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WHAT ARE THE ADVERSE EFFECTS OF LEAD? In man, lead exerts its effects in the renal, hematopoietic and nervous systems. The severity of effects is related to both the degree of illness and the frequency of recurring illness as well as the dosage and duration of exposure. There are basically three stages in childhood lead poisoning: 1) asymptomatic lead poisoning, in which no clinical symptoms are apparent, but in which measurable metabolic changes occur, 2) symptomatic lead poisoning, in which clinical symptoms such as anorexia, vomiting, apathy, ataxia, drowsiness or irritability occur, and 3) lead encephalopathy with cerebral edema, in which coma or convulsions occur (see Appendix D). The sequelae of lead encephalopathy include seizure disorders, severe mental retardation and death. The sequelae of symptomatic but less severe lead poisoning includes seizure disorders as well as various behavioral and functional disorders, usually grouped under the heading of minimal brain dysfunction. Clinical studies suggest that the latter syndrome may include hyperactivity, impulsive behavior, prolonged reaction time, perceptual disorders and slowed learning ability. Recent evidence suggests that minimal brain dysfunction might also follow asymptomatic lead poisoning. The sequelae associated with each diagnostic category of lead poisoning do not necessarily occur in every child with a par- ticular diagnosis. Each individual is unique in his response. The effects of lead in the hematopoietic system are reversible and therefore do not constitute sequelae. Lead interferes with the formation of hemoglobin at several stages. In addition, lead reduces the life span of the red blood cells and this results in lead induced anemia. In cases of encephalopathy, acute renal injury (Fanconi syn- drome) may also occur, and in children this is reversible. The "critical effect" concept, provides a framework for examining the effects of lead. The term "critical effect" is used to mean first effect, rather than most serious effect. Since effects in the kidney do not appear in the early stages of lead poisoning, the kidney cannot be considered the site of the critical or first effect. It is not presently known whether the first effects occur in the neurologic or hematopoietic systems. Subtle neurologic effects are difficult to measure. There are currently no simple neurochemical tests for measuring early metabolic changes in the nervous system. However, several labora- tory tests are currently available for measuring early effects in the hematopoietic systems. At the present time, the hematopoietic system is considered the site where the "critical effect" occurs (see Appendix A). If this is correct, then environmental limits, set to prevent reversible effects in the hematopoietic system, should serve to prevent potentially irreversible effects in the nervous system. WHAT DOSE OF LEAD IS REQUIRED TO PRODUCE ADVERSE EFFECTS? In relation to lead, the general term "dose" may be variously interpreted to mean: 1) the quantity of lead administered, 2) the

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quantity of lead absorbed, or 3) the quantity of lead present in the affected organs or tissues. In this report, we will use the terms "ex- ternal dose" and "internal dose" where necessary, to provide clarity. The external dose may be defined as the amount of lead entering the body through the gastrointestinal tract, lung, etc., some of which will be excreted before reaching the organs or tissues potentially affected by lead. The internal dose, or tissue concentration, may be defined as the amount of lead present in the organs or tissues. In experimental animals, the internal dose can be measured after sacrificing the animal. In humans, the analysis of tissue lead levels through biopsy or autopsy is rarely done; therefore, it is necessary to use some other indicator of "internal dose." We will use blood lead concentrations as an indi- cator of internal dose (see Appendix A). Individual Variability. We have found that individual variability influences the estimate of a dose necessary to produce an adverse effect. In a heterogeneous population, numerous factors modify the relationship between dose and effect in the individual so that some members of the population will appear to be affected by comparatively low doses of lead, while others will appear to be highly resistant, showing little or no effect at higher doses. In general, however, the percentage of indi- viduals in a population who exhibit a specific effect will increase in relation to an increase in dose. Not all factors which influence susceptibility are known. Therefore, this Committee feels that any estimate of a safe dose level should allow a margin of safety for highly susceptible individuals (see Appendix A) who are affected by relatively low doses. Known Conditions Affecting Susceptibility. Evidence in both animals and humans indicates that age and diet are primary factors influencing the absorption and effects of lead. Detailed discussions of these factors are given in Appendices B and D. Due to the very rapid rate of brain growth, the young animal or child is at greater risk for lead-induced neurologic damage than the adult. In humans, the "growth spurt" begins during the sixth month of pregnancy and continues into the third or fourth year postpartum. Glial replication and differentiation and cerebellar growth is most rapid during the first 18 months of life. Myelination continues into the third or fourth year of life. Permanent neurologic deficits can result from an insult to the brain during the growth spurt. Studies of children malnourished during the first two years of life have shown permanent adverse effects on learning ability and general adjustment. Studies in rats and lambs administered lead during the growth spurt have shown slowed learning abilities which persist in the adult animal, even after blood lead levels have returned to normal. Behavioral changes, including hyperactivity, aggressiveness, tremors and repetitive grooming behavior, have been produced in rats poisoned during the "growth spurt." The brain of suckling rats has been shown to have a significantly higher rate of lead uptake than the brain of adult rats. This may, in part, account for the greater central nervous system (CNS) vulnerability observed in young animals.

