Childhood is a time of rapid growth and development, accompanied by changes in organ system functioning, metabolic capabilities, physical size, and behavior that can dramatically modify the potential effects and illness caused by exposure to a toxicant.
Research has not yet satisfactorily answered how host characteristics can affect the harm caused by a toxic substance. The federal government has begun to mobilize the scientific community to focus on the possible unique vulnerabilities of children. Although for some selected agents, children are no more susceptible (and are sometimes less susceptible) than adults to an adverse outcome, theory and empirical observations point to common overall themes of increased susceptibility to environmental hazards throughout childhood.
Caregivers have a direct impact on the safety and health of children. Caregivers are entrusted to not only protect children from danger, but to consult child health care providers appropriately. A child relies on adults for protection from environmental tobacco smoke (ETS), excessive exposure to sunlight, pesticides in the home, take-home occupational exposure, and other environmental exposures including noise. Children's own behaviors, physical characteristics, and diet peculiar to each developmental phase (Table 2) can put them at greater risk for exposure to environmental hazards.
Opportunities for exposure change as a child grows from total dependence on his or her parents or other caregivers to adolescent independence. Economic circumstances, environmental regulations, and legislation can restrict or reinforce pediatric exposures.
Multiple factors that enhance a child's opportunity for exposure (Table 2 and Table 3) include the following:
Children breathe more air, drink more water, and eat more food per kilogram of body weight than adults do.
An infant's respiratory rate is more than twice an adult's rate.
In the first 6 months of life, children drink seven times as much water per kilogram of weight than an adult does.
From 1 to 5 years old, children consume three to four times more food per kilogram of weight than an adult does.
Restricted food choices in the dietary patterns of infants and toddlers lead to greater exposures to contaminants unique to certain foods that often dominate their diets. For example, because children consume about 15 times more apples and apple products per unit of body weight than adults do, risk assessments based on a typical adult diet might underestimate a child's risk of exposure to pesticide residues on apples.
Deficiencies of dietary iron and calcium can increase lead absorption.
Some toxicants more readily penetrate children's skin, especially in the newborn period when the skin is highly permeable (e.g., dermal exposure to lindane and hexachlorophene, with subsequent development of neurotoxicity).
Other factors influencing both exposure to and absorption of environmental agents include a child's
home, play, or day care environment;
physical stature;
mobility;
metabolic rate; and
increased surface area to body mass ratio (in young children).
For example, in a home contaminated with mercury (e.g., caused by spillage or from mercury carried home on work shoes), a toddler's high respiratory rate, proximity to surfaces likely to be contaminated, and playful rolling around on the floor will increase his or her chance for mercury exposure. Other possible contaminants that settle near the floor are pesticides, formaldehyde (from new synthetic carpet), and
radon.
As children age, changes in their physiology and body composition affect the absorption, distribution, storage, metabolism, and excretion of chemicals (Behrman et al. 1996). Organ-system function changes with development. As muscle and bone mass increase, internal organs become a smaller part of the total body. As the size and function of organs change, so does the dose necessary to alter those target tissues. The kinetics and toxicity of a chemical cannot simply be predicted from data derived entirely from adults or even from children of different ages. For example, methemoglobinemia from
nitrate exposure might occur in newborns more readily than in other age groups because during the first 4 months of life, newborns have low concentrations of reduced nicotinamide adenine dinucleotide (NADH) methemoglobin reductase (i.e., erythrocyte cytochrome b5 reductase). This enzyme reduces methemoglobin, rendering the enzyme nonfunctional for its oxygen-transporting function.
No simple generalization can be made about age-dependent changes in the metabolism of xenobiotics (i.e., foreign organic chemicals). First, efficient metabolism of a substance does not necessarily decrease its toxicity. In some cases, metabolic by-products are more toxic than their parent compound. Methyl parathion, an organophosphate pesticide for use on outdoor crops, but with a history of misuse indoors, is metabolized to more toxic by-products once exposure has occurred. It is the toxic by-products that cause organ damage.
