3
Perinatal and Pediatric Toxicity

BOTH ACUTE AND CHRONIC toxic reactions in the young are often considered together under the title of developmental toxicity. Such toxicity can be further subdivided by the organ system involved or by whether the toxic effect occurred before or after birth. The developmental purview of the committee extends from the beginning of the third trimester through 18 years of age; however, no single theoretical framework or unifying set of principles readily applies to so broad a developmental span. Teratology, the study of congenital malformations, has traditionally focused on the process of organogenesis, the sensitive period in prenatal development when birth defects can be induced by exposure to either endogenous (e.g., endocrine) or exogenous (e.g., xenobiotic) agents. One view of teratogenesis is that this type of abnormal development represents a special form of embryotoxicity.

Developmental toxicology includes the study of chemically induced alterations of the normal sequence of developmental processes. It both encompasses and expands the domain of abnormal development beyond that implied by teratology. Although the term denotes adverse chemical effects on development, its end points are not restricted to gross anatomical defects but encompass multiple expressions of abnormal outcome. This research specialty combines basic principles, concepts, and working assumptions from several disciplines, including developmental and cellular biology, pharmacology, and toxicology. A major objective is to understand how exogenous agents interfere with the normal progression of developmental events to produce phenotypically abnormal cells, tissues, organs, and function. Since this report's focus begins with the third trimester, the committee does not directly consider the teratogenicity of pesticides, i.e.,



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Pesticides in the Diets of Infants and Children 3 Perinatal and Pediatric Toxicity BOTH ACUTE AND CHRONIC toxic reactions in the young are often considered together under the title of developmental toxicity. Such toxicity can be further subdivided by the organ system involved or by whether the toxic effect occurred before or after birth. The developmental purview of the committee extends from the beginning of the third trimester through 18 years of age; however, no single theoretical framework or unifying set of principles readily applies to so broad a developmental span. Teratology, the study of congenital malformations, has traditionally focused on the process of organogenesis, the sensitive period in prenatal development when birth defects can be induced by exposure to either endogenous (e.g., endocrine) or exogenous (e.g., xenobiotic) agents. One view of teratogenesis is that this type of abnormal development represents a special form of embryotoxicity. Developmental toxicology includes the study of chemically induced alterations of the normal sequence of developmental processes. It both encompasses and expands the domain of abnormal development beyond that implied by teratology. Although the term denotes adverse chemical effects on development, its end points are not restricted to gross anatomical defects but encompass multiple expressions of abnormal outcome. This research specialty combines basic principles, concepts, and working assumptions from several disciplines, including developmental and cellular biology, pharmacology, and toxicology. A major objective is to understand how exogenous agents interfere with the normal progression of developmental events to produce phenotypically abnormal cells, tissues, organs, and function. Since this report's focus begins with the third trimester, the committee does not directly consider the teratogenicity of pesticides, i.e.,

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Pesticides in the Diets of Infants and Children their potential to produce gross structural malformations. Rather, the focus is on processes that occur after the completion of organogenesis and continue well into the postnatal period. However, the origins of this broader concern with peri- and postnatal toxicology are inextricably rooted in experimental teratology. Studies of the toxicity of xenobiotic compounds in children have demonstrated the potential for either acute or chronic exposure to result in serious malfunctions at a later age. This potential exists because of the developmental character of the physiologic/biochemical/molecular function of the young individual. While a biologic system is developing, a toxic event can alter one aspect of that development so that all subsequent reactions are altered or modified. For example, transient elevations of serum bilirubin during the newborn period may produce changes in the basal ganglia of the brain that may not become apparent until several years later but are then permanent in nature. ACUTE TOXICITY In this section, the committee discusses and summarizes the relative sensitivity of infants, children, and adults to the acute toxicity of chemicals. Acute toxicity here is defined as toxicity resulting from a single exposure to a chemical. The injury may be immediate or delayed in onset. Both lethality and target organ injury will be considered as toxic end points. A limited number of findings from studies of laboratory animals are summarized where data on humans are inadequate. Because of the meager data base on age-dependent acute toxicity of pesticides, some examples of pharmacologic effects and adverse effects of therapeutic agents in pediatric and adult populations are described. Attention is focused, in turn, on age-related differences in the lethality of pesticides and other chemicals, differential effects of cholinesterase inhibitors in immature and mature subjects, and age-related effects of toxic and pharmacologic actions of selected therapeutic agents. Data on age-related susceptibility to the lethal effects of chemicals are largely limited to acute LD50 studies in laboratory animals. Done (1964) was one of the first investigators to compile the results of LD50s and other measures of lethality of a variety of chemicals in immature and mature animals. Immature animals were more sensitive to 34 chemicals, whereas mature animals were more sensitive to 24 compounds. Thiourea was 50 to 400 times more toxic (i.e., lethal) in adult than in infant rats. Conversely, chloramphenicol was 5 to 16 times more toxic in 1- to 3-day-old rats. Thus, Done (1964) concluded that immaturity does not necessarily entail greater sensitivity and that age-dependent toxicity is chemical dependent. Goldenthal (1971) tabulated LD50 values for newborn and neonatal animals

