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From the spring of 1971 to September 1973, neighborhood surveys were conducted in 58 communities throughout the nation to determine whether children with confirmed elevated blood lead levels could be identified. Another purpose of these screenings was to assist communities in identifying children with elevated blood lead levels and thereby demonstrate to community officials that such children do exist in communities screened. The children screened were not a random sample.
In those communities where the initial elevated blood levels were confirmed all but seven had one or more children requiring followup and/or treatment. Of those children screened, black children had an elevated rate about three times as great as nonblack children.
With few exceptions, the homes in the neighborhoods had at least one interior surface with sufficient quantities of lead paint to be dangerous if the paint were ingested.
In the study of human populations, much emphasis is placed on the concentration of lead in whole peripheral blood. There is a considerable body of evidence which indicates that this measurement reflects recent and current assimilation of lead. While broad ranges in blood lead concentration have been associated with differing risks of toxicity for groups, it is not a precise index of adverse effect per se, even at elevated levels. Within the red blood cell itself there is not a close association between the concentration of lead and such adverse metabolic effects as the increased loss of potassium caused by lead. Above the apparent “threshold zone” of approximately 30–50 μg Pb/100 ml whole blood, equivalent metabolic effects on heme synthesis may be seen over an interval of at least 20 μg Pb/100 ml whole blood. This variation will be examined with particular reference to the interrelationship between the concentrations of lead and protoporphyrin in peripheral blood. The data indicate that limitations in both precision and accuracy of measurement account for a relatively small fraction of the observed variations. Together with other experimental and clinical information, they suggest that concurrent dietary deficiency of iron may be one of the important modifying factors in the responses of subjects with increased lead absorption. It is suggested that suspected adverse effects upon the various organ systems associated with increased lead absorption be measured directly and that the CaEDTA mobilization test for lead should be more fully explored as a measure of the “metabolically active” fraction of the total body lead burden.
Fifty-eight children with an increased lead burden underwent comprehensive investigations and were reevaluated 1½ to 3 years later. Of these children 23–27% were noted to have minor neurological dysfunction and various forms of motor impairment during each evaluation. While the initial psychological assessment revealed low average mental abilities in the majority of children, during follow-up examination a significant increase in certain areas of intellectual functioning was observed.
Hyperactive children were compared with a nonhyperactive control group on two measures that reflect the presence of body lead and on a lead exposure questionnaire.
The overall hypothesis that was tested was that a relationship exists between hyperactivity in children and a concommitant condition of increased body lead stores. Operationally, the hypothesis was reduced to a comparison of the hyperactive group and control group on the following measures: (1) blood lead levels; (2) post-penicillamine urine lead levels; (3) scores on a lead exposure questionnaire. The designation hyperactive or nonhyperactive was arrived at by using three different measurements: a doctor's diagnosis; a teacher's rating scale; a parent questionnaire.
Hyperactive children had significantly higher values on all three measures than did the controls. More than half the hyperactive children had blood lead levels in the range considered to be raised but not toxic, and 60% of post-penicillamine urine levels were in the “toxic” range.
It is concluded that there is an association between hyperactivity and raised lead levels, that a large body-lead burden may exact consequencies that have hitherto been unrealized; that the definition of what is a toxic level for blood lead needs reevaluation and that physicians should look for raised lead levels in children with hyperactivity.
Dentine lead levels were measured in 760 asymptomatic school children from two school districts, one considered high risk for lead exposure, one considered low risk. Elevated levels were found in black children living in deteriorated housing and in those white children from housing in good repair who lived and attended school in proximity to major manufacturer of paint and lead products.
