SUPPLEMENT ARTICLE |
A Pediatric Perspective on the Unique Vulnerability and Resilience of the Embryo and the Child to Environmental Toxicants: The Importance of Rigorous Research Concerning Age and Agent
* Thomas Jefferson University, Alfred I. duPont Hospital for Children, Laboratory of Clinical and Environmental Teratology, Wilmington, Delaware
American Academy of Pediatrics, Center for Child Health Research and Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York
Abbreviations: PCB, polychlorinated biphenyl • MPE, maximal permissible exposure • NOAEL, no observable adverse effect level
There is realistic concern about the impact of environmental influences on the health of human populations. First, exposure to environmental agents continues despite successes in reducing exposures to known toxicants such as lead, polychlorinated biphenyls (PCBs) and tobacco smoke. Second, there has been increasing concern about the cause of autism and other neurodevelopmental problems and hypotheses that environmental influences may play a role in the prevalence of these and other such childhood and adult conditions as asthma and obesity. Third, many other conditions are directly or indirectly related to environmental influences and are preventable, such as injuries, untoward consequences of alcohol, suicide, drug addiction, and gun-related deaths. There have been numerous publications since the 1970s of symposia, proceedings, monographs, and articles dealing with the increased susceptibility of the embryo, infant, and child to environmental toxicants,1–17 reflecting a greater level of concern about embryonic and childhood exposures. Indeed, great deal of attention has been paid to the vulnerability of the embryo and the fetus to environmental chemicals, drugs, and physical agents. In fact, the publication edited by Miller1 was primarily devoted to exposures to the embryo and the fetus. Because the embryo and the child are growing and their tissues and organs are differentiating, deleterious effects may occur at lower exposures to some chemicals, drugs, and physical agents and produce more severe effects than those seen in adults. In fact, some effects may not occur in adults. Thus, maximal permissible exposures (MPEs) for some environmental chemicals should be lower for the embryo and the child.
It is important to note that children and adolescents have better recuperative capacities than adults for many toxic agents, and, similarly, appropriate drug dosages may be lower or higher on a mg/kg or surface area basis in children than in adults to attain effective therapeutic blood levels or to avoid toxicity. In addition, effects produced by drugs, chemicals, and physical agents are not always deleterious or always irreversible. This means that for some exposures, the young can recover from some effects more rapidly and completely than adults (Table 1). If the exposure does result in irreversible effects by exceeding the threshold exposure, then the impact on a developing organism can be more severe than in the adult.
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Much of the discussion and publications that deal with the vulnerability of the developing embryo, infant, child, and adolescent to environmental agents have focused on particular environmental toxicants or agents, summarizing the spectrum of pathology that results from exposures to these agents. There is nothing wrong with this approach from the toxicologist’s point of view, because it is obvious that the developing child and adolescent can be more severely or differently affected by some environmental toxicants.
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GOALS |
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 TOP GOALS CONTROVERSIES AND CONCLUSIONSREFERENCES |
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This supplement to Pediatrics is being directed toward pediatric clinicians; thus, there are goals that are different from previous conferences, workshops, and publications.
- To bolster the enthusiasm of practicing pediatricians for diagnosing, treating, and preventing illnesses and subtle but serious long-term negative effects caused by toxic environmental exposures. This supplement contains an article by Dr Robert Miller that provides a historical perspective on the discoveries of environmental toxicants by pediatricians and other alert physicians and scientists. It is a thrilling article that honors practicing pediatricians for their accomplishments in discovering environmental toxicants. Dr Miller would like all pediatricians to think of themselves as environmental detectives, and the article is really a charge to every practitioner to become interested in discovering new and unique environmental toxicants. Discoveries of environmental toxicants have been made by alert practitioners who identified a cluster of patients with illnesses associated with an environmental exposure. Such discoveries are a low-probability event in any practitioner’s lifetime, given that most clusters of illnesses or diseases that are identified are not found to be causally associated with an environmental toxicant. However, "thinking environmentally" while practicing medicine will make every physician a better practitioner, even if not necessarily a famous one.18 Please read Dr Miller’s article.
