Lead Poisoning

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Chapter 702 Lead Poisoning

Lead is a metal that exists in four isotopic forms. Chemically, its low melting point and ability to form stable compounds have made it useful in the manufacture of hundreds of products. Clinically, it is purely a toxicant; no organism has an essential function that is lead-dependent. Nevertheless, its commercial attractiveness has resulted in the processing of millions of tons of lead ore, leading to widespread dissemination of lead in the human environment.

The threshold level at which lead causes biochemical, subclinical, or clinical disturbance has been redefined many times during the past 50 yr. The blood lead level (BLL) is the gold standard for determining health effects. The U.S. Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics (AAP), and numerous other national and international organizations (e.g., Global Lead Network—Alliance to End Childhood Lead Poisoning, and The National Referral Centre for Lead Poisoning in India) consider a BLL of 10 µg/dL or greater as a level of concern for public health purposes. However, lead toxicity occurs below this threshold, and no safe level has been identified. Current recommendations by the CDC address this gap.

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

TRADITIONAL MEDICAL SYSTEM	CASES OF LEAD ENCEPHALOPATHY N (%)	N (%) PEDIATRIC CASES WITHIN CAM SYSTEM OR MEDICATION
Ayurveda	5 (7)	1(20)
Ghasard	1 (1)	1 (100)
Traditional Middle Eastern practices	66 (87)	66 (100)
Azarcon and Greta	2 (3)	2 (100)
Traditional Chinese medicine	2 (3)	2 (100)
Total	76 (100)	72 (95)

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.

Behavior also is adversely affected by lead exposure. Hyperactivity is noted in young school-aged children with histories of lead poisoning or with concurrent elevations in BLL. Older children with higher bone lead content are more likely to be aggressive and to have behaviors that are predictive of later juvenile delinquency. One report supports the concept of long-term effects of early lead exposure. In this longitudinal study, the mothers of a cohort were enrolled during their pregnancies. BLLs were obtained early in pregnancy, at birth, and then multiple times in the offspring during the first 6 years. The investigators report that the relative rate of arrests, especially for violent crimes, increased significantly in relationship to the BLLs. For every 5-µg/dL increase in BLL the adjusted arrest rate was 1.40 (95% confidence interval [CI], 1.07–1.85) for prenatal BLLs and 1.27 (95% CI, 1.03–1.57) for 6-yr BLLs.

Whether the behavioral effects of lead are reversible is unclear. In one small, short-term study, 7 yr old hyperactive children with BLLs in the 20s were randomly allocated to receive a chelating agent (penicillamine), methylphenidate, or placebo. Teacher and parent ratings of behavior improved for the first two groups but not the placebo group. BLLs declined only in the chelated group. Two year old lead-poisoned children enrolled in a placebo-controlled trial of the chelating agent succimer showed no mean difference in behavior at 4 or 7 yr of age.

These studies support the concept that early exposure to lead can result in long-term deficits in cognition and behavior; they also hold out the possibility that reductions in lead burden may be associated with improvement in cognitive test scores.

Clinical Symptoms

Gastrointestinal Tract and Central Nervous System

GI symptoms of lead poisoning include anorexia, abdominal pain, vomiting, and constipation, often occurring and recurring over a period of weeks. Children with BLLs higher than 20 µg/dL are twice as likely to have GI complaints as those with lower BLLs. CNS symptoms are related to worsening cerebral edema and increased intracranial pressure. Headaches, change in mentation, lethargy, papilledema, seizures, and coma leading to death are rarely seen at levels lower than 100 µg/dL but have been reported in children with a BLL as low as 70 µg/dL. The last-reported death directly attributable to lead toxicity in the USA was in 2006 in a child with a BLL of 180 µg/dL. There is no clear cutoff BLL value for the appearance of hyperactivity, but it is more likely to be observed in children who have levels higher than 20 µg/dL.

Other organs also may be affected by lead toxicity, but symptoms usually are not apparent in children. At high levels (>100 µg/dL), renal tubular dysfunction is observed. Lead may induce a reversible Fanconi syndrome (Chapter 523). In addition, at high BLLs, red blood cell survival is shortened, possibly contributing to a hemolytic anemia, although most cases of anemia in lead-poisoned children are due to other factors, such as iron deficiency and hemoglobinopathies. Older patients may develop a peripheral neuropathy.

Diagnosis

Screening

It is estimated that 99% of lead-poisoned children are identified by screening procedures rather than through clinical recognition of lead-related symptoms. Until 1997 universal screening by blood lead testing of all children at ages 12 mo and 24 mo was the standard in the USA. Given the national decline in the prevalence of lead poisoning, the recommendations have been revised to target blood lead testing of high-risk populations. High risk is based on an evaluation of the likelihood of lead exposure. Departments of health are responsible for determining the local prevalence of lead poisoning as well as the percentage of housing built before 1950, the period of peak leaded paint use. When this information is available, informed screening guidelines for practitioners can be issued. For instance, in the state of New York, where a large percentage of housing was built pre-1950, the Department of Health mandates that all children be tested for lead poisoning via blood analyses. In the absence of such data the practitioner should continue to test all children at both 12 mo and 24 mo. In areas where the prevalence of lead poisoning and old housing is low, targeted screening may be performed on the basis of a risk assessment. Three questions form the basis of a questionnaire (Table 702-3), and items that are pertinent to the locale or individual may be added. If there is a lead-based industry in the child’s neighborhood, the child is a recent immigrant from a country that still permits use of leaded gasoline, or the child has pica or developmental delay, blood lead testing would be appropriate. All Medicaid-eligible children should be screened. Venous sampling is preferred to capillary sampling because the chances of false-positive and false-negative results are less with the former.