Second, enzymatic pathways do not mature at equal rates: some mature rapidly, others slowly. For example, caffeine has a half-life of about
4 days in the neonate, compared to about 4 hours in the adult. Infants achieve adult rates of metabolizing caffeine by 7 to 9 months of age. Metabolism of some substances, such as theophylline (which is metabolized by the P450 cytochrome system), begins slowly at birth, exceeds that of adults in early childhood, and then falls gradually to adult rates by late adolescence. Further, different enzymatic pathways might be used in the metabolism of a particular chemical at different ages. For all of these reasons, studies of the variation in toxicokinetics with age must be compound-specific.
Under some circumstances, the immaturity of certain metabolic pathways in children might result in a lower susceptibility to certain toxicants (e.g., acetaminophen). In the adult, high levels of acetaminophen can cause fatal hepatotoxicity. However, infants delivered by mothers with high levels of acetaminophen will also have elevated acetaminophen levels in their blood, but will not sustain liver damage. It is thought that the fetus' inability to metabolize the acetaminophen protects the fetus from end-organ damage. Therefore, the biotransformation of xenobiotics is developmentally regulated and can either protect or harm the individual.
The rapid development of a child's organ systems during embryonic, fetal, and early newborn periods makes him or her more vulnerable when exposed to environmental toxicants. These critical periods of vulnerabilities vary according to each organ system. CNS development occurs over a protracted period of time. Neuronal cell division is thought to be complete by 6 months of gestational age. However, CNS development continues to involve timed sequences of cell migration, differentiation, and myelination until adolescence. Disruption of these processes or their coordination before completion can result in irreparable damage. Different toxicants affect different aspects of these sequences of events (e.g., cell proliferation is affected by irradiation, cell migration by ethanol, and cell differentiation by hypothyroidism) (Rice and Barone 2000), each resulting in functional impairments. Notably, the myelination of the brain and alveolarization of the lungs continue to develop throughout adolescence. Also during adolescence, the reproductive organs undergo hyperplasia, as well as maturation of structure and function.
Because children are at the beginning of their lives, more opportunity exists for both exposure to and expression of harmful effects from exposure to toxicants-especially those diseases with a protracted latency period (cancer). For example, the 1986 Chernobyl radiation exposure in Belarus, Ukraine, and Russia resulted in substantial increases in reported cases of thyroid cancer. Alterations in immunologic and thyroid parameters were observed in the exposed children monitored in one study for health status and level of internal contamination (DeVita et al. 2000). The Ukraine Health Ministry announced in 1997 that 10 times as many people (i.e., 50) are being diagnosed with thyroid cancer each year, compared to 5 per year before the accident. The ministry also stated that the death rate among those who stayed in the contaminated area was 18.3% higher than the national average.
Much of the information in this section as well as in Table 2 is adapted from the work of Cynthia Bearer, MD, PhD (Bearer 1995a, 1995b).
Anticipatory guidance is the education provided to parents or caretakers during a routine prenatal or pediatric visit to prevent or reduce the risk that their fetuses or children will develop a particular health problem (CDC 1997).
Developmental milestones mark phases of changing susceptibility ("windows of vulnerability") that can profoundly affect the consequences of chemical exposures. This section highlights critical aspects of each stage to form the basis of anticipatory guidance and clinical evaluation (Table 2). Not only are children different from adults with regard to susceptibilities, they are different among themselves according to age. Various exposure scenarios, and issues important to each developmental stage, will be presented by route. Environmental exposures occur predominantly through three major routes: ingestion (oral), inhalation (respiratory), and dermal (skin). Specific examples of exposures through these major routes are included for newborns and toddlers.
Because oogonia fully develop during fetal life, oocytes rest dormant, vulnerable to environmental insults until the time of ovulation. Ova forming within the fetus of the future mother are affected by exposure from both her grandmother and her mother.
