Pesticides in the Diets of Infants and Children (1993) / Chapter Skim
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3 PERINATAL AND PEDIATRIC TOXICITY
3 PERINATAL AND PEDIATRIC TOXICITY
Pages 49-126
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From page 49... ...
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.
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From page 50... ...
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.
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From page 51... ...
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.
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From page 52... ...
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~.
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From page 53... ...
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)
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From page 54... ...
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.
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From page 55... ...
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 (Wamer, 1986~.
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From page 56... ...
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.
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From page 57... ...
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.
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From page 58... ...
The greater tolerance of children to many anticancer drugs may be attributable to higher rates of metabolic or renal clearance. Both Glaubiger et al.
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From page 59... ...
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.
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From page 60... ...
These critical periods or windows of vulnerability must be seriously considered when evaluating neurotoxic effects. Because human brain development continues for years after birth, it can be hypothesized that postnatal exposure to xenobiotic compounds would alter the structure or function of the human nervous system.
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From page 61... ...
The expansion of the knowledge base, particularly the refinement of animal models, is an important first step. Measuring Neurotox~c Effects in Humans Techniques for measuring neurotoxic effects attempt to match the various types of neurologic functions (Bondy, 1986; Triebig et al., 1987; Weiss, 19881.
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From page 62... ...
During the 1980s, neurobehavioral and neurotoxic effects of lead exposure were found in children and in the human fetus at progressively lower levels of exposure (Moore et al., 1982; Needleman, 1983; Winneke et al., 1985; Bellinger et al., 1986; Mayer-Popken et al., 1986; Dietrich et al., 1987; Ruff and Bijur, 19891. Exposure levels resulting in blood-lead levels less than 20 ,ug/dl were implicated.
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From page 63... ...
and in studies of adult animals (Overstreet, 1984~. The evidence on chronic effects, particularly neurobehavioral effects of
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From page 64... ...
However, when animal studies have shown that a pesticide functions by disrupting neurologic cellular function and when systemic toxic effects are known to occur after high-level acute exposures, the possibility of low-level chronic neurotoxic and behavioral effects must be considered. Effects of Pesticides in Children In reviewing the data on the effects of pesticides, two questions must be addressed: Is there evidence that pesticides cause neurotoxic effects in children after acute exposure to high doses?
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From page 65... ...
Comparability of Neurotoxicity Ejects In Laboratory Animals An evaluation of the accuracy with which adverse effects are detected across species (Stanton and Spear, 1990) was included in the proceedings of a workshop on "Similarities and Differences Between Children and Adults: Implications for Risk Assessment," sponsored by the International Life Sciences Institute (Kimmel et al., 1990~.
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From page 66... ...
Because the immune system is not fully developed until adolescence, immunotoxic effects of environmental exposure in children and adults may differ. Elects of Environmental Agents on the Immune System Environmental agents may affect the immune system in a variety of ways.
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From page 67... ...
Depression of red blood cell cholinesterase activity correlated with the immune suppression to show dose response. Oral ingestion of lindane- and carbaryl-containing food increased antibody production in response to the antigenic stimulus, sheep red blood cells, in mice.
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From page 68... ...
In laboratory animals, the immune system appears to be a sensitive target organ. Immunosuppression is characterized by depressed cell-mediated immunity, which is most evident after perinatal exposure during the period of thymic organogenesis.
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From page 69... ...
Adult women from 18 to 70 years of age were examined for immune status in 1985. The 23 women who consumed the contaminated groundwater were compared for health status, immune function, and fluid intake with 27 who consumed water with no known contamination.
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From page 70... ...
Carc~nogenesis In the Developing Organism Animal Studies Comparisons of tumor incidence observed in rodents at the same age and at the same dose rate but after different exposure durations indicate that tumor incidence is not solely a function of total accumulated lifetime dose but may depend on age at first exposure as well (Gaylor, 1988~. This conclusion is supported by the observations of Toth (1968)
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From page 71... ...
