Public Health History

Between 1976 and 1980, more than 85% of preschool children in the USA had BLLs of 10 µg/dL or higher; 98% of African-American preschoolers fulfilled this criterion. Over the next 25 yr, government regulations resulted in the significant reduction of three main contributors to lead exposure by means of (1) the elimination of the use of tetraethyl leaded gasoline, (2) the banning of lead-containing solder to seal food- and beverage-containing cans, and (3) the application of a federal rule that limited the amount of lead allowed in paint intended for household use to less than 0.06% by weight. Surveillance by the CDC has shown that the prevalence of elevated BLLs (≥ 10 µg/dL) has declined markedly, and by 2004 it was below 1.5% in all preschoolers. However, an additional 6% had a level between 5 and 10 µg/dL, and 23.6% had levels between 2.5 and 5 µg/dL. In sum, nearly a third of U.S. preschool children continued to have measurable BLLs as measured by currently available clinical laboratory methodologies. Thus, nearly 6 million children continue to have evidence of lead exposure and nearly 300,000 have values that reach the CDC level of concern. Fortunately, children with levels high enough to be life-threatening are only rarely seen, although deaths continue to occur. Factors that indicate increased risk of lead poisoning, in addition to preschool age, include low socioeconomic status; living in older housing, built primarily before 1960; urban location; and African-American race. Another high-risk group that has been identified consists of recent immigrants from less wealthy countries, including adoptees.

Progress is also being made globally. In Mexico, the introduction of unleaded gasoline in 1990 was associated with a decline in BLLs among first-grade students, from 17 µg/dL in 1990 to 6.2 µg/dL in 1997. By 2009, all but 17 countries had completely phased out leaded gasoline usage, with the remaining countries that continue to use leaded gasoline being primarily from the former Soviet Union and in North Africa. In Malta, after the import of red lead paint was banned and the use of lead-treated wood for fuel in bakeries was prohibited, mean BLLs of pregnant women and newborns decreased by 45%. After it was documented that children living in the neighborhood of a battery factory in Nicaragua had a mean BLL of 17.2 µg/dL, whereas children in the control community had a mean BLL of 7.4 µg/dL, the factory was closed. Despite these advances, the World Health Organization (WHO) estimates that nearly a quarter billion people have BLLs above 5 µg/dL; of those that are children, 90% live in developing countries, where in some regions BLLs may be 10- to 20-fold higher than in developed countries.

Unfortunately, lead-related disasters continue to occur. In 2010, the CDC identified numerous lead-contaminated villages in northern Nigeria. The grinding of ore to extract gold caused widespread leaded dust dissemination. It is likely that hundreds of children died as a consequence of this activity, and all remaining children in the villages assessed to date were lead poisoned, with 97% having a blood lead level ≥45 µg/dL.

Sources of Exposure

Lead poisoning may occur in utero, because lead readily crosses the placenta from maternal blood. The spectrum of toxicity is similar to that experienced by children after birth. The source of maternal blood lead content is either redistribution from endogenous stores (i.e., the mother’s skeleton) or lead newly acquired from ongoing environmental exposure.

Several hundred products contain lead, including batteries, cable sheathing, cosmetics, mineral supplements, plastics, toys (Table 702-1), and traditional medicines (Table 702-2). Major sources of exposure vary among and within countries; the major source of exposure in the USA remains old lead-based paint. About 38 million homes, mainly built before 1950, have lead-based paint (2000 estimate). As paint deteriorates, it chalks, flakes, and turns to dust. Improper rehabilitation work of painted surfaces (e.g., sanding) can result in dissemination of lead-containing dust throughout a home. The dust can coat all surfaces, including children’s hands. All of these forms of lead can be ingested. If heat is used to strip paint, then lead vapor concentrations in the room can reach levels sufficient to cause lead poisoning via inhalation.

Table 702-2 CASES OF LEAD ENCEPHALOPATHY ASSOCIATED WITH TRADITIONAL MEDICINES BY TYPE OF MEDICATION

CAM, complementary and alternative medicines.

From Karri SK, Saper RB, Kales SN: Lead encephalopathy due to traditional medicines, Curr Drug Safety 3:54–59, 2008.

Metabolism

The nonnutritive hand-to-mouth activity of young children is the most common pathway by which lead enters the body. In nearly all cases, lead is ingested, either as a component of dust licked off of surfaces or in swallowed paint chips, through water contaminated by its flow through lead pipes or brass fixtures, or from food or liquids contaminated by contact with lead-glazed ceramic ware. Cutaneous contamination with inorganic lead compounds, such as those found in pigments, does not result in a substantial amount of absorption. Organic lead compounds such as tetraethyl lead may penetrate through skin, however.

The percentage of lead absorbed from the gut depends on several factors: particle size, pH, other material in the gut, and nutritional status of essential elements. Large paint chips are difficult to digest and are mainly excreted. Fine dust can be dissolved more readily, however, especially in an acid medium. Lead eaten on an empty stomach is better absorbed than that taken with a meal. The presence of calcium and iron may decrease lead absorption by direct competition for binding sites; iron (and probably calcium) deficiency results in enhanced lead absorption, retention, and toxicity.