Although injury to stem-cell spermatogonia can occur at any time and lead to infertility, male reproductive biology presents repeated, narrow windows of vulnerability in parallel with the continual postpubertal production of semen and regeneration of spermatozoa. Paternal exposures might also lead to adverse reproductive outcomes by transmission of toxicants in seminal fluid. (See ATSDR's Case Studies in Environmental Medicine: Reproductive and Developmental Hazards [ATSDR 1993].)
Parental exposures before conception can result in an array of adverse reproductive effects ranging from infertility to spontaneous abortion, as well as genetic damage that can lead to a viable, though defective, fetus. For example, a woman who has experienced a prepregnancy exposure to lead and who was inadequately treated for lead poisoning in childhood might give birth to an infant with congenital lead poisoning (Shannon and Graef 1992). The most logical explanation for this would be storage of the lead in bone with mobilization during pregnancy (Silbergeld 1991).
Environmental tobacco smoke and alcohol are known, preventable human growth retardants. Anticipatory guidance by the primary health care provider to prospective parents can help prevent adverse fetal outcomes by encouraging prospective parents to protect their health and that of their unborn infant. Preconception counseling is imperative in proactively addressing issues that can significantly impact the health of the unborn child.
The fetus cannot escape the transplacental transport of toxicants encountered by the mother; that is a fact of fetal life. Both historic and gestational maternal exposures can affect the fetus. During gestation, the placenta, which establishes its circulation by around day 17 after fertilization, acts as the most important route of exposure. The placenta is a semipermeable membrane that permits easy transport of low-molecular-weight (i.e., carbon monoxide) and fat-soluble (i.e., polycyclic aromatic hydrocarbons and ethanol) compounds, as well as certain other compounds such as lead. Some water-soluble and high-molecular-weight compounds might also cross the placenta, albeit more slowly. The placenta has limited detoxification ability that helps mitigate only very low concentrations of toxicants.
Contaminants in a pregnant woman's current and past diet can harm the fetus. Physiologic changes during pregnancy mobilize stored toxicants, such as lead from bone or
polychlorinated biphenyls (PCBs) from fat cells, resulting in fetal exposure. Maternal alcohol ingestion can lead to fetal alcohol syndrome, and maternal smoking during pregnancy has been associated with lower mean birth weight, increased risk of infant mortality, and decrements in lung function noted later in the life of the exposed child.
Anticipatory guidance by the child health care provider can help stop the parental consumption of tobacco and alcohol.
Fetal exposures can also occur independently of the placenta. These exposures include heat, noise, and ionizing radiation (Paulson 2001). A mother's exposure to ionizing radiation can increase the likelihood of the occurrence of childhood leukemia and neurologic delays. Although the mechanism is uncertain, some parental exposures during gestation, including anesthetic gases and some solvents, might be associated with adverse reproductive outcomes (ATSDR 1993).
During critical periods of organogenesis (i.e., the 6-week period that follows the establishment of the placental circulation), exposures can cause profound systemic damage that is out of proportion with the usual dose response. The fetal brain is particularly vulnerable because it lacks a blood-brain barrier or detoxification capabilities. In utero exposure to lead during this stage causes more damage to the nervous system than does exposure at any other stage of development. In the fetal brain, neurons originate in a central location (germinal matrix) and later migrate to predetermined sites. Exposure to ethanol during this stage might interrupt migration and lead to brain malformation, as is sometimes seen in fetal alcohol syndrome. High levels of methylmercury exposure from maternal consumption of contaminated fish from Minimata Bay, Japan, caused cerebral palsy and severe mental retardation in children born in Minimata. Some studies suggest that lower concentrations of maternal dietary methylmercury also can lead to neurodevelopmental delays and mild retardation. The fetus is at an increased risk of acute toxicity from carbon monoxide; levels that are harmless to healthy children can create permanent deficits of cognitive and motor functions in a fetus.
Rapidly dividing fetal cells might have increased sensitivity to carcinogens. Epidemiological evidence, however, is contradictory on the relationship between age of exposure and cancer risk. As previously noted, it appears that during childhood, sensitivity to carcinogens increases in some organs and decreases in others. The only two generally accepted carcinogenic in utero exposures proven to result in cancer later in life in the exposed offspring include diethylstilbestrol (DES) (via placenta) and ionizing radiation (acting directly on the fetus) (Anderson et al. 2000; DeBaun and Gurney 2001; Lemasters et al. 2000).
Newborns (Birth to 2 Months), Infants (2 Months to 1 Year of Age), and Toddlers (1 to 2 Years of Age)
The growth rate during the first few months of life is faster that than during the rest of life. Tissues with rapidly dividing cells might be especially vulnerable to carcinogens; those vulnerable include tissues in the hematopoietic cells, lungs, and epithelium. Children's growth velocity smoothly decreases around 9 months, to about half the initial rate. Although resistance increases, toddlers exhibit similar vulnerabilities in absorption, detoxification, and organ development as do newborns and infants.
Exposure by Ingestion
The small intestine of a newborn responds to nutritional needs by increasing the absorption of specific nutrients. For example, calcium transport in newborns and infants is about five times the rate in adults. If
lead exposure occurs, the lead will compete with the calcium for transport at this high rate.
Breastfeeding
Breastfeeding is considered the optimal form of infant nutrition in most circumstances. Research indicates that human milk and breastfeeding of infants provide advantages with regard to general health, growth, and development, while significantly decreasing the child's risk for a large number of acute and chronic diseases. The many benefits to the infant provided by breastfeeding greatly outweigh the risk from possible contaminants in breast milk. For more information regarding contaminants in breast milk, a good resource is the AAP Handbook of Pediatric Environmental Health (Etzel and Balk 1999) chapter on human milk (Schreiber 2001).
When breastfed, a baby remains vulnerable to both current and historic maternal exposures. Lactation mobilizes previously sequestered fat-soluble toxicants such as dioxins, other chlorinated pesticides, PCBs, and bone lead, which then contaminate breast milk. Maternal toxicokinetics, the solubility and binding properties of a toxicant, and the characteristics of breast milk determine the milk-maternal plasma (M/P) ratio. The higher the ratio, the more complete the transfer of the substance into the breast milk. Neutral, basic, low-molecular-weight, highly lipophilic substances transfer most readily into breast milk. M/P ratios have been published for a variety of xenobiotics (Schreiber 2001). The M/P ratio for lipophilic substances
such as PCBs range from 4 to 10; the ratio for organic and inorganic mercury is 0.9.
Formula Feeding
On a daily basis, a newborn infant consumes a much larger amount of water (equivalent to 10%-15% of his or her body weight) compared to an adult (2%-4% of body weight). Formula-fed infants consume significant amounts of water; average daily consumption might be 180 mL/kg/day (6 fluid ounces/kg/day), which is the equivalent for an average adult male of thirty-five 360-mL (12 fluid ounces) cans of soft drink per day (Paulson 2001 and Table 3). Contaminants such as heavy metals and nitrates are not eliminated by boiling water, and are concentrated when water is boiled away. Water from municipal water systems is usually low in lead content, but the water can acquire lead from soldered pipe joints and brass fixtures inside the home. The first-draw water (i.e., water that has stood in pipes) should be discarded. Boiling before formula preparation need not exceed 1 minute. Water in municipal systems might also contain contaminants such as microbes and trace amounts of organic chemicals. Many families use private well water and consider it safe, perhaps safer than municipal water. However, private well water is largely unregulated and unmonitored and presents the potential for exposure to a spectrum of contaminants at high concentrations.
Nitrates are a well-recognized problem in private well water. Factors leading to increased risk of methemoglobinemia from nitrate exposure in infants younger than 6 months of age include the following:
Gastric pH of infants is higher for the first 1-2 months of life and does not drop to adult levels until 3 years of age (Marino 1991), leading to excess bacterial colonization, which increases the conversion of nitrates to
nitrites.
