Lead Poisoning
2000; American Academy of Pediatrics; Volume: 21; Issue: 10 Linguagem: Inglês
10.1542/pir.21.10.327
ISSN1529-7233
Autores Tópico(s)Aluminum toxicity and tolerance in plants and animals
ResumoAfter completing this article, readers should be able to:Our concept of lead poisoning has undergone a major evolution during the past few decades. Historically,lead poisoning was a classic disease; children and adults presented with symptoms and signs, generally pertaining to the gastrointestinal and central nervous systems, and had a history of exposure. In this century, advances in laboratory methods allowed correlation between blood lead levels (BLLs) and symptoms. Over the past 2 decades,our appreciation of lead as an agent capable of subtle but significant detrimental effects has progressed, as have our efforts at reducing exposure. Lead poisoning has been transformed into a disorder characterized by subclinical and biochemical findings in largely asymptomatic children. A BLL of 0.4826 mcmol/L (10 mcg/dL) or greater is indicative of increased exposure and absorption at some point in the past and is the current threshold for concern. The rise and fall of this man-made disease illustrates the conflicting traits in the human personality of ingenuity, greed, and altruism.Lead poisoning is an environmental disease that is the result of human activities. Anecdotes describing lead-poisoned workers date back at least 2,000 years. Reports resurfaced periodically and increasingly with the resurgence of metallurgy after the 16th century, and quantitative information on rates of lead poisoning due to occupational exposure began to be gathered around the end of the 19th century. However, the prevalence in the general population, as defined by BLLs,was unknown prior to the 1970s, the era when lead exposure and toxicity were at their peaks and were associated with significant mortality.Our knowledge of the prevalence of elevated BLLs in the United States population come primarily from three national health surveys. The National Health and Nutrition Examination Survey II (NHANES II)collected data from more than 20,000 individuals between 1976 and 1980. In the early 1980s, a smaller survey of the American Hispanic population was conducted (HHANES). NHANES III data were gathered in two phases—1988 to 1991 and 1991 to 1994. These three studies document a remarkable public health story.Analyses of NHANES II data identified several independent risk factors for having an elevated BLL, including poverty, age younger than 6 years old, African-American ethnicity, and dwelling in the city. Using the current definition of an elevated BLL as 0.4826 mcmol/L (10 mcg/dL), which was established in 1991 by the Centers for Disease Control and Prevention (CDC), more than 85% of preschool children had undue exposure and absorption of lead. More than 98% of African-American children were in this category. HHANES placed the prevalence of elevated BLLs in Hispanic children between that of Caucasians and African-Americans.By the time of NHANES III, the primary sources of environmental lead contamination had been recognized and their relation to childhood poisoning established. This resulted in federally mandated rules limiting the amount of lead allowed for some specific uses, especially as an additive to gasoline, paint, and sealants of canned food. This action contributed to an impressive 80% decline in average BLLs in the American population (Fig. 1) and a greater than 90% decline in the percentage of children defined as lead-poisoned (Fig 2) in fewer than 20 years. Although prevalence rates dropped markedly for all groups, risk factors remain.Lead is found in mineral deposits in nature and accounts for only 0.002% of the earth’s crust. It has been used for hundreds of products because of its malleability, low melting point, and ability to form compounds. Industries as disparate as plumbing, electrical,plastics, and nuclear have found lead to be efficacious. Products that may contain lead include pipes, solder, brass fixtures, ceramics,crystal, electric cable, paint, radiation shielding, gasoline,batteries, nonWestern (eg, Ayurvedic)medications, and cosmetics. Lead may be found in unexpected household items, such as window blinds,zippers, painted furniture, and mineral supplements. Other significant exposures result from poorly controlled industrial emissions at metal refineries and battery recycling plants, maintenance work on bridges and boats, and demolition of old housing. If target shooting is conducted in poorly ventilated spaces and lead-containing bullets are used, frequent visitors or employees at the range are at risk of increased lead absorption.Worldwide, six categories of products account for most cases of lead exposure: gasoline additives, food can soldering, lead-based paints,ceramic glazes, drinking water systems, and folk remedies. However,three products accounted for the majority of childhood exposure in the United States prior to 1980: lead-based paint for