- To provide information about children’s environmental health from a clinician’s viewpoint rather than that of a toxicologist. Although most previous publications have focused on the effects of particular toxic agents, this supplement presents both the clinical and the toxicologic perspective. Because it is clinicians who evaluate clinical symptoms and clinical disease, we have asked a number of clinicians to discuss the maturation of organ systems during prenatal development, infancy, childhood, and adolescence and their sensitivity to toxicants at different stages of childhood development. There are articles on the heart, lungs, liver, gastrointestinal tract, skin, kidney, central nervous system, hematopoietic system, teeth, and endocrine systems as well as discussions of the present state of our knowledge of the more prominent environmental toxicants. We have asked the authors to present the data and information so that clinicians can use this information when confronted with a clinical problem that may be attributable to an environmental toxicant or drug.19 In addition, there are articles that describe the role of federal agencies, recent changes in drug monitoring for children, and risk assessment. It is our hope that this supplement will provide pediatricians with a current overview of what is and is not known about the effect of the environment on children’s health.
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CONTROVERSIES AND CONCLUSIONS |
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TOPGOALSCONTROVERSIES AND CONCLUSIONSREFERENCES |
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Any discussion of the importance and magnitude of the contribution of environmental agents to human morbidity and mortality tends to provoke spokesmen on both sides of the issue. Segments of the scientific and lay community believe that environmental agents are major contributors to disease and death, whereas other scientists and lay individuals believe that environmental risks have been grossly exaggerated. When it comes to the issue of the vulnerability of children to environmental toxicants, a similar polarization of views exist. Only the facts, impeccable science, and more research will place the field of environmental toxicants and their effects on children into proper perspective. The facts clearly indicate that children are different from adults, which is amply documented in Tables 1 to 5. This necessitates obtaining data on each individual toxicant or potential toxicant to determine children’s vulnerability to a particular agent and to determine the magnitude of their increased or decreased sensitivity and vulnerability. Unfortunately, few generalizations about children’s vulnerability to environmental exposures apply, given that vulnerability and sensitivity are specific to a child’s age and developmental stage and also to the agent.
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We have accomplished a great deal in the past 40 years with regard to children’s vulnerability to environmental toxicants, and some of the accomplishments have had a very positive effect. The most dramatic example is the reduction in blood lead levels in children in the United States. The topic of lead toxicity is discussed eloquently by David Bellinger in one of the articles in this supplement, but even in the area of lead toxicity, we still have many unanswered questions and much to do to protect children from being exposed. We do not know the no observable adverse effect level (NOAEL) for most environmental toxicants, and, of course, those agents with genotoxic potential are considered to have no threshold.
Some scientists have suggested that because we do not have valid information on most environmental toxicants in adults and children that we should use a factor of 10 in establishing MPEs for children. There is little scientific evidence to validate this suggestion, however. For example, drugs such as morphine and chloramphenicol would still be hazardous even with a 10-fold reduction in the medication dosage. Other drugs and chemicals may be more hazardous to the child than the infant, and in some instances, adults are the most vulnerable. Although as a generalization infants and children are the most sensitive and vulnerable to the effects of environmental toxicants, we should not regulate or practice medicine on the basis of generalizations.
Tables 1 to 5 list numerous differences between developing humans and adults. Most pediatricians and obstetricians are aware of many of these vulnerabilities. For example, we know that the infant’s gastrointestinal tract will permit Clostridium botulinum to inhabit it and may result in infant botulism.20 Conversely, we know that the developing embryo, infant, child, or adolescent has better recuperative powers from some insults. The child who has sustained brain damage from an infection, a stroke, or other types of brain injury may regain more function than an adult who sustains the same damage.