NADH-dependent methemoglobin reductase activity in infants is 60% of that in adults. The relative lack of methemoglobin reductase enzyme necessary to convert methemoglobin back to functioning hemoglobin leads to methemoglobinemia. At about 6 months of age, infants begin to have adult levels of NADH-cytochrome b5 reductase, which converts methemoglobin back to hemoglobin (Avery 1999). Other causes of methemoglobinemia include genetic deficiency in methemoglobin-reducing enzymes; genetic abnormalities in the hemoglobin making the protein more susceptible to oxidation; GI infections and inflammation and the ensuing overproduction of nitric oxide; and exposure to oxidant drugs and chemicals, including nitrites.
Pica
The avid oral exploratory behavior of infants and toddlers makes ingestion an important exposure route to consider. Children who eat nonfood items are exhibiting pica behavior. Soil pica is the recurrent ingestion of unusually high amounts of soil (i.e., on the order of 1,000-5,000 mg per day). Groups at risk of soil-pica behavior include children age ≤6 years and individuals who are developmentally delayed (ATSDR 2001a). ATSDR uses 5,000 mg soil per day as an estimate of soil intake for children with soil-pica behavior. Accessible environments might be contaminated with lead paint, chips, or dust particles; pesticides; take-home contaminants (e.g., mercury); lawn chemicals; or floor-cleaning products.
Solid Foods
Because a typical toddler's diet is relatively rich in fruit, grains, and vegetables, the risk is higher for a toddler's exposure to food-borne pesticide residues than it is for adults, who routinely consume fewer of
these foods. Some regulations now acknowledge children's different exposures and susceptibilities in an attempt to lessen children's exposures to toxic chemicals. For example, the Food Quality Protection Act of 1996 states that pesticide tolerances need to be set to protect the health of infants and children.
Exposure by Dermal Absorption
The ratio of the newborn's skin surface area to body weight is approximately three times greater than that of an adult (Table 3). Therefore, covering a similar percentage of the body with a substance that can be dermally absorbed will lead to a larger dose on a weight basis in a child than in an adult. Other factors affecting dose include the surface area exposed and the vehicle (which may promote contact/residence time). In addition, characteristics of the skin of a newborn (birth to 2 months) enhance the absorption of xenobiotics. The thick keratin layer, which protects an adult's skin when in contact with a toxicant, does not form during the fetal stage. This keratin layer begins to develop in the first 3-5 days after birth; it remains more susceptible to absorption throughout the newborn period and is independent of gestational age. As a result, the newborn skin readily absorbs chemicals. Hexachlorophene-containing compounds were routinely used in the 1950s for the skin care of newborns as a prophylaxis against Staphylococcusaureus infection. By 1971, the use of hexachlorophene preparation as a skin cleanser for newborns was restricted because studies showed that it disrupted the cell walls and precipitated cellular protein, causing vacuolization in the CNS. Other examples include Betadine scrubs, which have caused hypothyroidism in infants, and dermal absorption of aniline dyes, which were used in a laundry service's advertisement printed on diapers and resulted in methemoglobinemia (Graubarth et al. 1945; Howarth 1951; Chai and Bearer 1999).
Exposure by Inhalation: Respiration
The younger the child, the higher the respiratory rate and the higher the weight-adjusted dose of an air pollutant (Table 3). A baby's exposure to indoor and outdoor air pollution closely mirrors that of its parents or caregivers; however, the vulnerability of the infant's respiratory system increases the risk that early exposures to combustion air pollutants (e.g., ETS) will slow the rate of pulmonary growth. Acute clinical effects in infants exposed to ETS can include laryngitis, tracheitis, pneumonia, increased morbidity from respiratory syncytial virus (RSV) infection, and chronic middle ear effusions (Cook and Strachan 1999; Gitterman and Bearer 2001). Respiratory exposures to air contaminants (e.g., ETS, dust mites, and cockroach antigens) during the first year of life have a greater influence on the incidence and severity of
asthma than do exposures later in life (Etzel 2001).
