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Principles of Pediatric Environmental Health
Why Do a Child's Age and Developmental Stage Affect Physiological Susceptibility to Toxic Substances?

Course: WB2089
CE Original Date: February 15, 2012
CE Renewal Date: February 15, 2014
CE Expiration Date: February 15, 2016
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Learning Objective

Upon completion of this section, you will be able to

  • identify reasons why children have unique and varying age-related susceptibilities to toxicants.

Introduction

As children age, changes in their physiology and body composition affect the:

  • absorption,
  • distribution,
  • storage,
  • metabolism, and
  • excretion of chemicals [Quang and Woolf 2000].

Organ system function changes with development. As muscle and bone mass increase, internal organs take up a smaller proportion of the body. As the size and function of each organ changes, so does the dose of a toxicant needed to affect each target tissue.

No one can simply predict a chemical's kinetics and toxicity from data derived from adults or even from children of different ages. For example, methemoglobinemia from nitrate exposure occurs in newborns more readily than in other age groups. Infants in the first 4 months of life have a high stomach pH; this favors the growth of nitrate-reducing bacteria. A proportion of hemoglobin in young infants is still in the form of fetal hemoglobin, more readily oxidized to methemoglobin (MHg) by nitrites than is adult hemoglobin. Therefore, infants, and especially premature infants, are particularly susceptible. In addition, NADH-dependent methemoglobin reductase, the enzyme responsible for reduction of induced MHg back to normal hemoglobin, has only about half the activity in infants as it does in adults [ATSDR CSEM Nitrate/Nitrite Toxicity 2007b].

Variations in Susceptibility with Developmental Stages

Each phase in human development has different susceptibilities to the effects of environmental toxicants. "Windows of vulnerability" (i.e., times in development that the fetus or child is especially toxicant-sensitive) can profoundly affect the consequences of chemical exposures. Table 2 lists developmental stages [Bearer 1995a, 1995b].

Table 2. Human developmental stages

Developmental stage Time Period in Human Development
Preconception Pre fertilization
Preimplantation embryo Conception to implantation
Postimplantation embryo Implantation to 8 weeks of pregnancy
Fetus 8 weeks of pregnancy to birth
Preterm birth 24-37 weeks of pregnancy
Normal term birth 40 2 weeks of pregnancy
Perinatal stage 29 weeks of pregnancy to 7 days after birth
Neonate Birth to 28 days of age
Infant Birth to 1 year
Child 1 year to 12 years of age
Adolescent Beginning with the appearance of secondary sexual characteristics to achievement of full maturity (usually 12 to 18 years for physical characteristics. Full maturity of certain organs - such as brain - occurs up to the mid-20s).

Later in this primer, differing susceptibilities will be discussed by developmental stage.

Age-dependent Toxicokinetic Differences

No one can make simple generalizations about age-dependent changes in the metabolism of a xenobiotic (defined as a chemical foreign to the body).

The biotransformation of xenobiotics is developmentally regulated and can harm or, in some cases, protect a person.

Enzymatic pathways do not mature at equal rates: some mature very rapidly, others slowly. Metabolism of some substances varies with age. For example, the cholinesterase enzyme system in neonates and young infants may be more vulnerable to inactivation than in adults, contributing to children's increased sensitivity to poisoning from organophosphate pesticides [Pope and Jiu 1997]. Many hepatic phase 1 detoxifying enzymes, including CYP1A2, CYP2C9, and CYP2C19, are not fully operational in early infancy [Kearns et al. 2003]. Cytochrome CYP 2E1, which metabolizes xenobiotics such as ethanol, nitrosamines, chlorinated solvents, and benzene, is not fully operational until 6-12 months of life [Ginsberg et al. 2002]. Hepatic phase 2 conjugating enzymes are not fully functional in the newborn period [Scheuplein et al. 2002; Kearns et al. 2003]. Further, different enzymatic pathways may be used to metabolize particular chemicals at different ages; such shifts in metabolic processing may underestimate or obscure differences in kinetics.

Phase 2 metabolism and renal elimination pathways are not fully mature in the first year of life [Ginsberg et al. 2002] compared with

  • child and adult pharmacokinetic functions across a variety of cytochrome pathways,
  • phase 2 conjugation reactions, and
  • renal excretory patterns.

Half lives of many chemicals metabolized by premature and term infants were 3-9 times longer than were the half-lives found in adults. These differences diminish over the first 6 months of life. Kidney function is immature in the newborn and clearance is reduced, especially in the first 12 weeks of life [Renwick 1998]. Studies of toxicokinetics must therefore be age-specific and compound-specific.