It is also important for the clinician to be aware that most environmental toxicants have a toxicologic dose-response curve after various exposures. As the exposure increases into the toxic range, the incidence and the magnitude of the deleterious effects increase. Below certain exposures, the NOAEL, there are no known deleterious effects.21–24(Fig 1) The problem for the clinician is that the NOAEL has not been determined or is controversial for many environmental toxicants and may differ by age as a result of variations in absorption, metabolism, and excretion that themselves change over the course of the child’s development. Similarly, when the clinician is confronted with a patient who has been "exposed," he or she may not be able to determine the amount or the length of exposure or even when it occurred. The clinician needs to know which environmental agents can have a greater impact on the developing child and at what exposure.
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Animal studies can provide information on the variability of chemical sensitivity.19 For example, some anesthetics are unable to anesthetize newborn animals at exposures that anesthetize adults, whereas ether alters reflexes at lower concentrations in newborn animals than in adults.25 Newborn mice and other animal species have demonstrated a tolerance to hypoxic conditions that is not present in adult animals,26–30 and newborn mice continue to breathe for a longer period when exposed to ether than adult mice.31 Newborn mice also have a prolonged survival when compared with adults when asphyxiated as a result of exposure to CO, HCN, CO2, H2, and CH3. Longer exposures to strychnine, curare, cyanide injection, strangulation, hypoxia, or nitrobenzol are necessary to produce respiratory arrest in newborn mice as compared with adult mice.29
In a summary of much of this animal information, Done32 was cautious, pointing out the multiplicity and variability of experimental details in these studies. He concluded, "Some tentative generalizations and observations may be worth making... . It is apparent that immaturity does not necessarily entail greater sensitivity."
Another example in which infant animals are protected relative to adults is thiourea, which is 50 to 400 times as toxic in the adult as in infant rats.33,34 Conversely, animal experiments with chloramphenicol clearly demonstrate that this drug is more toxic in the infant rat than in the adult, providing animal toxicity studies that corroborate the toxicity reported in human infants.35–37 In Done’s review of developmental toxicology,32 he indicated that the newborn or infant animal was more sensitive to many drugs (chloramphenicol, morphine, some other opiates, picrotoxin, tetracycline, novobiocin, some organophosphate anticholinesterases, atropine, histamine, and sodium salicylate) and less sensitive to others (ethanol, strychnine, Metrazol, codeine, acet-cycloheximide, thiourea, and thyroid hormone). Many other drugs have sensitivities that were similar in the neonate and the adult animal.
Tables 1 to 5 list a number of agents that are more toxic in the adult than in the infant and the child. There are many infections that produce more morbidity in adults than in children (eg, hepatitis, varicella, poliomyelitis). Drugs also may be more toxic or result in idiosyncratic effects in adults that occur rarely in children. For example, isoniazid produces hepatitis and methotrexate produces cirrhosis more frequently in adults.
Not only are adults sometimes more vulnerable than children, but also adolescents can be more vulnerable than infants and children. For example, a number of publications have indicated that exposure of adolescents to extensive and repeated radiology examinations increases their risk of developing breast cancer later in life.38 One might expect that infants would be more susceptible to radiation-induced breast cancer than adolescents; however, the developing and proliferating adolescent breast seems to be more sensitive to radiation-induced oncogenesis than the infant breast.
In the following presentations, you will read about the vulnerability and sensitivity of the infant, child, and adolescent. In many instances, environmental agents will exploit these vulnerabilities and sensitivities. In other instances, there will be no difference between the developing organism and the adult when exposed to toxicants, and in some instances, the developing organism may even withstand the exposures with less insult. The difficulty that we have at this time is that we do not have enough data to arrive at conclusions about the relative sensitivity of the developing organism to many environmental agents. Rather than hypothesize about environmental agents or exposures for which there are insufficient data, we need to initiate investigative approaches to obtain the necessary data concerning agents and exposures that have not been clarified. It is important that there be an increase in quality research in environmental toxicology.