The purpose of this study is to assess the nature and magnitude of the deleterious health effects of subclinical over-exposure to lead in children. The study stems from concerns about the impact on the health of children in city slums who ingest leaded paint without overt evidence of poisoning and the health implication of rising levels of lead in the environment from automotive emissions. The study sample was derived mainly from a registry of children on whom blood lead determinations had been made by the New York City Department of Health and was supplemented by siblings of the registry cases and children from a lead belt area who had extractions of deciduous teeth in dental clinics. Information was obtained through parental interview, medical records, and psychometric evaluation. The data show that deleterious health effects occur in children who were treated for severe lead poisoning and in children without diagnosed lead poisoning who had elevated blood leads (≥0.06 mg-%). In the absence of diagnosed lead poisoning or elevated blood leads, excess lead exposure, measured in terms of high levels of lead in teeth, was not associated with deleterious health effects.
A biphase program of screening and treating high-risk children for lead poisoning resulted in a 30% fall in mean lead values in the target areas over a 5-year period. The mean and median for subjects under 6 years was 4–10 μg/100 ml higher than for those over 6. Median for a high incidence area was 42 μg/100 ml in 1967 and 30.0 in 1971; for a low incidence area, 33 and 20 μg/100 ml in the equivalent years.
Ingestion of lead paint was observed or demonstrated by x-ray in 90% of 2200 patients treated in the Lead Clinic. Gross neurologic sequelae were limited to two cases of mild, persistent ataxia. Impaired intellectual performance was observed subsequently in several asymptomatic patients with initial blood lead levels (PbB) ≥ 100 μg/100 ml.
Current questions about lead exposure focus on the consequences of levels too low to have erupted into blatantly discernible defects. The present paper addresses two sets of interrelated problems derived from this issue. One is how to define the behavioral consequences of asymptomatic lead absorption, and the second focuses on behavioral assessment procedures.
Current primary prevention programs emphasize environmental monitoring, and early detection programs emphasize lead body burden measurements. The evaluation of behavioral problems in school children as a function of body burden is rarely performed. Epidemiologic data indicate sufficient natural variability to determine the degree of association between indices of total body burden and behavior. Assessment procedures are described and research suggestions offered that sample concretely defined target behaviors in social environments.
Children may be exposed to lead in their environment by a variety of mechanisms, but the final two common pathways involve ingestion and/or inhalation. The serious public health problem of overt lead intoxication from eating lead-based paint has tended to obscure low level toxicity which may be related to atmospheric lead pollution. No data exist which relate potential body burden or blood lead levels in children to ambient air lead levels. Extrapolation from respiratory lead uptake kinetics in adults is complicated by the differences in respiratory physiology, metabolism, and body compartment sizes existing between children and adults. These differences and models from pediatric pharmacology have been used to approach the problem of predicting respiratory lead dose in children from data based on adult uptake studies.
The lead content of a number of foodstuffs, particularly baby fruit juices and milk, is reported. Samples were analyzed in quadruplicate by using an automated Delves cup atomic absorption procedure. A large proportion of the products examined contained significant amounts of lead. Of 256 metal can examined, the contents of 62% contained a lead level of 100 μg/l. or more, 37% contained 200 μg/l. or more and 12% contained 400 μg/l. lead or more. Of products in glass and aluminum containers, only 1% had lead levels in excess of 200 μg/l. Lead levels of contents also correlate with the seam length/volume ratio of the leaded seam can. A survey of bulk milk showed a mean lead level of 40 μg/l. for 270 samples; for canned evaporated milk the mean level was 202 μg/l. These data indicate a potential health hazard.
Exposures to lead have emanated from various sources, including food, throughout human history. Occupational and environmental exposures (especially pica) appear to account for much of the identified human disease, however, food-borne exposures deserve further investigation. Lead residues in food can result from: biological uptake from soils into plants consumed by food animals or man, usage of lead arsenate pesticides, inadvertent addition during food processing, and by leaching them improperly glazed pottery used as food storage or dining utensils. Estimates of total dietary exposure should reflect frequency distribution data on lead levels in specific food commodities in relation to the quantities actually ingested by various sample populations to distinguish degrees of risk associated with particular dietary habits. Earlier estimates of average total dietary intake of lead by adults have been reported to range from above 500 μg/day downward with more recent estimates suggesting averages of 200 μg/day or lower. The strengths and weaknesses of these data are discussed along with analytical and sampling considerations.