Table 702-3 MINIMUM PERSONAL RISK QUESTIONNAIRE

1 Does the child live in or visit regularly a house that was built before 1950? (Include settings such as daycare, babysitter’s or relative’s home.)

2 Does the child live in or regularly visit a house built before 1978 with recent (past 6 months) or ongoing renovations or remodeling?

3 Does the child have a sibling or playmate who has or did have lead poisoning?

From Screening young children for lead poisoning: guidance for state and local public health officials, Atlanta, 1997, Centers for Disease Control and Prevention.

Interpretation of Blood Lead Levels

The threshold for lead effects and the level of concern for risk management purposes are not the same. Laboratory issues make the interpretation of values between 0 and 5 µg/dL more difficult. Some labs certified as proficient by the CDC or other testing programs can accurately measure BLLs to 2 µg/dL; others only to 5 µg/dL. A screening value at or above 2 µg/dL is consistent with exposure and requires a second round of testing for a diagnosis and to determine the appropriate intervention. The timing for the “repeat” evaluation depends on the initial value (Table 702-4). If the diagnostic (second) test confirms that the BLL is elevated, then further testing is required by the recommended schedule (Table 702-5). A confirmed venous BLL of 45 µg/dL or higher requires prompt chelation therapy.

Table 702-4 FOLLOW-UP OF BLOOD LEAD LEVEL SCREENING TEST

IF SCREENING BLOOD LEAD LEVEL (µg/dL) IS:	CDC: REPEAT DIAGNOSTIC VENOUS BLOOD LEAD TESTING BY:	AAP: REPEAT DIAGNOSTIC VENOUS BLOOD LEAD TESTING BY:
<10	Not defined; < 1 year	Not defined
10-19	3 mo	1 mo
20-44	1 wk-1 mo (sooner the higher the lead)	1 wk
45-59	48 hr	48hr
60-69	24 hr	48 hr
≥70	Immediately	Immediately

AAP, American Academy of Pediatrics; CDC, Centers for Disease Control and Prevention.

Adapted from Screening young children for lead poisoning: guidance for state and local public health officials, Atlanta, 1997, Centers for Disease Control and Prevention; and American Academy of Pediatrics, Committee on Environmental Health: Screening for elevated blood lead levels, Pediatrics 101:1072–1078, 1998.

Table 702-5 SUMMARY OF RECOMMENDATIONS FOR CHILDREN WITH CONFIRMED (VENOUS) ELEVATED BLOOD LEAD CONCENTRATIONS

BLOOD LEAD CONCENTRATION (µg/dL)	RECOMMENDATIONS
<10	As levels approach 10 µg/dL use the 10-14 µg/dL recommendations
10-14	Lead education (sources, route of entry):
	Dietary counseling (calcium and iron)
	Environmental (methods for hazard reduction)
	Follow-up blood lead monitoring in 1-3 mo
15-19	Lead education:
	Dietary
	Environmental
	Follow-up blood lead monitoring in 1-2 mo
	Proceed according to actions for 20-24 µg/dL if:
	A follow-up blood lead concentration is in this range at least 3 mo after initial venous test or
	Blood lead concentration increases
20-44	Lead education:
	Dietary
	Environmental
	Follow-up blood lead monitoring in 1 wk-1 mo (sooner if value is higher)
	Complete history and physical examination
	Laboratory studies:
	Hemoglobin or hematocrit
	Iron status
	Environmental investigation
	Lead hazard reduction
	Neurodevelopmental monitoring
	Abdominal radiography (if particulate lead ingestion is suspected) with bowel decontamination if indicated
45-69	Lead education:
	Dietary
	Environmental
	Follow-up blood lead monitoring
	Complete history and physical examination
	Laboratory studies:
	Hemoglobin or hematocrit
	Iron status
	Free erythrocyte protoporphyrin (EP) or zinc protoporphyrin (ZPP)
	Environmental investigation
	Lead hazard reduction
	Neurodevelopmental monitoring
	Abdominal radiography with bowel decontamination if indicated
	Chelation therapy
≥70	Hospitalize and commence chelation therapy
≥70	Proceed according to actions for 45-69 µg/dL
NOT RECOMMENDED AT ANY BLOOD LEAD CONCENTRATION
Searching for gingival lead lines
Evaluation of renal function (except during chelation with CaNa₂EDTA [ethylenediaminetetraacetic acid])
Testing of hair, teeth, or fingernails for lead
Radiographic imaging of long bones
X-ray fluorescence of long bones