In human epidemiologic studies, we need to know the exposure sustained by infants, children, adolescents, and adults to environmental agents. In some instances, an apparent increase in sensitivity may actually be because certain child behaviors result in higher exposures. After the intense efforts of individual scientists and regulatory agencies in the United States, the exposures to lead and PCBs are dropping,39 but that is not so with many other toxicants. The situation in the rest of the world varies considerably. Although some parts of Western Europe also have decreased their population’s exposure to lead and PCBs, exposures have not been reduced in many third-world countries. Improving our epidemiologic surveillance is important to quantify more accurately the risks of environmental toxicants and any change in risks after interventional programs. With limited resources, we must invest in research and interventional programs that will have the greatest likelihood of success and the potential for affecting the most individuals.
What can we do to improve our knowledge of the risk of environmental toxicants for children? What information would be helpful to clinicians to assist them in understanding the complexity of the situation? Why are there scientists and clinicians who denigrate and others who exaggerate the impact of environmental toxicants on children as well as all humans?
We propose the following:
- Rigorous methods must be used to evaluate environmental risks.40–43 Diverse opinions occur because some scientists reach conclusions without adequate data. Single epidemiologic studies do not refute or demonstrate causality. The most important criteria to permit conclusions from epidemiologic studies are consistent, biologically plausible findings across a number of studies. Causality must be determined by a) epidemiologic studies; b) secular trends or ecological trends; c) mammalian animal toxicologic studies; d) pharmacokinetic and toxicokinetic studies; e) method-of-action studies; and f) biological plausibility: specificity, nature of the effect, receptor affinity, organ selectivity, stage of development, multiple causality, in vitro studies, etc.
- Information on children’s exposure to a wide range of environmental agents and how these exposures are changing over time must be improved.
- Epidemiologic research dealing with environmental agents and using modern techniques of pharmacokinetics and toxicokinetics must be expanded. It is very difficult to determine toxic exposure levels, NOAEL, or therapeutic levels either in humans or from animal studies without the use of pharmacokinetics and toxicokinetics.
- A national surveillance system, monitoring changes over time, must be created to determine the prevalence of a wide range of diseases and rapidly identify unusual clusters of conditions in children and in adults.
- Whenever possible, animal studies at different stages of development should be included in the body of research on which we base public health and clinical policy and practices. It also is essential that we acknowledge the danger of generalizing findings across species.
- Competent environmental epidemiologists should focus on the special vulnerabilities of developing children.
- Physicians should be educated about the safe and toxic levels of chemicals and drugs to evaluate individual patients or perform epidemiologic studies.
- We must counter the individuals who zealously exaggerate or denigrate the risks of environmental toxicants and drugs with data from rigorous scientific studies that treat each environmental agent as a separate entity with regard to its risks and benefits.
It is our hope that this volume will assist pediatricians, other health care workers, toxicologists, epidemiologists, and environmental health experts to understand our current state of knowledge about children’s unique vulnerabilities and resistance to environmental agents. We also hope to encourage the investigations and activities of our many colleagues to determine the variable risks of these agents for the purpose of preventing or reducing environmentally produced diseases.
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FOOTNOTES |
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Received for publication Oct 7, 2003; Accepted Oct 20, 2003.
Reprint requests to (R.L.B.) Rm 308, R/A, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail: rbrent{at}nemours.org
Dr Brent’s research support has been derived from government research grants from NIH, DOE, and AEC. He has never received research funds from industry and is presently supported by his own institution, the Nemours Foundation. He has been a consultant to Congress, AAP, NIH, FDA, CDC, and industry in his area of expertise, environmental causes of reproductive pathology and oncogenesis. He is a consultant to the Health Physics Society’s Web site, "Ask the Expert," and counsels, at no fee, 
600 consultations each year. He has been an expert witness to the courts in the Bendectin and progestational drug lawsuits as a defense expert, the former resulting in the important Daubert decision, as well as other nonmeritorious litigation involving allegations of teratogenicity. He was one of the experts who volunteered to provide expert testimony in litigation against the alcoholic beverage industry to have all alcoholic beverages provide a warning for pregnant women. All of the fees for consulting were deposited in medical school departmental accounts and more recently in a philanthropic fund. He did not accept any fees from EPA for editing this supplement.
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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