For both adults and children, note that efficient metabolism of a substance does not necessarily decrease toxicity. In some cases, metabolic byproducts are more toxic than the parent compound. For example, methyl parathion is an organophosphate pesticide registered by the U.S. Environmental Protection Agency for use on some outdoor crops (but not on many others such as those often consumed by children). It has a history of misuse indoors. Methyl parathion metabolizes to a more toxic byproduct once exposure has occurred - the toxic byproduct methyl paraoxon is what causes organ damage.

Differing Organ Susceptibilities

The rapid development of organ systems during embryonic, fetal, infant, and early childhood periods make children vulnerable when exposed to environmental toxicants. Critical periods of vulnerabilities vary according to each organ system. Central nervous sytem (CNS) development occurs over a protracted period. Neuronal cell division is thought to be complete by 6 months of gestational age. CNS development, however, continues to involve timed sequences of cell migration, differentiation, and myelination until adolescence - in fact, CNS development may not be complete until the mid-20s.

Disruption before completion of the processes themselves or their coordination can result in irreparable damage. Different toxicants affect different aspects of these event sequences (e.g., irradiation affects cell proliferation, ethanol affects cell migration, and hypothyroidism affects cell differentiation) [Rice and Barone 2000]. Each of these disruptions results in functional impairments. Notably, the myelination of the brain and alveolarization of the lung continue to develop throughout adolescence. Also during adolescence, the reproductive organs undergo growth, and maturation of structure and function. Chemicals such as polychlorinated biphenyls, dichloro-diphenyl-trichloroethane, and dioxin may disrupt hormonal function in fetal life, leading to long-term consequences for

  • reproduction,
  • growth,
  • neurodevelopment, and
  • immune function.

The ability of specific organs to limit cellular uptake of xenobiotics depends in part on the expression and localization of the ABC family of membrane transporters. Specifically, membrane transporters that are capable of extruding toxicants from cells (e.g., blood-brain barrier, hepatocytes, renal tubular cells). Expression of these transporters, including P-glycoprotein, changes during fetal and early life development [Tsai et al. 2002; Ek et al. 2010]. Although medical science previously believed that the fetal blood-brain barrier was anatomically incomplete, research to date shows an anatomically complete barrier [Saunders et al. 2008]. Changes in blood flow and pore density may contribute to the developing blood-brain barrier in infants, making them susceptible to passive diffusion of toxicants into the CNS. And we now know that hypoxic episodes in fetuses and infants render them more susceptible to toxic exposures across the blood-brain barrier. Research continues into the function and structure of the blood-brain barrier in early life [Scheuplein et al. 2002; Kearns et al. 2003].

Because children are at the beginning of their lives, they have more opportunities for exposure to toxicants and expression of their harmful effects. This is especially true for diseases (e.g., cancer) with protracted latency periods. For example, the 1986 Chernobyl radiation exposure in Belarus, Ukraine, and Russia resulted in a substantial increase in thyroid cancer cases. In one study in which researchers monitored for health status and level of internal contamination, alterations in immunologic and thyroid parameters were observed in the exposed children [DeVita et al. 2000]. The Belarus Health Ministry announced in 1992 that the number of persons diagnosed with thyroid cancer after the incident increased 10-fold from four cases in 1986 to 55 in 1991. Many of the thyroid cancer victims were children at the time of exposure. The ministry also stated that the death rate among those who stayed in the contaminated area was 18.3% higher than the national average [Kazakov et al.1992].

Key Points

  • As children age, changes in their physiology and body composition affect the:
    • absorption,
    • distribution,
    • storage,
    • metabolism, and
    • excretion of chemicals.
  • The biotransformation of xenobiotics is developmentally regulated and can either harm or protect each person.
  • The rapid development of a child's organ systems during embryonic, fetal, and early newborn periods makes the young more vulnerable when exposed to environmental toxicants. These critical periods of vulnerabilities vary according to each organ system.

   

Progress Check

5. Some physiological factors leading to altered effects of xenobiotics in early life include

A. Changing body compositions affecting the absorption, distribution, storage, metabolism and excretion of foreign chemicals.
B. Enzymatic pathways that mature at different rates.
C. Renal function, which is not fully mature until a year of life.
D. All of the above.

Answer:

To review relevant content, see "Age-dependent Toxicokinetic Changes" in this section.

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