There are likely to be a multitude of factors in addition to age and rates of cell proliferation that modulate carcinogenesis. Increased susceptibility to carcinogenesis at younger ages, when it occurs, may be attributable to two factors: increased rates of cell proliferation and differing metabolic capabilities.
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From page 73... ...
73 be so o _ .~ ~ o Go _ Go as - v _: o ~ ~ a, so An: ._ ~ an, _ _ C; ° , JO oo Cal .
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From page 74... ...
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From page 75... ...
No study has been performed to determine whether similar treatment of adults has the same outcome, however, so it is not possible to conclude that children are more susceptible to chemically induced carcinogenesis on the basis of these limited data. Evidence from epidemiologic studies is thus inadequate to demonstrate a consistent increased susceptibility to carcinogenesis among children, nor would one assume that children would regularly be more susceptible to toxic end points in pesticide toxicity.
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From page 76... ...
. Consideration in this section is largely limited to information from studies in humans, since there are major difficulties in extrapolating from immature animals to immature humans.
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From page 77... ...
There is little evidence to suggest that percutaneous absorption of chemicals varies greatly with age during the preadolescent period, since the overall thickness of the stratum corneum remains relatively constant throughout postnatal development (Rasmussen, 1979~. There is a paucity of information, however, from well-controlled studies on percutaneous absorption of chemicals in this age group.
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From page 78... ...
, suggesting that this very early age group could be at increased risk of toxicity from direct skin contact with pesticides. Several factors may contribute to increased percutaneous absorption
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From page 79... ...
For example, the effect of increased respiratory volume may be offset by the infant's smaller surface area for absorption. Unfortunately, little information is available on the pulmonary absorption and bioavailability of xenobiotic compounds in infants and children.
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From page 80... ...
Absorption depends on the physical and chemical properties of the pesticide, as well as on conditions within the gastrointestinal tract itself. Some of the more important conditions, or factors, include gastric emptying and intestinal motility, gut flora, acid and enzyme secretory activity, mucosal structure and surface area, cellular transport systems, and gastrointestinal blood supply.
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From page 81... ...
. The period of macromolecular uptake varies in laboratory animals, from as short as 1 to 2 days after birth in guinea pigs to as long as 23 to 24 days in rabbits (Hoffmann, 1982~.
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From page 82... ...
Although there is a paucity of data on absorption of drugs as related to age in human neonates and infants, some definitive investigations have been conducted using laboratory animals. Hoffmann (1982)
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From page 83... ...
Subsequent studies demonstrated that young children had higher lead blood levels than adults living with the children (Barltrop et al., 1974; McNeil et al., 1975~. Research findings for both laboratory animals and humans indicate that increased absorption and retention of lead are important factors in the relatively high incidence of lead toxicity in the young.
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From page 84... ...
found that the blood supply to the gastrointestinal tract of rats changed with age. Fractional blood flow to the total gastrointestinal tract decreased from 20% in 20-day-old rats to 8% to 12% in adult animals.
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From page 85... ...
These include plasma protein binding, extracellular fluid volume, adipose tissue mass, organ blood flow, tissue uptake, and tissue binding. The factors exert their influence concurrently and may compete with one another.
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From page 86... ...
, and it is known that during the perinatal period there is a decrease in plasma protein binding. There appear to be four primary reasons for this decrease.
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From page 87... ...
The extent of plasma protein binding can have a major impact on the magnitude and duration of chemical action and toxicity. Diminished binding, as mentioned previously, results in higher concentrations of free drug available for diffusion from the blood to sites of action in target tissues and sites of metabolism and/ or excretion.
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From page 88... ...
This resistance can be attributed to the distribution of these small, highly ionized molecules in the relatively large extracellular fluid volume, which in effect reduces their concentration and their resulting pharmacologic action. Penicillins have a higher volume of distributions in neonates because of lower plasma protein binding and higher extracellular water content.
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From page 89... ...