As infants and toddlers begin to explore the world away from the arms of parents or caregivers, they are often in the microenvironments of the floor and ground. Some toxic gases, including mercury vapor, are heavier than air and layer close to the floor in these microenvironments. A child's high respiratory rate in breathing zones close to the floor results in higher inhaled doses of toxicants than an adult would receive in the same room. Mercury vapors can cause severe respiratory complications and other health effects.
Young Child (2 Years to 6 Years of Age)
Special circumstances increase susceptibility in this age range. With the newly acquired ability to run, climb, ride tricycles, and perform other mobile activities, the young child's environment expands and so does the risk of exposure. Exploratory behaviors also continue, making this age group's susceptibilities very different than those of their younger peers.
If a young child's diet is deficient in iron or calcium, as is possible with children in this age group, the small intestine will be able to avidly absorb lead. Pica is also a consideration for this age group. Children ≤6 years are at high risk for soil pica (ATSDR 2001a).
School-aged children spend increasingly greater amounts of time outdoors and in school and after-school environments-each of which has its own hazards. Outdoor air pollution includes widespread air pollutants such as ozone, particulates, and oxides of nitrogen and sulfur, which result primarily from fossil fuel combustion. Although these pollutants concentrate in urban and industrial areas, they are wind-borne and distribute widely. Wood-burning and industry in rural towns can create local pockets of intense exposure. Toxic air and soil pollutants might result from local sources such as hazardous waste sites, leaking underground storage tanks, or local industry. Children exposed to high doses of lead released into the air from a lead smelter in Idaho showed reduced neurobehavioral and peripheral nerve function when tested 15 to 20 years later (ATSDR 1997, 2001b).
History of school and after-school environments should be included when assessing exposure to indoor and outdoor air pollutants and contaminated drinking water and soil. During play or normal activity, children might ingest or inhale dirt or dust contaminated with
arsenic, mercury, or other environmental toxicants.
Adolescent behavior leads to new categories of potential exposures. Risk-taking behaviors of adolescents might result in exploring off-limit industrial waste sites or abandoned buildings or experimenting with psychoactive substances (e.g., glue sniffing). Adolescents might take jobs or enter vocational schools where they are exposed to workplace hazards. For more information about labor issues and adolescents, see Goldman et al. (2001). Adolescents sustain more occupational injuries and suffer more illnesses than their elder co-workers. Hobbies and school activities, such as arts and crafts or chemistry, are also more likely to involve exposure to hazards than are the activities of younger children. Few schools include basic training in industrial hygiene as a foundation for safety at work, at school, or while enjoying hobbies. For example, there have been reports of teenagers taking elemental mercury from an old industrial facility and playing with and spilling the elemental mercury in homes and cars (Nadakavukaren 2000).
During the adolescent period, the metabolism rate of some xenobiotics dependent on the cytochrome P450 (CYP enzyme) system decreases as a result of changes in cytochrome P450 expression (Nebert and Gonzalez 1987) (e.g., theophylline, which has a subsequent increase in blood) (Gitterman and Bearer 2001). Studies indicate that the metabolic rate of some xenobiotics is reduced in response to the increased secretion of growth hormone and/or steroids that occur during the adolescent years (steroids compete with theophylline metabolism) (Gitterman and Bearer 2001). The implications of these changes for environmental contaminants is an area of intense research. Pubertal changes lead to new tissues with the special vulnerabilities associated with rapidly growing, dividing, and differentiating cells. Profound scientific and public interest in endocrine disruptors reflects concerns about the impact of persistent synthetic organic chemicals on the developing reproductive system. Studies have shown that by the end of puberty, the metabolism of some xenobiotics have achieved adult levels.