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Pesticides in the Diets of Infants and Children as compared to adult animals primarily from data submitted by pharmaceutical firms in drug applications. Approximately 225 of these compounds were more acutely toxic (lethal) to neonates, whereas about 45 were more toxic to adult animals. Almost all the age-related differences in LD50s in the reports of Goldenthal (1971) and Done (1964) were less than 1 order of magnitude; indeed, most varied no more than two- to threefold. As discussed in Chapter 2, there are important differences between immature laboratory animals and humans. Nonprimate species are generally less mature at birth than are humans. Newborn mice and rats are among the most immature of commonly used test species, so it is not surprising that they often differ markedly from adult animals in sensitivity to chemicals. This phenomenon is particularly evident in the paper by Goldenthal (1971), who reported five times as many chemicals to be more acutely toxic to newborn than to adult animals. Since full-term human newborns are more mature, such pronounced age-dependent differences in toxicity would not be anticipated. Maturation in rodents is very rapid, so that even a few days of age can result in a marked disparity in test results (Done, 1964). Furthermore, organs and their associated functions mature at different rates in different species. Uncertainty in extrapolating findings among different species of mature animals is appreciable. When the additional variable of interspecies maturation patterns is introduced, the choice of an appropriate animal model for pesticide toxicity of neonates, infants, and children becomes even more complex. The relative acute lethality of pesticides to immature and mature animals has been the subject of a number of studies. Goldenthal (1971), in his extensive compilation of LD50 values for newborn and adult animals, included several fungicides, herbicides, and the insecticide heptachlor. Each of these compounds was more toxic to newborn than to adult rats. Gaines and Linder (1986) more recently contrasted the acute toxicity of 36 pesticides given orally to weanling (4 to 6 weeks old) and to young adult Sherman rats. Age-related differences, where they existed, were usually no more than two- to threefold. Weanlings were more sensitive than adults to only 4 of the 36 compounds. Lu et al. (1965) observed that 14- to 16-day-old rats were intermediate between newborns (most sensitive) and adults (least sensitive) in their susceptibility to malathion poisoning. Such findings are in agreement with the observation that physiological and biochemical processes, which govern the pharmacodynamics of pesticides, mature quite rapidly in rodents. Indeed, metabolism and renal clearance of xenobiotic compounds and their metabolites soon approach and may exceed adult capacities in rodents within 2 to 3 weeks. This same phenomenon occurs in humans, albeit at a somewhat slower pace (i.e., within the first weeks to months of life). Higher metabolism

