sequence
of events. A clinical example is the epidemic of scrotal cancer among the
pubertal chimney sweeps of Victorian England (76). Chimney sweeps
were usually adolescents with developing secondary sexual characteristics.
Occupational exposure to carcinogens such as soot was common, but the site
of the tumor is uncommon outside this situation. Thus, it can be hypothesized
that the scrotum, while undergoing terminal differentiation, had increased
susceptibility to the carcinogen.
Summary
This presentation has attempted to outline the reasons why children cannot
be considered little adults in the area of environmental medicine. Their
exposures are different, their pathways of absorption are different, their
tissue distribution is different, their ability to biotransform and eliminate
chemicals is different, and their bodies respond differently to environmental
chemicals and radiation. Each of these differences is dependent on the developmental
stage of the child--all children are not the same! Each of these differences
must be taken into account when considering the health impacts of a particular
exposure on the population. Our database is still incomplete as regards
pediatric environmental medicine.
What can the practitioner do? The roles of educator, investigator, and
advocate are extremely important when assessing children for their environmental
health. Prevention is the most important intervention in this field.
Parents, children, teachers, community leaders, and policy makers need to
be educated about the unique vulnerability of children to environmental
pollution. Most environmentally caused diseases have been diagnosed by an
alert clinician. Publication of case studies has allowed further description
of environmentally mediated diseases. Finally, clinicians must be advocates
for their patients. Most regulatory policies do not take the unique vulnerability
of children into account when setting limits. A clinician must understand
the basis for this unique vulnerability and all the factors that influence
it to be an effective advocate.
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