household use,tetraethyl lead as a gasoline additive, and lead solder for sealing canned food.The use of these products has been reduced markedly as the result of federal regulations limiting lead content and the development of cost-effective alternatives. Since 1977, newly manufactured paint intended for household use may contain no more than 0.06% lead by weight (reduced from a preregulatory peak of 50%), gasoline lead content is limited to less than 0.1 g/L (reduced from ∼1.5 g/L), and cans no longer are soldered.Concern about the hazard from lead-based paint led several countries,including France and Belgium, to restrict its use as early as 1909. In the United States, the lead industry maintained a successful advertising campaign, even promoting the health benefits of lead paint for hospitals because of its durability with repeated washings. The content of lead in paint intended for household use peaked in the 1930s and 1940s. Other metals, such as titanium, gradually were substituted during the 1950s, long before federal regulations were promulgated. Similar concerns about the risk of burning tetraethyl lead were raised by an environmental movement active in the United States in the 1920s. These warnings were not heeded for 50 years.Unfortunately, lead isotopes are very stable; they do not decay for millions of years. Thus, prior dissemination of lead that resulted in widespread environmental contamination continues to represent ongoing risks of exposure. High-risk populations have a greater likelihood of living in housing built prior to 1960. Tangentially, workers and homeowners involved in the rehabilitation of old buildings are at risk for lead poisoning and for bringing lead-containing dust home to their families.Many lead-containing products may be imported inadvertently. In addition to living in substandard old housing, immigrant populations may import lead-containing items such as ceramic ware or folk remedies. Mexican pottery has been implicated most often as a source of food contamination, especially if acidic fluids are stored in it. Topical agents applied around the eyes such as surma or kohl, which are used in Asian and Arabic countries, may be ingested, and “alternative”medicines for gastrointestinal or urologic disorders may consist largely of lead. Toys or crayons of Chinese manufacture have been found to contain lead. Even imported spices and dried fish may be contaminated.Theoretically, lead may enter the body through the intestine after ingestion, through the lung with inhalation, through direct injection,or through the skin. The most common pathway among children is through the mouth, with ensuing gut absorption. Pica behavior brings lead-containing or -coated objects to the mouth. Swallowed paint chips contribute a very small portion of lead to the body burden; fine dust licked from dirty hands or toys may provide proportionally greater amounts for absorption. Inorganic lead salts are generally poorly soluble in aqueous solutions; dissolution of lead-containing particulate depends on particle size, pH, and the presence of other dietary components. Thus, the lead in a paint chip primarily passes through the gut. Lead absorption appears, in part, to occur via the mechanisms evolved for essential elements, in particular calcium and possibly iron. These competitive pathways result in increased lead absorption when dietary mineral intake is inadequate. Other dietary components also could affect lead absorption. Theoretically, phytates,found in leafy green vegetables such as spinach, may bind metals and increase their excretion. Fat intake has been correlated directly with BLLs in epidemiologic studies, although a mechanism to explain this association has not been clarified.Inhalation of lead-containing dust is not likely to add significantly to children’s lead burden because the particle size is usually large and the material eventually is coughed up. However, because young children rarely expectorate, they swallow this material more frequently, allowing for gut absorption. An exception to this rule is exposure to airborne lead during heat gun stripping of painted surfaces or burning of lead-contaminated materials where lead is suspended as a very fine particulate. Lead vapor readily penetrates the lung and may cause massive acute poisoning. One historical cause of acute encephalopathy was sniffing of leaded gasoline by teenagers in an attempt to induce a “high”; at least part of the etiology also could be attributed to the hydrocarbons.There is little transcutaneous absorption of lead as assessed by change in BLLs when inorganic lead compounds such as those found in paint are applied to skin. However, some lead does penetrate to the dermis. In contrast, lead in organic matrices such as tetraethyl lead may enter through skin. This route may have contributed to lead poisoning in chemical workers during the development of this gasoline additive in the 1920s.Many cases have been reported of gunshot wound survivors who subsequently