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Pesticides in the Diets of Infants and Children may confer protection against pesticides or increased susceptibility to injury, depending on the relative toxicity (and rate of elimination) of the parent compound compared to its metabolites. The findings of Lu et al. (1965) are a good case in point. These investigators contrasted acute oral LD50 values for newborn, 14- to 16-day-old, and young adult Wistar rats. The adult animals were the most resistant to malathion, as would be anticipated, since adult rats most efficiently metabolize organophosphates and organophosphates are metabolically inactivated (Benke and Murphy, 1975). Conversely, the older rats of Lu et al. (1965) were the most sensitive to the acute toxicity of dieldrin. Thus, susceptibility to acute pesticide toxicity appears to be a function of age, species, and chemical. Limitations of acute lethality data should be recognized. Acute doses of chemicals high enough to cause death may damage organ systems by mechanisms that are quite different from those that produce biological effects from chronic exposures to lower levels. MacPhail et al. (1987) examined age-related effects of a number of pesticides on lethality, serum chemistry, and motor activity in weanling and adult male rats. Although age was generally not an important determinant of toxicity for most of the pesticides, there were age-related differences in the effects of carbaryl and diazinon on motor activity. These results could not have been predicted on the basis of LD50 values for the two groups, leading MacPhail et al. (1987) to conclude that mortality may be a poor predictor of morbidity and that nonlethal end points should be used to assess the age-dependency of the neurobehavioral toxicity of pesticides. More sensitive indices should also be used to monitor other potentially vulnerable systems in infants and children, including the hormonal and reproductive systems, the immune system, the nervous system, developmental effects, and carcinogenesis/mutagenesis. Unfortunately, relatively few well-controlled studies have been conducted, particularly in humans, in which sensitive end points are used to assess the relative toxicity of comparable doses of pesticides or other chemicals in pediatric and adult populations. Cholinesterase inhibition, a mechanism by which organophosphate and carbamate insecticides produce excessive cholinergic effects, is a sensitive end point that can be monitored in humans and other mammals. Brodeur and DuBois (1963) reported that weanling (23-day-old) rats were more susceptible than adults to the acute toxicity of 14 of 15 organophosphates tested. The greater toxicity of parathion in weanling rats was tentatively attributed to deficient hepatic detoxification of parathion and its bioactive oxygen analogue, paraoxon (Gagne and Brodeur, 1972). A comprehensive investigation was reported by Benke and Murphy (1975) in five age groups of male and female Holtzman rats: 1, 12 to 13, 23 to 24, 35 to 40, and 56 to 63 days old. There was a progressive decrease in susceptibility to poisoning by parathion and parathion-methyl with increasing age up to

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Pesticides in the Diets of Infants and Children 35 to 40 days for both sexes. Detailed experiments were conducted to determine the influence of aging on metabolic activation of the two compounds, as well as on detoxification systems (e.g., aryl esterase-catalyzed hydrolysis, glutathione-dependent dearylation and dealkylation, and binding in the liver and plasma). Benke and Murphy (1975) concluded that increased detoxification of the active oxygen analogues of parathion and parathion-methyl was largely responsible for the lower acute toxicity of the two insecticides in adult animals. Murphy (1982) subsequently pointed to two other factors that contributed to the lower sensitivity of adult rats to organophosphates: greater binding to noncritical tissue constituents and more rapid catabolism of the parent compounds. The limited information available suggests that immature humans also experience greater susceptibility to organophosphate- and carbamate-induced cholinesterase inhibition and related effects. In 1976 in Jamaica, 79 people were acutely poisoned as a result of eating parathion-contaminated flour (Diggory et al., 1977). Seventeen of the patients died. Case-fatality ratios were highest (i.e., 40%) among children ranging from newborns to 4 years of age. Zwiener and Ginsburg (1988) presented the clinical histories of 37 infants and children exhibiting moderate to severe organophosphate and carbamate toxicity. Although most of these patients ingested the pesticides, six became intoxicated after playing on sprayed surfaces. Zwiener and Ginsburg (1988) noted that 76% of their subjects were younger than 3 years old. The investigators found there was a paucity of information in the literature on the toxicity of cholinesterase inhibitors in infants and children. Parathion contamination of stored foodstuffs (Diggory et al., 1977) and aldicarb contamination of crops (Goldman et al., 1990) have resulted in the most widespread outbreaks of foodborne pesticide toxicity in North America. Goldman and co-workers investigated more than 1,000 cases of illness caused by consumption of aldicarb-contaminated watermelons and cucumbers. Unfortunately, infants and children were not studied as a subpopulation at risk. The investigators did calculate doses of aldicarb sulfoxide that produced illness in the general population and estimated that a 10-kg child could readily consume enough of the pesticide on watermelons to experience toxicity. The U.S. Environmental Protection Agency (EPA, 1988) concluded that infants and children are at the greatest risk of acute aldicarb toxicity. This conclusion was based on dietary consumption and contamination patterns, however, rather than on the greater sensitivity of infants and children to this potent cholinesterase inhibitor. Although immature humans appear to be more susceptible than adults to the acute effects of cholinesterase inhibitors, the age-dependency of this phenomenon is not entirely clear. Some of the most applicable information has been provided by a study of the perinatal development of