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Age also appears to modify the intestinal absorption rate for lead. Alexander's balance study in eight healthy children showed that approximately 50 percent of dietary lead was absorbed. Kehoe's balance studies in adults showed that only 10 percent of dietary lead was absorbed. Studies in rats confirm these observations in humans (see Appendix B). Using the average dietary lead intake for normal "non-exposed" adults and the different absorption ratios and caloric requirements for children and adults, a 3-year-old child would absorb 12 times more dietary lead than an adult receiving the same diet (see Appendix F). Both dietary components and dietary deficiencies have been shown to alter the intestinal absorption rate of lead. In experimental animals, the intestinal absorption of lead is significantly increased if lead is administered in oils, fats or milk rather than in a diet of dry feed. Similar studies are not available, nor would they be possible, in young children. Dietary deficiencies, including deficiencies of calcium, copper, and iron have been shown to increase the absorption of lead in rats. Dietary deficiencies of calcium and particularly iron have been reported to be prevalent among preschool age children, especially those in the lower socioeconomic groups. Because of the rapid growth rate during early childhood, iron stores are marginal even in apparently healthy children. Pica, as an additional risk factor, occurs among preschool age children. Pica, the repetitive ingestion of non-food substances, occurs in at least 50 percent of children between 12 and 36 months of age. In summary, a variety of factors combine to make the young child less resistant to lower levels of lead than the adult. The habit of pica may lead to ingestion of lead-containing paint chips; the young age makes the child vulnerable to lead-induced neurologic damage; and both age and diet contribute to produce a relatively high intestinal absorption rate for lead. Relationship Between Dose and Effect. The effects of lead occur in the hematopoietic, neurologic and renal systems. Whether the critical (first) effect of lead occurs in the hematopoietic or neurologic system is unknown. Presently, the hematopoietic system is considered the critical site for lead's effect. Using blood lead (Pb-B) as a measure of the "internal dose" of lead, different effects can be seen as blood lead levels increase. Lead-induced anemia has been reported in both children and adults. Lead's interference in the formation of hemoglobin results in the accumulation of free erythrocyte protoporphyrin (FEP) in blood and 6-aminolevulinic acid (ALA-U) in urine. In several small groups of women and children FEP begins to increase as levels rise above a range of 25-30 yg Pb/dl (micrograms of lead per deciliter). The urinary excre- tion of ALA begins to increase in children and adults when blood lead levels reach a range of 40-50 yg Pb/dl. Decreasing hematocrit levels have been reported in children when blood lead levels exceed 40 ug Pb/dl while decreasing hemoglobin levels in both adults and children have been reported at levels equal to or greater than 50-60 yg Pb/dl. In summary, the first metabolic evidence of lead's effect in the hematopoietic system appears at approximately 25-30 yg Pb/dl, while anemia usually does not

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appear until blood lead levels reach 50-60 yg Pb/dl (see Appendix D). Neurologic changes, including slowed learning ability, paraplegia, clumsiness and hyperactivity have been produced by administering lead to young experimental animals. The slowed learning ability appears to be an irreversible effect (see Appendix B). Studies in children have been difficult to perform. None by itself has provided all of the requisite data. Only one truly prospective study has been reported. Taken together, the several reports strongly suggest that both decreased cognitive functioning and an increased fre- quency of behavioral abnormalities become evident in groups of school- aged children who have been unduly exposed to lead during the preschool years (see Appendix D). The behavioral aberrations which include hyperkinesis, short attention span and impulsive and aggressive conduct, appear to be more important than minimal intellectual deficits in impeding progress in school. A similar observation was made by Byers and Lord over 30 years ago. In addition, a higher frequency of seizure disorders and school failures are reported in children with lead poisoning. An increased frequency of neurologic effects has been demonstrated only in those children with blood lead elevations greater than 50-60 yg Pb/dl. Severe mental retardation, blindness and death have been reported in children with lead encephalopathy. In children, lead encephalopathy is usually associated with blood lead levels greater than 120 yg Pb/dl. Relationship Between External Dose and Internal Dose. An estimate of the external dose (lead intake) necessary to produce a specific internal dose (blood lead) concentration must abcount for the chemical and physical form of lead ingested (see Appendix A). In children, up to 50 percent of dietary lead may be absorbed and 50 percent excreted in the feces. Although balance data in children are limited they are in agreement with data from suckling animals which show a high rate of lead absorption (see Appendix B). Animal studies have also shown that lead in paint films is less well absorbed than dietary lead. Lead chromate, one of the least well absorbed compounds found in paint, is absorbed approxi- mately one-third as well as the free salts of lead when added to the diet. Other lead compounds found in paint, such as lead naphthenate, have higher rates of absorption but are still absorbed to a lesser extent when incorporated into a paint matrix. Thus, 17 percent (1/3 x 50%) would be a conservative estimate for the amount of lead absorbed from paint by a young child (see Appendix E). Barltrop found a mean daily fecal excretion of 67.8 yg Pb/day in a group of two- to three-year-old children with a mean blood lead level of 20 yg Pb/dl. These data would be consistent with a dietary intake of 135 yg Pb/day if 50% is absorbed. On the basis of body weight for an average three-year-old child weighing 15 kg., Barltrop's group of children with a mean blood level of 20 yg Pb/dl would have a daily intake of 9.0 yg Pb/kg/day with an absorption of 4.5 yg Pb/kg/day. This agrees well with Alexander's estimates of dietary intake in young children (see Appendix D). 6