developed lead poisoning from retained bullets or pellets. Bullets may be composed largely of lead. The location of the bullet in tissues determines the extent and likelihood of poisoning. If the bullet lodges in an area bathed by fluids, such as a joint or spinal column, dissolution occurs slowly, elevating BLLs and disseminating lead throughout the body. If it is located in muscle, local inflammation eventually will result in scar tissue that walls off the bullet.Lead exists naturally in four stable isotopic forms that do not decay on a human lifetime scale. The mining site of origin may be identified by the specific ratios between these isotopes. Thus, lead originating in Eastern Europe has a different isotopic “signature”than lead from Australia. The body appears not to distinguish between isotopes; all are potentially toxic. Measurement of lead isotopic ratios allows investigators to trace the lead in a biologic or environmental sample to a specific source of exposure. This process has been used in elegant studies to determine the contribution of bone lead stores to BLLs over time in a group of pregnant and postpartum women. These immigrants originally were exposed to lead containing isotopic ratios that differed from their current sources of exposure during the study. Measurement of the change over time in the lead isotopic ratios in the subjects’ blood permitted the investigators to calculate the contributions of current and historic sources of lead exposure and accumulation. Regardless of its original source and isotopic signature,once lead is processed for use and disseminated, it persists in soil,dust, and drinking water, both in and outside of homes.Lead entering the intravascular space attaches rapidly to red blood cells; less than 3% in a blood sample is found in plasma. The half-life in the blood of adults is about 3 weeks, based on radioisotope studies. The half-life in children is less clear. Departure from the blood results in increased soft- and hard-tissue accumulation or excretion. Excretion is primarily through the kidney,although small amounts also are found in bile, hair, and nails. The lead that remains in the body accumulates mostly in bone. In adults,more than 90% of the lead found in the body is in the skeleton; in children, about 65% is found in the skeleton. Models of lead metabolism in bone indicate at least two compartments, with variation between types of bone. One of the compartments has a turnover measured in years to decades. Thus, once lead has entered the body, especially the skeleton, some may remain throughout childhood or beyond.Because lead can enter any cell, toxicity may occur in any tissue or organ. Conceptually, toxic effects of lead can be considered at three levels: biochemical, subclinical, and clinical.Fundamentally, lead in the aqueous solution of cells is in an ionic form that interacts with other elements. It is particularly attracted to sulfhydryls, amides, and oxides, molecules that are components of proteins. For example, when calcium and lead are added in equimolar concentrations to solutions containing calcium-binding proteins such as troponin, the lead will bind preferentially over the calcium. The protein-lead combination may not function normally,disrupting both intra- and intercellular communication, the latter because neurotransmitter release is, in part, calcium-mediated.Enzyme function may decrease as a consequence of lead binding. For example, in the multistep process of producing heme, a pathway found in all cells, at least three of the enzymes are sensitive to lead. A cascade in lead toxicities may ensue because the decrease in enzyme activity results not only in less product (eg, heme), but also in the accumulation of precursors (eg, aminolevulinic acid,protoporphyrin). In excess, these biochemicals also may be toxic, as in the porphyria syndromes.One of the puzzles in the field of lead poisoning is the apparent variability in sensitivity among individuals. Part of the answer may lie in genetic variants of proteins that bind lead. Recent work has examined the interaction between the two primary alleles that code for delta aminolevulinic acid dehydratase, a heme pathway enzyme. People who have the type II allele appear less sensitive to lead than those who have the more common type I allele. This area deserves more research.Other biochemical abnormalities have been associated with lead. Anemia could be due to impaired heme synthesis. However, in a lead-poisoned child, it is more likely due to concomitant iron deficiency or a hemoglobinopathy. At very high levels (4.83 mcmol/L [100 mcg/dL]),lead can cause a Fanconi syndrome with tubular dysfunction manifested by glycosuria, proteinuria, and phosphaturia.Most children who have lead effects will have subclinical disease(ie, presence of disease without symptoms). Investigations into the subclinical effects of lead were stimulated by theoretical extrapolations from symptomatic patients. If survivors of lead encephalopathy had obvious signs of