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Pesticides in the Diets of Infants and Children human blood esterases (Ecobichon and Stephens, 1973). Erythrocyte acetylcholinesterase and plasma pseudocholinesterase and arylesterase activities were measured in premature newborns of varying gestational age as well as in full-term newborns, children of different ages, and adults. Apparent Km values for the three enzymes did not vary significantly with age for a variety of substrates, indicating that the enzyme properties were similar in all age groups. Enzymatic activity, however, did vary significantly with age. Levels of all three enzymes progressively increased during gestation, then rose markedly during the first year of life. Thereafter, erythrocyte cholinesterase and pseudocholinesterase activities increased gradually to adult levels. If one were to assume that one of these peripheral enzymes (e.g., erythrocyte cholinesterase) reflects brain acetylcholinesterase levels, then the most pronounced effects of cholinesterase inhibitors may be expected to occur in newborns, neonates, and infants, since a chemically induced depression of enzymatic activity may be more apparent when baseline cholinesterase levels are relatively low. Ecobichon and Stephens (1973) provided evidence of another mechanism of increased susceptibility of newborns—namely, diminished detoxification capacity (i.e., significantly lower plasma arylesterase and paraoxon hydrolysis activities). Children 2 to 8 years old had slightly lower activities than adults, suggesting that younger children may be somewhat more susceptible to cholinesterase inhibitors. The consequences of brain acetylcholinesterase inhibition on nervous system development and postnatal function remain largely unexplored. Because of the paucity of data on the age-dependency of acute toxicity of pesticides in humans, the remainder of this section focuses on relative effects of therapeutic agents in pediatric and adult populations. Substantially more information should be available on drugs, due to their common use in all age groups and stringent requirements by the Food and Drug Administration (FDA) for demonstration of safety and efficacy. Data from well-controlled, parallel studies in infants, children, and adults, however, are quite limited for most drugs. Done et al. (1977) reported what was termed a therapeutic orphan problem—namely, that safety and efficacy for children had not been proved for 78% of new drugs then marketed in the United States. A 1990 survey by the American Academy of Pediatrics revealed that the labeling of 80% of new drugs approved by the FDA between 1984 and 1989 did not include information on pediatric use. The FDA's policy has allowed the marketing of drugs that have been approved for adults but not studied in children, as long as labeling included disclaimers and no instructions about pediatric use. Without adequate information, physicians commonly prescribe such medications for children, possibly placing pediatric populations at increased risk of uncertain efficacy or adverse reactions.