FDA programs related to food surveillance, epidemiology, and toxicological investigation are briefly described.
The lead exposure of children and their mothers has been studied in two towns with mean soil lead contents of 900 and 400 ppm. No significant difference in blood or fecal lead contents was demonstrated between the two populations, but a small difference in hair lead content was shown. The blood lead content of children was greater than that of their mothers and was higher in the summer than in the spring samples. Children with pica for soil in the control area had increased lead content of blood and hair.
Preliminary data for children and mothers from villages with mean soil lead contents of 500 ppm and 10,000 ppm are reported which show significant differences in blood and hair lead content within the normal range. The data suggest that soil lead content of 10,000 ppm may result in increased absorption of lead in children, but to a degree which is unlikely to be of biological significance.
It has been known for many years that the eating of leaded paint is the prime cause of lead poisoning and elevated blood leads of children living in deteriorated housing. Recently, there has been speculation that children may eat dirt and dust contaminated with lead exhausted from cars and that this amount of ingested lead is sufficient to contribute significantly to the childhood lead problem.
This paper reports on a twopart study conducted to evaluate the validity of the dirt-and-dust hypotheses.
The first part of the study was made to determine the source of lead in dirt to which children are normally exposed. Dirt samples were taken in old urban areas around 18 painted frame houses and 18 houses of brick construction. Samples also were taken around seven old frame farmhouses remote from traffic. Based on the fact that lead concentrations in the dirt were similar in city and rural yards at corresponding distances from the houses, it is clear that nearly all of the lead in dirt around these houses is due to paint from the houses. Lead antiknock additives are therefore not a significant contributor to the lead content of dirt around houses where children usually play.
The second part of the study used a naturally occurring radioactive tracer 210Pb to determine the relative amounts of dust and other lead-containing materials (e.g., paint) eaten by young children. This tracer is present in very low concentrations in paint and in significantly higher concentrations in fallout dust. Stable lead and 210Pb were analyzed in fecal material from eight children suspected of having elevated body burdens of lead and ten children living in good housing where lead poisoning is not a problem.
The normal children averaged 4 μg Pb/g dry feces, with a range of 2 to 7. Of the eight children suspected of having elevated lead body burdens, two had fecal lead values within the normal range. However, the remaining six were 4 to 400 times as high. Despite these differences in fecal lead between the two groups, the groups were essentially identified in the 210Pb content of their feces. The “elevated” children averaged 0.040 pCi of 210Pb dry feces, while the normal group averaged 0.044 pCi/g. The results provide sound evidence that these children suspected of elevated lead body burden were not ingesting dust or air-suspended particulate.
A method has been developed to test the hypothesis that lead-containing house dust is responsible for the elevated levels of lead in blood of inner city children. Dust analyses of smears from the floors, walls, and windowsills in low-income inner city dwellings have shown a median concentration of lead five times as high in suburban homes. It is suggested that lead-containing dust may be one of the most important environmental sources of increased lead exposure in this specific population group.
The ingestion of airborne lead fallout is the mechanism responsible for increased lead body burdens found in 10 urban Connecticut children. The mean indoor lead levels found in housedust was 11,000 μg/g; highest concentrations occurred on windowsills and in floor dust. The mean lead content of Hartford street dirt was 1,200 μg/g; levels were highest near the street and next to the buildings. The mean lead concentration of hand samples taken from the subject children was 2,400 μg/g; the mean weight of hand samples was 11 mg. The concentration of lead in dirt and househould dust was high enough to theoretically result in excessive lead accumulation in young children who are putting their dusty, dirty hands in their mouths during play. While we believe that lead emitted from automobiles contributes significantly to air, dirt and dust lead levels the environmental impact of reducing or eliminating lead from gasoline is not yet completely understood.