residual brain damage, did children who were exposed to lesser amounts of lead have more subtle consequences? The answers to these types of questions are derived primarily from epidemiologic studies, with support from experiments in animals. Inverse associations between measures of blood or bone lead and cognition, behavior, height, and hearing have been documented repeatedly. Other studies have implicated lead as a contributor to poor balance and hand-eye coordination and sleep disturbance.It is the detrimental effect of lead on subtle, but measurable,cognitive functions that has provided the primary impetus for current public health efforts. Although subclinical decrements in cognitive function were suggested as a lead effect in the 1940s, definitive data to support this contention were not accumulated for another 40 years. Since Needleman’s pioneering cross-sectional analyses of dentine lead and cognitive test scores, published in 1979, many longitudinal studies have confirmed the inverse relation between measures of lead in the body and cognitive function. There are discrepancies about the exact nature and magnitude of the lead effects. In general, about one quarter to one half of an “IQ” point is lost, possibly permanently, for each 0.04826 mcmol/L (1 mcg/dL) increase in the BLL over measurements during preschool years. This relationship has held true even if the cognitive tests were administered 10 years after the BLLs were obtained in cohorts of 2-year-olds. This lag between the time of peak BLLs and later tests of function highlights both the limitation and the necessity of BLL testing during the preschool years;impairments suggested by poor school performance usually cannot be attributed or correlated to current BLLs. Thus, in the absence of historical BLL data, the diagnosis of lead-related toxicity is more difficult to establish, and potential opportunities to intervene may be missed.Whether early intervention to reduce lead in the body is capable of reversing its effects on the central nervous system has received limited attention. The two published studies in this area both documented improved cognitive scores or behavior as BLLs declined. The specific role of chelation therapy as a component of the intervention in this improvement is under investigation.The gastrointestinal and central nervous systems yield symptoms,but fewer than 5% of children are diagnosed as having lead poisoning based on clinical presentation. Gastrointestinal-related symptoms include anorexia, nausea, vomiting, abdominal pain, and constipation. The combination of recurrent or intermittent abdominal pain, vomiting,and constipation should raise the suspicion of lead poisoning. The BLL threshold for gastrointestinal symptoms has been stated to be approximately 2.4 mcmol/L (50 mcg/dL). However, a recent preliminary report suggests that symptoms may be present in nearly 50%of children who have BLLs of 0.97 to 2.2 mcmol (20 to 45 mcg/dL).Lead poisoning was a lethal disease in the United States and continues to contribute to mortality in developing countries. At levels above 4.83 mcmol/L (100 mcg/dL), some children may show evidence of encephalopathy, including a marked change in mentation or activity,ataxia, seizures, and coma. Physical examination may yield evidence of increased intracranial pressure. Since the advent of lead screening and restrictions in lead usage, lead-related deaths have become extremely rare. Sequelae in survivors include retardation, palsies, and growth failure.Lead poisoning is primarily a subclinical disease. Encephalopathy is an unlikely presenting finding, and gastroinestinal complaints may be vague, although the combination of constipation and abdominal pain or anorexia suggests the diagnosis. The diagnosis can be suspected if responses to routine questions are affirmative for sources of exposure such as peeling paint in old housing and behaviors such as pica,chewing on surfaces, and placing nonfood items in the mouth. Ultimately, the diagnosis rests on the results of blood testing.At each health supervision visit, a very brief personal risk questionnaire (Table 1) may be used as initial screening. If answers indicate risk, BLLs should be measured. Unfortunately, the overall sensitivity of questionnaires designed to identify lead poisoning in children is about 60% to 70%. Sensitivity can be improved when local conditions are considered and appropriate questions added. For example, adding the question, “Do you live near the town’s battery factory or metal smelter?” may improve the sensitivity. Such additions require an intimate knowledge of the environment in the catchment area of the clinical practice. Questionnaires should be available in the primary languages of the local residents. Screening is recommended to begin no later than 1 year of age and should be repeated as needed, but at least once more at 2 years of age. These ages were selected because the risk of exposure to sources within the home increases as the infant gains mobility