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Pesticides in the Diets of Infants and Children The FDA (1992) proposed to amend labeling requirements for prescription drugs to promote their safe and effective use in children. Misunderstandings and concern about legal and ethical implications have limited clinical research in pediatric populations. The newly proposed guidelines provide alternative ways to assess effectiveness and safety in children without necessarily having to conduct comprehensive studies. Results from well-controlled studies in adults can be extrapolated to children under some circumstances, although separate pharmacokinetic studies are needed to establish appropriate pediatric dosage regimens. The intent of the proposed amendment is to provide more complete information on labeling of prescription drugs concerning use and possible hazards for children. Several instances of severe adverse effect from pharmaceutical agents in pediatric populations have attracted widespread attention. During the 1950s, chloramphenicol produced a pallid cyanosis, which progressed to circulatory collapse and death in some newborns (Sutherland, 1959). This so-called gray baby syndrome has been attributed to the diminished hepatic glucuronide conjugation and renal secretory capacities of newborns. Weiss et al. (1960) reported blood half-lives of 26, 10, and 4 hours for chloramphenicol at birth, at 10 to 16 days of age, and in children 4 to 5 years old, respectively. Thus, there is a substantial increase in chloramphenicol metabolism and excretion capacity during the first days and weeks of life. Decreased metabolic and excretory capacities of newborns and neonates have been associated with exaggerated toxicity of a number of other chemicals, including benzyl alcohol (Gershanik et al., 1982), hexachlorophene (Tyrala et al., 1977), and diazepam (Nau et al., 1984). The hexachlorophene poisonings appeared to be associated with increased percutaneous absorption as well as deficient metabolism in newborns. Floppy infant syndrome in babies born to mothers given diazepam is apparently the result of a number of age-dependent factors, including a smaller volume of distribution and thus greater target organ concentrations of the lipophilic drug due to a smaller adipose tissue volume in newborns, increased amounts of free diazepam due to displacement of the drug from plasma protein binding sites by elevated free fatty acid levels, and a prolonged half-life as a result of diminished oxidative and conjugative metabolism (Warner, 1986). As discussed in Chapter 2, most physiological processes that govern the kinetics of drugs and other chemicals mature during the first year after birth. Indeed, profound changes in some processes (e.g., phase I and II metabolism) occur during the first days and weeks of life (Morselli, 1989). Thus, the most pronounced differences from adults in susceptibility to drug toxicity would be expected in newborns, neonates, and infants; the youngest are most likely to experience the most aberrant responses.

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Pesticides in the Diets of Infants and Children The net effect of immature physiological and biochemical processes on drug efficacy and toxicity is difficult to predict. The various processes mature of different rates and may enhance or offset one another. Local anesthetics provide a good illustration. These drugs are commonly administered to the mother during labor and delivery and may readily enter the maternal circulation and cross the placenta (Tucker and Mather, 1979). Cardiovascular depression and respiratory depression in newborns have occasionally been reported, although subtle neurophysiological impairment and behavioral changes are probably more common consequences (Dodson, 1976; Ostheimer, 1979). Premature and full-term newborns exhibit lower plasma protein binding of local anesthetics. This should result in increased amounts of free drug and a more pronounced pharmacologic response, but the greater volume of distribution in newborns reduces the concentration of drug at sites of action. Rates of hepatic microsomal metabolism and plasma pseudocholinesterase-catalyzed hydrolysis of anesthetics such as procaine are quite low in newborns. This deficit in metabolism, coupled with the larger distribution volume that must be cleared of drug, accounts for the prolonged half-life and long duration of action of lidocaine and its analogues in neonates (Morselli, et al., 1980). Hepatic metabolism and renal clearance of xenobiotic compounds change dramatically during the first year of life. Phase I metabolic reactions (e.g., oxidation) may rise from one-fifth to one-third of the adult rate during the first 2 to 3 postnatal weeks to two to six times the adult rate (Neims et al., 1976; Morselli, 1989). Different isozymes and enzymes mature at different ages. Certain phase II (e.g., glucuronidation) reactions do not reach adult levels for months, while maturation of alcohol dehydrogenase activity may take as long as 5 years (Kearns and Reed, 1989). The majority of xenobiotics, however, are metabolized most rapidly by individuals between 2 to 4 months and about 3 years of age. Thereafter, drug metabolism gradually declines to adult levels (Warner, 1986). Development of renal function displays a similar age-dependency. Glomerular filtration increases dramatically during the first week of life, approaching and exceeding adult values within 3 to 5 months. Renal tubular secretory and absorptive processes mature more slowly (Kearns and Reed, 1989). Older infants and children, therefore, may be less susceptible than adults to drugs that are metabolized to less toxic, more readily excretable metabolites. Spielberg (1992) noted that clearance of nearly all anticonvulsant drugs is quite limited in newborns, especially premature newborns. Conversely, clearance of such drugs (e.g., phenytoin, phenobarbital, carbamazepine, and diazepam) in infants and children, when calculated on a milligram-per-kilogram-of-body-weight basis, was well above that in adults until around puberty. Thus, children are less likely than adults to exhibit toxicity and require higher doses (on a milligram-per-kilogram-