Frank lead poisoning was found in some inhabitants of houses in the Scottish Highlands, exposed to soft water and lead-lined drinking water tanks. Further investigations were carried out on the clinical and metabolic effects of lead acquired by drinking soft domestic water from lead plumbing systems in 23 Glasgow households. The lead content of water from cold taps was up to 18 times the upper acceptable limit and was proportional to the amount of lead in the plumbing system. The blood lead of 71 inhabitants of these houses showed a significant positive correlation with water lead content. Delta aminolaevulic acid dehydrase activity, an extremely sensitive indicator of lead exposure, showed a significant negative correlation with water-lead content. Atmospheric lead was within acceptable limits in all but one house and no significant correlation could be found with biochemical measurements. A small number of clinical abnormalities were found but could not be directly attributed to lead toxicity. The results of the study underline the possible danger to health of lead plumbing systems in soft-water regions.
Although the quantities of lead (Pb) to which individuals are exposed vary widely, susceptibility of an individual to the effects of a specific level of exposure is another highly important factor in development of lead toxicity. For example, susceptibility to lead toxicity can be modified by several dietary factors. Low dietary intakes of calcium or iron (20% of recommended levels) substantially increase the toxicity of the same level of lead exposure to rats. In the studies of calcium effect, when calcium was fed to rats at ⅕ of the recommended intake, 12 μg Pb/ml drinking water produced the same degree of toxicity as did 200 μg Pb/ml with a normal calcium diet. The maximal dose for a 10-week period that does not impair heme synthesis or renal function in the rat has been established to be 200 μg Pb/ml drinking water. The role of low calcium diet on increasing susceptibility to lead has been confirmed in several species.
Mechanisms explaining the effect of calcium on lead toxicity may be related to absorption of lead from the gastrointestinal tract or renal tubule or to function of the parathyroid. Preliminary histological investigations on the parathyroids of control and lead-treated rats on normal and low calcium diets show no effect of lead.
Studies are currently underway to evaluate the lead, calcium and iron contents of the diets of children with normal and elevated concentrations of blood lead.
Lead acetate was administered continuously in the drinking water to CD–1 male mice beginning at 4 weeks of age. An LD10–20 of the lytic viruses or 300 plaque-forming units of RLV was inoculated intrapertioneally at 6 weeks of age. Lead increased the response of the mice to all classes of viruses against which it was tested: an RNA picornavirus-encephalomyocarditis (EMCV), a DNA herpesvirus-pseudoribies, an RNA leukemia-virus-Rauscher leukemia (RLV), an RNA arbovirus B-St. Louis encephalitis, and an RNA arbovirus A-western encephalitis. Most studies were performed between lead and EMCV. Increases in EMCV mortality in lead treated mice over controls ranged from 2× at a lead level of 0.004M to 7× (100% mortality) at a 0.1M lead level. Splenomegaly with spleens 800 to 1100 mg in weight containing high titers of RLV occurred in lead (0.03M)-treated mice 3 and 6 weeks after RLV inoculation; spleens or RLV controls were normal in weight (200 mg) and were free of virus. Lead did not reduce the protective effect of mouse interferon (IF) against the lethal action of EMCV, but it did repress the EMCV antiviral effect of poly I/poly C (PIC) and of Newcastle disease virus (NDV) against EMCV mortality. These data indicate several new facts concerning adverse effects lead may have on an animal: (1) lead aggravates viral disease, most likely in part, through reduced IF synthesis; (2) lead represses the anti-EMCV protective effects of both PIC and of NDV, which, in other reports, were shown to induce IF in radioresistant macrophages (PIC) or in radiosensitive lymphocytes (NDV); (3) lead may then be said to repress IF induction in two kinds of cells; (4) however, lead does not inhibit IF action.