but retains active hand-to-mouth behavior and because BLLs peak at about age 2 years.To determine whether lead absorption has occurred requires the measurement of a BLL. Numerous studies have correlated toxicity to this measure. A BLL reflects the confluence of absorption, entry to and from soft- and hard-tissue stores, and renal filtration. Of the methods currently available for confirming lead exposure and absorption, it also is the easiest to perform. A BLL of 0.48 mcmol/L(10 mcg/dL) or greater is considered elevated. However, there are significant limitations to this measure. Falsely elevated results may be caused by contamination of the tube or the collection equipment or by poor laboratory methodology. Capillary blood samples are more likely to be inaccurate than larger volume venous samples. Blood samples obtained from capillaries also may underestimate the true BLL if the finger is squeezed to obtain the sample. If tissue fluids (lymph) enter the blood sample, the lead content will be diluted because a BLL primarily measures lead in or on the red blood cell. Finally, lead does not remain in blood for long periods relative to its turnover in bone. Thus, a BLL is a “snapshot” of a narrow window in time. Low BLLs do not exclude the possibility of substantial bone lead stores. Conversely, high BLLs do not necessarily signify a large body burden.For a period of time before 1997, recognizing that lead poisoning was widespread and that most children who had lead poisoning had subclinical disease, the CDC and American Academy of Pediatrics (AAP)recommended universal screening of all preschool children by blood testing rather than risk assessment questionnaire. As epidemiologic studies documented a decrease in the overall prevalence of lead poisoning in the United States, they revised the guidelines. Criteria for continued universal screening by BLL testing include a prevalence of elevated levels of more than 11% or if more than 26% of the housing was built prior to 1959. Otherwise, blood sampling may be targeted at selected populations based on local risk assessment of lead exposure as determined by state health departments. High risk that necessitates blood lead testing includes residence in a geographic area known to have large amounts of lead or membership in a high-risk group such as indigent, urban, minority children. However, in the absence of formal local guidance, universal screening should be undertaken. Thus,if epidemiologic or housing age data are unavailable for a geographic area, all children should be screened by blood lead measurement at ages 1 and 2 years and at 36 to 72 months of age if not screened previously. Where local risk has been defined and found to be low, the need for blood lead testing is based on the results of individual risk assessment.What should be done if the BLL screening test shows a level of 0.48 mcmol/L (10 mcg/dL) or greater? The CDC and AAP have developed algorithms for follow-up by confirmatory retesting (Table 2). If the diagnostic test confirms an elevated BLL, specific management of the patient is recommended by the CDC and AAP (Table 3). A level greater than 2.12 mcmol/L(44 mcg/dL) is widely accepted as indicating a need for urgent chelation therapy (within 48 h); a level ≥3.38 mcmol/L (70 mcg/dL) should prompt immediate hospitalization and chelation.Because BLL measures the blood concentration at a single point in time, it is not surprising that it does not predict bone lead stores accurately or correlate perfectly with measures of toxicity. Lead poisoning also has been assessed by bone, urine, and hair lead measurements as well as examination of biochemical markers of toxicity.Spontaneous lead excretion in urine usually is low, even in children who have substantial body burdens, which limits its clinical utility. Urinary lead levels can be useful as guides to determining the efficacy of treatments aimed at removing lead. For this purpose, a provocative test employs a single or several doses of a chelating agent in a standardized protocol. The Lead Mobilization Test most commonly consists of the injection of a dose of calcium disodium edetate(CaNa2EDTA) followed by a timed urine collection of 6 to 8 hours. The CaNa2EDTA-induced lead excretion correlates with bone lead content, as measured by x-ray fluorescence,and is a predictor of lead excretion during a course of chelation therapy. Criteria have been established that define a positive test as one in which the drug induces a significant lead diuresis. Positive test results should prompt an immediate full course of chelation therapy. A negative test result signifies the inability of the drug to enhance lead removal from the child, either as a consequence of a low lead burden or a mitigating factor. Iron deficiency is one such factor; iron-deficient children excrete less lead in response to this drug than do iron-sufficient children. Children whose BLLs are higher than 2.12 mcmol/L (44 mcg/dL) are very likely to have positive test results. Conversely, those