After absorption, lead is disseminated throughout the body. Most retained lead accumulates in bone, where it may reside for years. It circulates bound to erythrocytes; about 97% in blood is bound on or in the red blood cells. The plasma fraction is too small to be measured by conventional techniques; it is presumably the plasma portion that may enter cells and induce toxicity. Thus, clinical laboratories report the blood lead level, not the serum or plasma lead level.

Lead has multiple effects in cells. It binds to enzymes, particularly those with available sulfhydryl groups, changing the contour and diminishing function. The heme pathway, present in all cells, has three enzymes susceptible to lead inhibitory effects. The last enzyme in this pathway, ferrochelatase, enables protoporphyrin to chelate iron, thus forming heme. Protoporphyrin is readily measurable in red blood cells. Levels of protoporphyrin higher than 35 µg/dL are abnormal and are consistent with lead poisoning, iron deficiency, or recent inflammatory disease.

Lack of heme affects multiple metabolic pathways. The accumulation of excess amounts of protoporphyrin and other heme precursors also is toxic. Measurement of the erythrocyte protoporphyrin (EP) level is, therefore, a useful tool for monitoring biochemical lead toxicity. EP levels begin to rise several weeks after BLLs have reached 20 µg/dL in a susceptible portion of the population and are elevated in nearly all children with BLLs higher than 50 µg/dL. A drop in EP levels also lags behind a decline in BLLs by several weeks, because it depends on both cell turnover and cessation of further overproduction by marrow red blood cell precursors.

A second mechanism of lead toxicity works via its competition with calcium. Many calcium-binding proteins have a higher affinity for lead than for calcium. Lead bound to these proteins may alter function, resulting in abnormal intracellular and intercellular signaling. Neurotransmitter release is, in part, a calcium-dependent process that is adversely affected by lead.

Although these two mechanisms of toxicity may be reversible, a third mechanism prevents the development of the normal tertiary brain structure. In immature mammals the normal neuronal pruning process that results in elimination of multiple intercellular brain connections is inhibited by lead. Failure to construct the appropriate tertiary brain structure during the first few years of life may result in a permanent abnormality. It is tempting to extrapolate from these anatomic findings to the clinical correlate of attention-deficit/hyperactivity disorder observed in lead-poisoned children.

Clinical Effects

The BLL is the best-studied measure of the lead burden in children. Although subclinical and clinical findings correlate with BLLs in populations, there is considerable interindividual variability in this relationship. Lead encephalopathy is more likely to be observed in children with BLLs higher than 100 µg/dL; however, one child with a BLL of 300 µg/dL may have no symptoms, whereas another with the same level may be comatose. Susceptibility may be associated with polymorphisms in genes coding for lead-binding proteins, such as delta-aminolevulinic acid dehydratase, an enzyme in the heme pathway.

Several subclinical effects of lead have been demonstrated in cross-sectional epidemiologic studies. Hearing and height are inversely related to BLLs in children; in neither case, however, does the lead effect reach a level that would bring an individual child to medical attention. As BLLs increased in the study population, more sound (at all frequencies) was needed to reach the hearing threshold. Children with higher BLLs are slightly shorter than those with lower levels; for every 10-µg increase in the BLL, the children are 1 cm shorter. Chronic lead exposure also may delay puberty.

Several longitudinal studies have followed cohorts of children from birth for as long as 20 yr and examined the relationship between BLLs and cognitive test scores over time. In general, there is agreement that BLLs, expressed as either a level obtained at around 2 yr of age or a measure that integrates multiple BLLs drawn from a subject over time, are inversely related to cognitive test scores. On average, for each 1-µg/dL elevation in BLL the cognitive score is approximately 0.25-0.50 points lower. Because the BLLs from early childhood are predictors of the cognitive test results performed years later, this finding implies that the effects of lead can be permanent. Concurrent testing of lead levels and cognition sometimes also shows an association.

The effect of in utero lead exposure is less clear. Scores on the Bayley Scale of Mental Development were obtained repeatedly every 6 mo for the first 2 yr of life in a cohort of infants born to middle-class families. Results correlated inversely with cord BLL, a measure of in utero exposure, but not with BLLs obtained concurrently at the time of developmental testing. However, after 2 yr of age, all other cognitive tests performed on the cohort over the next 10y r correlated with the BLLs at age 2 yr but not with cord BLLs, indicating that the effects of prenatal lead exposure on brain function were superseded by early childhood events and later BLLs. Later studies performed in cohorts of Mexican children monitored from the prenatal period confirms the association between in utero lead exposure and later cognitive outcomes. No threshold for BLL was identified in these studies; maternal blood lead levels between 0 and 10 µg/dL even as early as the first trimester were associated with about a 6-point drop in cognitive test score results when the children were tested up to age 10 yr.

An intervention study, in which moderately lead-poisoned children with initial BLLs 20-55 µg/dL were aggressively managed over 6 mo, addressed the issue of the effects of treatment on cognitive development. Components of treatment included education regarding sources of lead and its abatement, nutritional guidance, multiple home and clinic visits, and, for a subset, chelation therapy. Average BLLs declined and cognitive scores were inversely related to the change in BLL. For every 1-µg/dL fall in BLL, cognitive scores were 0.25 point higher.