Lead-induced inclusion bodies in renal tubular cells of rats have been studied in vitro after isolation by differential centrifugation. The inclusion bodies are insoluble in physiological media but may be dissolved in denaturants like 6M urea and sodium deoxycholate. They contain about 40–50 μg of lead/mg protein, but only about 10% of this is tightly bound. They also contain calcium, iron, zinc, copper, and cadmium. The protein is rich in glutamic and aspartic acids, glycine and cystine. When dissolved in 6M urea, the protein migrates as a single band on acrylamide gel electrophoresis and has a molecular weight of 27,500. It is suggested that the inclusion bodies function as an intracellular depot of nondiffusible lead.
Further studies have been directed toward finding a free, unaggregated lead-containing protein fraction. Nuclear proteins from kidneys of lead-toxic rats were separated into NaCl-, Tris-, and NaOH-soluble fractions and an insoluble acidic fraction. A quantitatively small lead-containing protein was found in the 0.14M NaCl fraction. Amino acid composition, electrophoretic mobility, molecular weight, and ability to bind lead are similar to those of insoluble inclusion body protein. The possible role of this soluble lead-binding protein in the formation of nuclear inclusion bodies is at present time not certain. These studies do suggest, however, that protein-bound lead in renal tubular cells may be partitioned between insoluble and nondiffusible morphologically discrete inclusion bodies and a soluble, extractable fraction which is presumably diffusable.
The detection of lead in fetal tissues by chemical analysis has long been accepted as prima facie evidence for the permeability of the placenta to this nonessential trace metal. However, only a few investigations, all on lower mammalian species, have contributed any direct experimental data bearing on this physiological process. Recent radioactive tracer and radioautographic studies on rodents have shown that lead crosses the placental membranes rapidly and in significant amounts even at relatively low maternal blood levels. While it is not possible to extrapolate directly the results of these experiments to humans because of differences in placental structure and other factors, the results do serve as a warning of the possible hazard to the human embryo and fetus of even low levels of lead in the maternal system.
Simultaneous assay of blood lead (Pb-B) and red cell lead (Pb-Rbc) in 123 samples from 104 urban and suburban students, ages 10–18, shows the ratio of concentration (Pb-Rbc)/(Pb-B) to increase as the hematocrit decreases. On direct assay in 40 samples, plasma lead (Pb-P) was fixed in a narrow range. In 28 students with Pb-Rbc >40 μg/100 ml, the mean red cell 2,3-diphosphoglycerate (2,3-DPG) was 6.05±0.28 (±S.E.), significantly higher (P<.025) than the 5.25±0.18 of 51 students with Pb-Rbc<40 μg/100 ml, although hemoglobin values were comparable (13.83±0.31 versus 13.55±0.20). Analysis of the individual population groups showed this correlation of Pb-Rbc with 2,3-DPG to be primarily related to the intercorrelation of each parameter with hemoglobin.
Rbc membrane Na/K ATPase, as per cent of total membrane ATPase, had a median value of 60% in 48 subjects. Na/K ATPase below 60% was found in 10 (77%) of the 13 students with Pb-Rbc≥40 μg/100 ml, but in only 14 of the 35 with Pb-Rbc<40 μg/100 ml (χ2=5.1, df=1, P<0.05).
Correlation of significant enzyme changes with Pb-Rbc, but not with Pb-B in the normal urban range of Pb-B<35 μg/100 ml suggests Pb-Rbc, increased in anemia, to be a critical factor in the hematotoxicity of lead.
Plasma lead (Pb) levels have been measured in normal and lead-intoxicated children, newborns, and children with sickle cell disease. The results in all groups were contant over a wide range of red cell Pb concentration. These results support the thesis that the red cell represents a large repository for Pb, maintaining plasma Pb concentration within closely defined limits, and that methods other than measurements of plasma Pb will be necessary to uncover a presumably dynamic transport system between red cell and plasma. Indeed, we have demonstrated in vitro that ionized calcium (Ca2+) lowers red cell Pb content according to a linear dose–response curve. Ca2+ may thereby control Pb transport from red cell to plasma, and fluctuations in the concentration of Ca2+ in serum and extracellular fluid may influence the toxic activities of Pb. In bone organ culture, changes in the concentration of Ca2+ and phosphate in the medium alter the release of previously incorporated 210Pb from fetal rat bones in response to parathyroid hormone (PTH). Therefore, both PTH and the ionic milieu of the medium apparently regulate bone Pb metabolism.