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Pesticides in the Diets of Infants and Children of-body-weight basis) of anticonvulsants to achieve therapeutic levels. In contrast, infants and children may be at greater risk from other drugs and chemicals that undergo metabolic activation (i.e., conversion to bioactive or cytotoxic metabolites). Unfortunately, there is lack of information on such agents in humans in the published literature. There was concern that acetaminophen (Tylenol), a drug that undergoes metabolic activation to hepatocytotoxic metabolite(s) via a P-450-mediated mixed-function oxidase (MFO) pathway, would cause increased morbidity and mortality in young children. This concern was never realized, however, since hepatotoxicity in young children was found to be less severe than in adults, and has rarely (Rumack, 1984). Acetaminophen is metabolized by several parallel pathways. The two major detoxification pathways involve conjugation of the parent compound with sulfate or glucuronide. Thus only a small fraction of the drug remains to be oxidized by the P-450-mediated pathway to a reactive intermediate (N-acetyl-p-benzoquinonimine). This metabolite is conjugated with glutathione to produce nontoxic products or can bind covalently to cell proteins and nucleic acids, causing cellular injury (Hinson et al., 1990). Although prepubescent children have relatively high hepatic MFO activity, they also exhibit a greater capacity than adults to detoxify acetaminophen by phase II metabolic reactions, primarily sulfate conjugation (Miller et al., 1977). Also, higher glutathione levels in the young may contribute to protection from hepatotoxicity. Thus, the lower susceptibility of children to acetaminophen poisoning is due to their greater capacity to eliminate the drug by nontoxic pathways (Kauffman, 1992). Clinical trials in infants and children are relatively infrequent for most classes of drugs, but this is not the case for many antineoplastic agents. Although some types of childhood cancer are refractory to chemotheraphy, others have excellent cure rates (Petros and Evans, 1992). Therefore, phase I clinical trials are frequently conducted in both adult and pediatric populations to define the maximum tolerated dose (MTD) for appropriate dosage schedules in phase II trials. Antineoplastic agents include a wide variety of different types of chemicals that act by diverse mechanisms. Thus, results of phase I studies of anticancer drugs afford scientists some of the most comprehensive data sets for contrasting toxic effects of chemicals in children and adults. The investigations typically involve repetitive dosage regimens lasting days or weeks, however, rather than single, acute exposures. Comparable clinical trials of antineoplastic agents in pediatric and adult patient populations have revealed toxic effects that are often similar qualitatively but different quantitatively (Glaubiger et al., 1982; Marsoni et al., 1985; Evans et al., 1989). In compilation of data on 16 compounds for which there had been comparable phase I trials in adults and children,

