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PEDIATRICS Vol. 113 No. 4 April 2004, pp. 1044-1050

SUPPLEMENT ARTICLE

Gastrointestinal Tract

Raman Sreedharan, MD* and Devendra I. Mehta, MD{ddagger}

* Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
{ddagger} Nemours Children’s Clinic, Wilmington, Alfred I. duPont Hospital for Children, Wilmington, Delaware


   ABSTRACT
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 DIFFERENTIAL VULNERABILITIES AND...
 CHILDHOOD GI DISORDERS FOR...
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The developing gastrointestinal tract from conception to adolescence is in constant direct interaction with an increasingly complex environment. This sets up the potential for unrecognized acute as well as chronic disorders, some of which may be difficult to pinpoint in a developing infant and child, given the wide variations that exist. It is startling to note how early some environmental toxins can come into contact with the developing human, where vulnerability may be heightened and maturation of detoxifying pathways may be incomplete. Although the complex process of recognizing, detoxifying, and avoiding the toxic substance by the body has presumably evolved over a substantial period of time, in this rapidly changing world, the array of novel toxins that make their way into the gastrointestinal tract is increasing. There remain many gaps in understanding the effects of environmental toxins on all of the developmental stages from conception to adolescence. Although threshold levels have typically been derived from adult or animal data, factors such as size, relative differences in consumption in proportion to size especially in infancy, and variable physiologic maturation of metabolic pathways are not well understood. The vulnerability may be further accentuated by physical factors that alter with maturity, such as permeability and critical times during organogenesis or organ maturation. Also of concern is how little is known about low-dose, long-term exposure, as well as any interplay with common illnesses. This article focuses on environmental toxins that have been shown to have toxic effects on the gastrointestinal tract.

Key Words: development • intestinal mucosa • toxins

Abbreviations: GI, gastrointestinal • CYP, cytochrome P450

The gastrointestinal (GI) tract, like the skin and the respiratory system, is in constant direct interaction with the environment. The functions of the GI tract as a protective barrier are as important as its functions of digestion and absorption but vary with age and maturity. The large surface area and prolonged exposure time increase risk of toxin-mediated damage, and increased permeability in early infancy may augment this further. Complex processes of recognizing, detoxifying, and avoiding toxic substances also undergo physiologic maturation. In addition to recognized environmental toxic agents, in this rapidly changing world, the array of novel toxins that make their way into the GI tract poses significant threats and needs to be better understood.


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Environmental toxins taken orally may be modified in the GI tract by gastric pH, digestive enzymes, or even bacteria that live in the intestines. Environmental toxins that are internalized by skin absorption or by inhalation may be secreted into the lumen through the biliary system and lead to toxicity. Also, toxins suspended in air make their way into the intestinal tract by drainage from the sinuses into the pharynx and esophagus.

Mucosal Factors
A thin preepithelial water layer ("unstirred water layer") and a mucous layer cover the intestinal mucosa and limit absorption to toxins that can diffuse. Lipid solubility will increase the absorption, as will smaller particle size. The intestinal luminal pH plays a role by altering the ionization of molecules so that nonionized forms of the weak bases and acids are absorbed more rapidly than the ionized forms. The mucous binding and absorption of metals such as cobalt, zinc, lead, and iron are pH dependent.

The rapid turnover of the intestinal mucosa helps to protect the mucosa and the body against toxic injuries. The regenerative capacity after injury and damage are remarkable because of the mucosa’s capacity for rapid turnover and has been studied extensively with the dog ileum after interruption of blood supply. The lower two thirds of the crypts form the proliferative compartment of the mucosa and, because of their location, are protected from the reach of toxic substances. This could explain the low incidence of small intestinal carcinoma despite its large area. The presence of cytotoxic substances stimulates exfoliation of the cells into the lumen. Also, studies have demonstrated that during the periods of cytotoxic exposure, glucose absorption and enzyme activities are decreased.

Detoxification
The detoxification mechanism that exists in the intestinal mucosa serves as a second-line barrier and has been studied well in animal models and also to an extent in humans. Regional differences are also noted, with most enzymes diminishing in expression in distal small bowel. Studies conducted in rat small intestines have shown that cytochrome P450 (CYP), NADPH-CYP reductase, p-nitroansole o-demethylase, and benzpyrene hydroxylase activities are expressed 3 to 10 times more in the upper villous cells of the proximal small bowel.1 This may represent an evolutionary adaptation as the highest concentrations of environmental toxins are presented to the upper small bowel.