We would expect that understanding further the dynamics of Pb transport in plasma and bone may lead to a more exact definition of the real hazards of low level Pb toxicity in children.
Dynamics of lead metabolism were studied by replacement of a portion of the dietary lead with stable isotope tracers, and maintaining subjects on controlled diets for about 6 months. Results for one subject have been previously reported. Preliminary data are now available for a second subject.
Although the data on the two subjects are basically similar, there are also significant differences. The two subjects have different blood lead concentrations (0.25 and 0.18 μg/g). Both subjects received the same dietary and similar atmospheric lead exposure, and the lead concentration of their blood was shown to be nearly in a steady state. The difference in blood lead concentration appears primarily attributable to differences in the fraction of lead absorbed from the gut, although there are also differences in other physiological parameters, as well as probable small differences in their intake of atmospheric lead.
The quantity of lead absorbed from a typical urban atmosphere (Pb concentration = 1–2 μg/m3) has been shown by our isotopic data and balance studies to be 15±3 μg/day. Measurement of the contribution of atmospheric lead to the lead intake of the second subject was also carried out by removal of lead from the atmosphere. Decline in the blood concentration of lead of normal isotopic composition was shown to be equivalent to the removal of 15 g/day.
Measurements made during the course of a day show complexities in the absorption and distribution of lead, which are averaged out on a time scale of ca. 5 days.
Balance studies have been performed for lead upon eight healthy children in three different home environments and upon eight children with inborn errors of metabolism in hospital (consuming two different types of synthetic diet). The balances were for 3 days and involved the use of metal-free diapers where indicated. The concentration of lead in all the samples was determined by atomic absorption spectroscopy after suitable sample preparation.
In addition, the total population of children under the age of 16 living in a working class area exposed to undue amounts of lead was examined in an attempt to determine whether their mental development had been affected. Blood lead levels, general intelligence, reading ability, and rate of behavior disorder were measured.
The results of the balances showed that the mean daily intake of lead in both groups of children was lower than previously recorded figures, being lowest of all in the breastfed infant. The healthy group absorbed a mean value of 53% and retained 18% of the dietary intake and there was no relationship to age or month of the year of study. The children with inborn errors showed a significantly lower percentage absorption of lead.
The preliminary results of the population survey showed that distance from the polluting lead source was related to blood lead level, but no relationship could be found between blood lead level and any measure of mental function.
In an effort to define the toxicology and disposition of lead compounds that presently exist in paint (i.e., organic driers), a controlled dose feeding study was initiated early this year with the use of 28 infant baboons as experimental animals. The infant baboon, established as a metabolic model for a child ingesting lead, will be used to determine the adequacy of present as well as recently recommended limitations for lead in paint to assure protection from this potential source of lead exposure.
To accomplish this goal, research has been designed to determine basic dose–response relationships in animals ingesting constant daily doses of a dried paint, a lead octoate drier, and lead acetate. Doses for these compounds have been chosen to cover a broad range of concentrations including that recommended by the American Academy of Pediatrics from the maximum daily permissible lead ingestion, and associated estimates of paint intake by children with pica.
Parameters of metabolic response for each lead compound, include: general clinical surveillance, lead concentrations in blood, urine and feces, erythrocytic δ-aminolevulinic acid dehydratase and free erythrocytic porphyrin. The response of several of these measures of lead exposure as a function of time will be discussed for each compound at the several dose levels administered.