It is argued that children exhibit neurological disturbances at lower blood lead concentrations than adults, suggesting that lead enters the central nervous system of children in larger amounts (Barltrop, 1982~. Although data on humans are lacking, laboratory studies show that heavy metals accumulate in the brain of immature animals in much greater amounts than in adults Jugo, 1977; Kostial et al., 1978~.
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From page 90... ...
Investigations have shown greater whole body retention, elevated blood levels, and higher target organ concentrations in young animals than in older animals given heavy metals by injection (Kostial et al., 1978; Wong and Klaassen, 1980~. Possible explanations for these age-related differences include diminished excretory capacity, high growth rates and high rate of protein synthesis, altered binding to proteins and other ligands in tissues, higher extracellular fluid volume, and greater permeability of tissue barriers in the immature organism.
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From page 91... ...
In contrast, mixed-function-catalyzed oxidation of a number of other drugs increases rapidly during the first days of life, soon approaching and exceeding adult values (Neims, 1982~. Thus, the ontogeny of metabolism of the xenobiotic compounds, and its implications in toxicology, is quite compound-specific.
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From page 92... ...
The researchers found that the proportion of individual metabolites varied until an adultlike metabolite pattern was reached at 7 to 9 months. The toxicological implications of age-dependent qualitative differences in the metabolism of xenobiotic compounds are for the most part unknown.
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From page 93... ...
Levels of cytochrome P-450 and other monooxygenase components appear to remain relatively constant through parturition. Measurements at term have shown that P-450 levels and NADPHcytochrome c reductase activity are each about 50% of adult values (Aranda et al., 1974~.
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From page 94... ...
are low. The gradual decline in metabolism to adult levels at puberty parallels the increase in sex steroids accompanying maturation.
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From page 95... ...
Developmental changes in glomerular filtration rate parallel changes in renal blood flow (Lorenz and Kleinman, 1988~. Glomerular filtration rate in premature newborns may be as low as 5.0% of that in adults, whereas in full-term newborns it is typically 30% to 40% of adult values.
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From page 96... ...
They are primarily eliminated by glomerular filtration. Total body clearance values for premature newborns are only about 5% of adult values, whereas full-term newborn values are about 10% to 30% of the values of adults.
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From page 97... ...
Other Effects of Body Size Another way to scale dosages of xenobiotic compounds between large and small animals is on the basis of some function of body size other than weight. The growth rate varies from organ to organ or component to component in relation to increases in body size.
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From page 98... ...
Total energy expenditure involves the energy required for resting metabolism, for diet-induced thermogenesis, and for physical activity. The total expenditure of energy is the overall metabolic rate, and this can be closely approximated by the total energy intake when body weight is relatively stable.
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From page 99... ...
Infants, children, and adults, just as immature and mature animals of other species, differ from each other in stages of functional development of individual organ systems, the processes of growth, and maturation of enzyme systems involved in the metabolism of xenobiotic compounds, as well as in their metabolic rates expressed on a weight or surface-area basis (see Table 3-5~. Compounds such as chloramphenicol, which is poorly detoxified in the newborn (Calabrese, 19781; acetaminophen, which is excreted primarily as a sulfate conjugate in the young and as a glucuronide in the adult (Sonawane,1982~; isoniazid, which is acetylated at a reduced rate in the newborn (Nyhan, 1961~; and caffeine, which is poorly biotransformed in the infant (Neims, 1982)
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From page 100... ...
100 ·5 o ._ Cat ¢ Cat Cot _` do ._ ._ a, o in a, .~ cn ¢ Lo V]
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From page 101... ...
, whose calculations of the dosage of lysergic acid needed to produce the condition called musth in the male elephant were as follows: Based on body weight, elephant versus cat Based on metabolic rate, elephant versus cat Based on body weight, elephant versus human Based on metabolic rate, elephant versus human Based on brain weight, elephant versus human = 297 mg 80 mg 8 mg 3 mg - 0.4 mg Another problem arises when one considers whether compounds are metabolized to less toxic or to more toxic substances in the liver. This difference is of particular importance in extrapolation from one animal
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From page 102... ...