Pharmacokinetic differences may play a part in the age-related differences in the incidence of adverse effects of environmental toxins. Phase I reactions depend predominantly on CYP enzymes, particularly as most drugs are lipophilic. Specific CYP enzymes are developmentally regulated and affect production of metabolites, including possibly toxic ones, as well as efficacy of drug therapy. Thus, CYP2D6 activity is <1% of the adult level and remains low until after 28 days of age. Drugs that use these pathways, such as ß-blockers and tricyclic antidepressants, could result in toxicity, including anticholinergic gastrointestinal side effects.2 Conversely, CYP3A, used to metabolize a large number of drugs, is present in significant amounts in the fetal liver. Extraintestinal CYP3A may be the most important enzyme for orally administered drugs, although the ontogeny has not been evaluated.3 Indeed, the activity of these enzymes is greater in infants and children compared with adolescents and adults. In children, CYP-catalyzed metabolism is increased, and uridine diphosphate-glucuronosyltransferase-catalyzed metabolism is not significantly different from that in adults.4

Phase II enzymes also show developmental regulation that affect drug metabolism. N acetyl transferase 2 activity is low in infants and children younger than 3 years, essentially making them phenotypically resemble slow metabolizers. By extrapolation, slow metabolizers are at greater risk of toxicity, including toxic epidermal necrolysis and Stevens-Johnson syndrome.5 In contrast, higher red blood cell thiopurine methyltransferase activity observed in newborn infants may have therapeutic implications in terms of levels of azathioprine and 6-mercaptopurine and hence efficacy and toxicity, but no data to date indicate how long this higher activity is maintained.6 In general, pharmacokinetic studies in infants and children have been used to provide inferential information on the impact of development on the activity of drug-metabolizing enzymes. Because different pathways often metabolize these drugs, the information obtained provides only an overview. In some cases, these enzyme systems may instead activate toxins, such as carbon tetrachloride, which then dissociates into toxic free radicals in the lumen. Finally, the different processes involved in absorption, such as diffusion, nonionic diffusion, facilitated diffusion, specific active transport, and toxins, might usurp solvent drag, and mechanisms to counter these with respect to a particular toxin may be useful therapeutically.


   DIFFERENTIAL VULNERABILITIES AND CRITICAL WINDOWS OF EXPOSURE OF THE GI TRACT: FROM CONCEPTION TO ADOLESCENCE
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Antenatal
Maternal diet is the major factor governing exposure at conception and in utero. The rapidly growing fetus is susceptible, but the placenta acts as barrier. Although transplacental transport of environmental toxins, such as lead and mercury, is recognized, toxins in amniotic fluid, such as nicotine and cotinin, have been poorly studied for possible absorption by either the skin or the GI tract.7 Specific GI effects of maternal smoking are cleft lip and palate and postnatal growth retardation.

Postnatal Changes
The postnatal maturing GI tract undergoes several changes that may significantly alter risk of toxicity (Table 1). Changes in vulnerability to toxins as a result of many of these factors have largely been studied only in animal models and may not be applicable. Mucosal permeability to macromolecules diminishes in the first few days of life in humans but diminishes much later in animals. In addition, influence of GI disease, more common in infancy and early childhood, may alter absorption by changes in motility, mucosal integrity, or surface area. Lead (Table 2) and cadmium absorption is markedly increased in early childhood. Absorption of both metals increases in iron deficiency states as the number of carriers shared by all 3 metals increases in the duodenum.8


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  		TABLE 1. Age-Dependent Changes in Gastrointestinal Functions

 

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  		TABLE 2. Some Specific Environmental Toxins

 
Low gastric acid production in infants may lead to increased small bowel bacterial overgrowth. Methemoglobinemia in infants may have resulted from conversion of nitrate from contaminated well water to nitrite.9

The disposition of drugs and other environmental toxins varies at different stages of child development. Generally, absorption is slower in younger children. The extracellular volume is higher, and the extent of protein binding is lower. Renal excretion is lower, and environmental toxin metabolic pathways that depend on glucuronidation activity in the liver may increase concentration of toxins. Animal studies show diminished or absent hydrolase, reductase, or demethylase activity at birth in the rabbit and lack of uridine diphosphate-glucuronyl transferase in the guinea pig but not in the rabbit.10 Interspecies differences highlight the dangers of extrapolation to humans.