Lead subacetate (0.5g) and 1000 units of vitamin D were given three times a week to four newly-weaned rhesus monkeys. In addition, two animals received only the vitamin D. The poisoned animals had an increase in the urinary excretion of δ-aminolevulinic acid, an elevated content of lead in the blood, and a fall in hemoglobin concentration. Between 6 and 18 weeks the animals suddenly developed ataxia, nystagmus, generalized weakness, and convulsions. At this time the animals were killed by perfusion of fixative and the brain prepared for light and electron microscopic studies. Definite morphological evidence of disease was confined to the central nervous system, except for one animal which showed the characteristic renal inclusions of lead poisoning. All animals showed PAS-positive globules associated with blood vessels and an exudative edema involving the white matter of the cerebral hemispheres and cerebellum. Ultra-structurally, this appeared as a granular precipitate within an expanded extracellular space. Alterations of nerve fibers were not seen in the white matter but axonal swelling was observed in the cerebral cortex. The perikaryon and neuropil appeared normal. The control animals showed no significant cerebral changes.
Lead encephalopathy was induced in developing Long-Evans rats by adding lead carbonate (4% w/w) to the diet of nursing mother immediately after delivery. The morphological and biochemical features of cerebral ontogenesis were studied in 30-day-old rats.
By the 30th postnatal day, the overall effect of lead intoxication was retardation of brain growth. The mass of both the cerebral gray and white matter was appreciably reduced in the lead rats without any reduction in cell populations. While the neuronal population was preserved, the growth of neurons was reduced and their maturation retarded. The retarded neuronal growth was characterized by the limited proliferation of processes in the neuropil and by the reduction in the number of synapses per neuron. However, synaptogenesis was neither delayed nor perturbed but reduced by the limited development of neuronal dendritic fields. The myelination was altered and its cerebral content significantly reduced. The effect of lead on myelination was one of hypomyelination. The hypomyelination appears to be primarily related to retarded growth and maturation of the neuron and is not a reflection of a defect in the myelinating glia or a delay in the initiation of myelination.
Inorganic lead produces cerebral dysfunction and clinically definable encephalopathies in man. To date there have been few studies on the biochemical changes in brain following exposure to inorganic lead. Studies correlating toxicity with behavioral and brain neurochemical changes following lead exposure have been hindered because adult laboratory animals are resistant to the central nervous system effects of lead poisoning. Such studies have been impeded by lack of suitable experimental models until Pentschew and Garro showed that brain lesions develop in neonatal rats when a pregnant rat newly delivered of her litter is placed on a 4% lead carbonate containing diet. Lead passes into the developing sucklings via maternal milk. Lead-poisoned new-borns have pronounced retardation of growth and during the fourth week of ilfe develop the severe signs of lead encephalopathy, namely, extensive histological lesions of the cerebellum, brain edema, and paraplegia. There is an approximate 85-fold increase in the lead concentration of both the cerebellum and cerebral cortex relative to controls, but edema and gross vascular changes are confined to the cerebellum. Ingested lead had little effect on RNA, DNA, and protein concentrations of developing rat cerebellum and cerebral cortex. However, there was a reduction of between 10 and 20% in the DNA content of the cerebellum around 3 weeks of age in the lead-exposed sucklings. This suggests a failure of cell multiplication in this part of the brain.
A critical evaluation of this experimental approach indicated that under similar dietary conditions experimental lactating rats eat 30% less food than controls resulting in: (a) sustained loss in body weight of nursing mothers and that (b) offsprings who develop paraplegia and cerebellar damage do so after gaining access to lead containing diet.
We have studied mothers' food consumption and body weight changes and blood, milk, and brain lead content; and newborns' body and brain weight changes, blood and brain lead content, and brain serotonin (5HT), norepinephrine (NE), dopamine (DA), and γ-aminobutyric acid (GABA). We have found that a lactating mother rat eating 5% lead acetate (2.73% Pb) produced milk containing 25 ppm lead. When the mothers' diet is changed at day 16 from 5% PbAc to one containing 25 ppm Pb, and neonates allowed free access to the solid diet, the sucklings still have retarded body growth but do not develop paraplegia or grossly apparent vascular damage of the cerebellum. However, during the fourth week these animals exhibit a less severe form of “encephalopathy” consisting of hyperactivity, tremors, and stereotype behavior. Pair-fed controls coetaneous to experimental groups do not display such activities. There was no change in brain 5HT, GABA, or NE, but a 15–20% decrease in brain DA. Change in DA relative to other monoamines suggests a relationship between CNS dysfunction due to lead and DA metabolism in the brain.