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Pesticides in the Diets of Infants and Children TABLE 3-1 Maximum Tolerated Dose (MTD) of Some Anticancer Drugs in Children and Adults   MTD (mg/m2) Drug Children Adults Ratio, MTD for Children/ MTD for Adults Dianhydrogalactitiol 25 30 0.83 5-Azacytidine 200 225 0.89 TIC mustard 900 1,000 0.90 Piperazinedione 3 3 1.0 VP16-213 150 125 1.20 Diglycoaldehyde =7,500 6,000 1.25 m-AMSA 50 40 1.25 Daunomycin (mg/kg) 1.0 0.8 1.25 Adriamycin (mg/kg) 0.8 0.6 1.33 VM-26 (mg/kg) 4.0 3.0 1.33 3-Deazauridine (leukemia patients) 8.2 6.0 1.40 Azaserine (mg/kg) (total dose) 156 108 1.44 Anhydro-5-flouro-cyclocytidine =300 =200 1.50 Dihydroxyanthracenedione 18 12 1.5 3-Deazauridine (solid tumors) 2.8 1.5 1.85 Cyclocytidine 600 300 2.00 ICRF-187 >2,750 1,250 >2.20   SOURCE: Glaubiger et al., 1982. the types of toxic effects that limited further dosage escalation were generally the same (Glaubiger et al., 1982). As shown in Table 3-1, the MTD for children was higher than that for adults for 13 of the compounds. Similar findings were reported by Marsoni et al. (1985). These investigators compared the MTDs and recommended phase II doses in children and adults for 14 drugs in patients with solid tumors and 8 drugs in patients with acute leukemia. Children with solid tumors exhibited a greater dose tolerance for 12 of the 14 drugs. Children with leukemia appeared to have tolerances similar to those of adults. Data on daunomycin in relation to the incidence of congestive heart failure in children and adults have been compiled. Children seem to be more sensitive than adults to this complication at comparable doses, even through the MTD is approximately 20% higher in children than in adults. The greater tolerance of children to many anticancer drugs may be attributable to higher rates of metabolic or renal clearance. Both Glaubiger et al. (1982) and Marsoni et al. (1985) expressed MTDs on a milligram-per-square-meter rather than a milligram-per-kilogram-of body-weight basis. Had the relative doses been calculated as milligram per kilogram, the interage differences should have been even more pronounced. Pinkel (1958) observed that pediatric patients tolerated more methotrexate on a

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Pesticides in the Diets of Infants and Children milligram-per-kilogram basis than did adults, but the MTDs were similar when calculated on the basis of body surface area. Methotrexate is eliminated primarily by glomerular filtration and active renal tubular secretion of the parent compound. It is not surprising, therefore, that children with relatively high renal function exhibit greater rates of plasma elimination than do adults (Wang et al., 1979). In a study of 47 patients (3 to 39 years old) receiving methotrexate, Bleyer (1977) found a significantly higher incidence of neurotoxicity in the adults. Conversely, young infants have diminished renal function and exhibit lower systemic clearance and a greater potential for injury than do children (McLeod et al., 1992). As maturation of xenobiotic metabolism and renal function generally parallel one another during the first year of life, it is not surprising that neonates and young infants may be at increased risk of injury from anticancer drugs that undergo metabolic inactivation. Vincristine is one such drug. It is detoxified in the liver and eliminated primarily via biliary excretion. Woods et al. (1981) reported a significantly higher incidence of neurotoxicity and hepatotoxicity in small infants than in children receiving vincristine. On the other hand, compounds that undergo metabolic activation may place children at greater risk than neonates or adults, since children have a higher metabolic capacity. Marsoni et al. (1985) observed that indicine N-oxide was one of the few anticancer drugs tested to have a lower MTD in children than in adults. Indicine N-oxide is believed to be converted to the toxic metabolite dehydroindicine by the liver. Cyclophosphamide is another drug that undergoes metabolic activation to cytotoxic metabolites. Certain of its metabolic pathways, however, also involve inactivation/detoxification. The half-life of cyclophosphamide is shorter in children (1 to 6.5 hours) than in adults (4 to 10 hours) (Crom et al., 1987). Although metabolic activation of drugs such as cyclophosphamide may be highest in children, the operability of concurrent detoxification pathways and inactivation of the reactive metabolites, coupled with rapid urinary excretion of the metabolites, apparently combine to hasten the elimination and thereby to negate expression of greater toxicity in children. Because of the rapid increase in human immunodeficiency virus (HIV) positive children and the significant morbidity and mortality of the resultant disease, drugs for HIV treatment are being tested in both pediatric and adult populations. One of the most widely tested anti-HIV drugs is azidothymidine (AZT, Restrovir). McKinney et al. (1991) studied the effects of AZT in 88 children (mean age, 3.9 years; range, 4 months to 11 years). Maha (1992) reported that the efficacy and incidence of side effects (e.g., hematological abnormalities, primarily neutropenia) were similar in both adults and children but noted that the mean duration of therapy was

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