Infancy
Maternal diet remains an important source of environmental toxins in breastfed infants. Many environmental toxins, including halogenated pesticides such as polychlorinated biphenyls and dioxins, may be concentrated significantly in the milk fat. Because milk is typically the main diet, constant exposure over several months may occur. Currently, however, there is no evidence that these concentrations reach thresholds that are harmful, and breast milk is still recommended by the American Academy of Pediatrics as the best choice. Milk formulas from cow milk may be less concentrated, especially as the fat source is nondairy. However, possible risks of other contaminants such as antibiotics warrant additional study, as the amounts ingested are large over a sustained period of months.

Childhood
Several environmental factors affect exposure to toxins in childhood. Household powders and liquids may be ingested and lead to caustic esophageal injuries. These injuries markedly increase the risk of esophageal cancer in later life.11 Toxic plants, such as Dieffenbachia, including mother-in-law’s tongue and berries such as holly berries (Table 3), can lead to severe oral and GI disturbances and are most common in childhood. Schools, child care facilities, and playgrounds expose children to a wide array of environmental toxins ranging from lead to herbicides, heavy metals, and pesticides. Outdoor play areas such as wooden playground equipment may be a source of arsenic or chromium if ingested.


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  		TABLE 3. Some Specific Biological Toxins

 
A child’s diet is typically less varied than in adolescents or adults but may contain proportionally more fruits and vegetables. This exposes them to greater amounts of pesticides. Common childhood disorders, such as constipation, may significantly increase toxin absorption because of delayed transit time.

The environmental toxin metabolic pathways continue to change, as exemplified by peak theophylline metabolism occurring at this age and leading to different urinary metabolite levels than in infancy.

Adolescence
Risk-taking behaviors such as smoking, ingestion of intoxicants, or part-time manual jobs affect exposure to environmental toxins. Smoking is a risk factor for peptic ulcer disease. Hormonal changes lead to growth and differentiation of tissues, making these more vulnerable to toxins. A change in the metabolic rate of environmental toxins pathways occurs, leading to reduced CYP expression, and theophylline metabolism decreases to adult levels.

Specific Environmental Toxins
Minor GI symptoms are common in many toxic exposures, although other organs may be more involved. In Table 2, environmental toxins for which GI symptoms either are common or may be the major presenting signs are listed. Age-specific features are noted. In Table 3, some biological toxins for which GI symptoms predominate are listed.


   CHILDHOOD GI DISORDERS FOR WHICH ENVIRONMENTAL TOXINS MAY BE CONSIDERED
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Acute exposures may lead to nausea, vomiting, and diarrhea and may be difficult to identify, as infectious causes are more common. However, additional features, such as excessive drowsiness, involving other organs should raise suspicion. Gingivitis, edema, and erythema of oral mucosa; dysphagia; and GI hemorrhage also may suggest environmental toxin exposure, especially heavy metals. Copper, pokeweed, and toxalbumins may lead to bloody diarrhea, mimicking acute colitis. Indeed, in inflammatory bowel disease, environmental toxins such as ultrafine particles of titanium oxide have been postulated as causes.46


   CONCLUSION
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Changes in diet and exposure to environmental toxins vary tremendously with age. Developmental stages of protective mechanisms such as mucosal permeability also lead to age-specific risks. Although many gaps in understanding effects of environmental toxins on all of the developmental stages from conception to adolescence remain, it is clear that the various age groups need to be considered separately. The GI tract, despite being an important detoxification site, is also vulnerable because of its specific features that allow optimal digestion and absorption. The vulnerability is further accentuated by developmental factors such as permeability and the critical timing for many target organs. Low dose, long-term exposure and high-dose, short-term exposure both need to be studied, and the impact of common illnesses on toxicity needs to be evaluated. Furthermore, although safe threshold levels have been derived from adult or animal data, factors such as size, relative differences in consumption, and different maturity of metabolic pathways suggest that these could be misleading. Little is known about specific changes and risks during adolescence, and caution should be used when applying adult-based threshold values.


   FOOTNOTES
 
Received for publication Oct 7, 2003; Accepted Oct 20, 2003.

Reprint requests to (D.I.M.) Division of Gastroenterology, NCC-Wilmington, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail: dmehta{at}nemours.org


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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

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