The significance of this concept for pesticide toxicology is that the hepatic metabolism of many xenobiotics in the mature human subject will occur at a reduced rate when compared to the rates in other mature animals even when corrected for scaling difference. It remains uncertain at this time how the problem of neoteny applies to immature animals.
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From page 103... ...
In acute toxicity, for example, if the toxicity depended on peak concentration, comparable dosage would be on a simple weight basis because volumes of distribution based on body water compartments are more closely related directly to weight than to surface area or metabolic rate. Even under such circumstances, differences in rates of absorption, extent of protein binding,
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From page 104... ...
104 cn $ x :~ 'c up ¢ o u)
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From page 105... ...
In chronic exposures, the differential rate of development of metabolizing enzymes such as glucuronyl transferase and the P-450-dependent mixed-function oxidases can have an impact on toxicity that is independent of overall metabolic rate. If the parent compound were the toxic substance, delayed enzymatic degradation would enhance toxicity.
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From page 106... ...
· Studies of the toxicity of xenobiotic compounds in developing mammals both laboratory animals and humans-demonstrate the potential for acute and chronic toxicity. Toxicity in the perinatal and pediatric periods is of special concern, since systems and structures under development at those times are important for survival over the lifetime of the mammal.
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From page 107... ...
Most laboratory animals are less mature than humans at birth, although maturation in animals is more rapid. In addition, various body structures and associated functions mature at different rates in different speaes.
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From page 108... ...
· Despite the difficulties in measuring effects, exposure to xenobiotic compounds has been found to alter CNS development at the anatomic and functional level. The alteration~in development can be irreversible, thus resulting in permanent loss of function.
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From page 109... ...
The committee recommends that a standard protocol for evaluation of immature animals be established and required as part of the basic assessment of pesticides for toxicity to immature animals. · Given the potential for lifelong effects following perinatal or pediatric toxicity, it is essential to develop toxicity testing procedures that specifically evaluate in appropriate animal models vulnerability during the developmental period and the adverse effects, if any, over the life of the animal.
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From page 110... ...
of the substance is, in fact, proportional to the an~mal's rate of metabolism, as is often the case, Men comparisons on a metabolic rate basis, on a surface area basis, or weighty basis would be reasonable. If surface area is used for adjusting from animals to humans, it should also be used for adjusting from infants to adults.
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From page 111... ...
1988. Anatomical and biochemical ontogeny of the gastrointestinal tract and liver.
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From page 112... ...
1963. Comparison of acute toxicity of anticholinesterase insecticides to weanling and adult male rats.
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From page 113... ...
1987. Low-level fetal lead exposure effect on neurobehavioral development in early infancy.
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From page 114... ...
1986. Acute toxicity of pesticides in adult and weanling rats.
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From page 115... ...
1971. A compilation of LD50 values in newborn and adult animals.
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From page 116... ...
1990. Special issue on qualitative and quantitative comparability of human and animal developmental neurotoxicity.
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From page 117... ...
1965. Toxicity of pesticides in young versus adult rats.
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From page 118... ...
1975. Evaluation of long-term effects of elevated blood lead concentrations in asymptomatic children.
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From page 119... ...
1984. Decreased serum protein binding of diazepam and its major metabolite in the neonate during the first postnatal week relate to increased free fatty acid levels.
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From page 120... ...
1971. Plasma protein binding of diphenylhydantoin in normal and hyperbilirubinemic infants.
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From page 121... ...
1975. 5,7-Dihydroxytryptamine induced changes in the postnatal development of central 5-hydroxytryptamine.
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From page 122... ...
Work group I report: Comparability of measures of developmental neurotoxicity in humans and laboratory animals. Neurotoxicol.
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From page 123... ...
Conference on the Qualitative and Quantitative Comparability of Human and Animal Developmental Neurotoxicity. Work Group III Report.
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From page 124... ...
1948. Glomerular filtration rate, effective renal blood flow, and maximal tubular excretory capacity in infancy.
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From page 125... ...
1985. Comparing the effects of perinatal and later childhood lead exposure on neuropsychological outcome.
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