whose BLLs are less than 1.21 mcmol/L (25 mcg/dL) are very unlikely to excrete significant amounts of lead with drug treatment. Thus, the test is most suited for children whose BLLs are between 1.21 and 2.17 mcmol/L (25 and 45 mcg/dL). Additional criteria for selecting children for this test include erythrocyte protoporphyrin levels greater than 50 mcg/dL and no evidence of severe iron deficiency. If these criteria are met, one in three children will have a positive test. If any of the criteria is not met, the observed frequency of positive test results is only 5% (excluding children who have BLLs greater than 2.12 mcmol/L [44 mcg/dL]). Whether one or even multiple courses of chelation therapy administered on the basis of these test results has any long-term effect is unknown. The Lead Mobilization Test is not recommended by the AAP.Long-term exposure and ingestion of lead results in skeletal accumulation. Bone lead content may be assessed noninvasively by using a novel radiographic technique called x-ray fluorescence (XRF). The principle behind the XRF instrumentation for bone lead measurement also has been applied to the measurement of lead on painted surfaces,although the actual instrumentation differs. In brief, x-rays are generated, filtered, and aimed at a particular bone, generally the tibia. Lead atoms respond to the x-ray excitation by fluorescing, with greater fluorescence associated with higher concentrations of lead. The photons are collected in a detector and counted, yielding an estimate of bone lead content. The amount of radiation is minimal, considerably less than a dental radiograph. Bone lead measurements by XRF are limited primarily to research.Few studies have measured hair lead content in children. Contamination of samples has been a significant problem, as has standardization of protocols for obtaining samples and analyzing their lead content. Currently, this does not appear to be a clinically useful method for assessing lead poisoning in the pediatric population.The preceding measures of lead reveal nothing about its effects in any individual, although we can extrapolate from published studies of lead-poisoned populations. Biochemical measures of lead toxicity provide additional information. Measurement of the heme precursor,protoporphyrin (EP), has proven useful for providing clues about the duration of exposure and the degree of lead accumulation. EP levels rise in response to lead in a log-linear relation but lag behind BLLs by several weeks. Most children who have BLLs greater than 2.41 mcmol/L (50 mcg/dL) will have EP levels of 35 mcg/dL or greater in whole blood. At BLLs less than 0.97 mcmol/L (20 mcg/dL), very few children will have elevated EP levels related to the lead. There is a continuum between these lead concentrations in the likelihood of observing an elevated EP level. With intervention, EP levels fall, again lagging behind BLLs. Thus, EP levels can measure both the toxicity and the success of treatment and should be obtained in children who have BLLs higher than 0.97 mcmol/L (20 mcg/dL). Other causes of elevated EP levels include iron deficiency,inflammatory disease, and very rarely, porphyria.The primary aims of treatment are prevention of future lead exposure and absorption and enhancement of excretion. The four steps to accomplish these goals include: 1) assessing the environment to identify sources and making efforts to eliminate these sources or to remove the child from the contaminated environment; 2) modifying the behavior of the child to reduce hand-to-mouth activity for other than feeding purposes; 3) ensuring adequate nutrition, especially of minerals, to limit lead absorption; and 4) administering medications to increase lead excretion.Once lead has entered the body, especially the skeleton, it is very difficult to remove. Accordingly, prevention is the mainstay of treatment. For the majority of children, the success of treatment depends most heavily on identifying and eliminating sources of lead exposure. The list of products containing lead is extensive, but only a few sources account for most cases of lead poisoning, the most important of which is lead-based paint. Homes can be assessed by trained professionals using XRF instruments, but also by parents who can collect paint chips to be sent to certified laboratories for analysis. Inspection of surfaces will reveal whether the paint poses an immediate hazard (eg, peeling, flaking, or chalking) or is a potential hazard for the future if currently intact. All surfaces need to be examined, but especially friction surfaces such as on windows and doors. Windowsills are tempting biting surfaces for toddlers and should be examined for tooth marks. Dust derived from lead-based paint can be present in sufficient quantity to be visible; the highest levels are found in window wells. However, dust also can cover toys, furniture,tables, plates, and hands in minute quantities that are not readily apparent
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