The experimental design as discribed provides a model of CNS dysfunction due to lead exposure without debilitating histopathologies. It is possible that our findings on increased motor activity and changes in brain dopamine may correspond to early responses to lead exposure before recognized overt signs of toxicity.
Mice were exposed to lead from birth by substituting solutions of lead acetate for the drinking water of their mothers. The suckling mice were thus exposed to lead through their mother's milk and, at weaning, directly through the drinking water. Controls received equal concentrations of sodium acetate. No deaths of offspring or mothers occurred during the first 90 days of exposure. It has been suggested recently that lead exposure may account for some incidences of behavior disorders in children. Levels of motor activity of individual offspring were measured from weaning until 70 days of age in specially designed activity cages. Lead-treated mice were more than three times as active as age-matched or size-matched controls.
Treated and control animals were administered drugs currently used in the treatment and diagnosis of hyperactivity in children. All control animals responded as expected to all drugs used in this study. However, lead-treated mice responded paradoxically to d- and l-amphetamine, methylphenidate, and phenobarbital. That is, the CNS stimulants suppressed their hyperactivity while phenobarbital exacerbated the lead-induced hyperactivity. These findings suggest that lead produces an animal model of hyperactivity which may have clinical relevance and which may explain some cases of hyperactivity in children.
Reports of neurologic impairment of children following recovery from acute lead encephalopathy have raised questions concerning the effects of chronic low-level lead exposure on the central nervous system. Behavioral toxicologic techniques have been employed to assess the effects of lead on the central nervous system in sheep. Mature sheep receiving daily doses of 100 mg lead/kg showed a significant decrease in performance on an auditory signal detection task. Daily oral doses of 120 and 230 mg lead/sheep for 27 weeks did not alter the performance of mature sheep on a fixed-interval schedule of reinforcement behavioral task. Prenatal exposure to maternal blood lead levels of 16 or 34 μg/100 ml during gestation and postnatal daily ingestion of 16, 8, 4, or 2 mg lead/kg did not alter performance of lambs on a closed-field maze task. Slowed learning was demonstrated in lambs prenatally exposed to maternal blood lead levels of 34 μg/100 ml during gestation when tested on nonspatial, two-choice visual discrimination problems at 10–15 months of age.
When infant rhesus monkeys were exposed to lead via the addition of lead acetate (0.5–9 mg/kg body weight) to their formula or by the consumption of lead particles from lead-based surrogate mothers, they developed symptoms of lead intoxication within 6 weeks. Seizures, muscular tremors, and altered social interaction were the predominant changes. Visual impairment was also apparent in the more severely affected animals. In the animals showing obvious symptoms lead levels varied between 300 to 500 μg/100 ml of blood. Even in those animals having blood lead levels below 100 μg, hyperactivity and insomnia were observed. When the exposure to lead was eliminated, seizures subsided and visual impairment was reduced; however, the abnormal social interaction persisted. These animals also experienced a gradual decline in hematocrit and hemoglobin values during the period of examination. Liver and kidney biopsies obtained from these lead-exposed animals revealed characteristic intranuclear inclusions.
When adolescent and adult monkeys were exposed to doses of lead acetate similar to those employed in the infant experiments, lead levels in excess of 200 μg/100 ml of blood were recorded. However, there were no obvious behavioral abnormalities observed. There were, however, numerous lead inclusion bodies in kidney biopsy specimens from these animals.
These data suggest that, like man, the infant nonhuman primate is much more susceptible to lead intoxication than is the adult. The clinical and behavioral changes recorded in these infant rhesus monkeys suggest their use as an experimental model to evaluate lead intoxication.