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.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.This supplement to Pediatrics is being directed toward pediatric clinicians; thus, there are goals that are different from previous conferences, workshops, and publications. 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.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.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.29In 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: 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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Brent et al. (2004) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: