Clinical manifestations

Presentation and course

Most children with elevated blood lead levels appear asymptomatic, or they exhibit a range of mild to severe symptoms. Because children may have no or very mild symptoms, and yet still be at risk of adverse cognitive and neurobehavioral outcomes, the Centers for Disease Control and Prevention advocates periodic screening of blood lead levels in all children between 9 and 36 months (28; 68). Lead poisoning in both children and adults is associated with a wide range of neurologic and nonneurologic symptoms and signs.

Nonspecific symptoms, erroneously attributed to other causes are temperamental lability, irritability, behavioral changes, sleep disturbance, and decreased play. Some children may experience more pronounced and more worrisome symptoms such as hyperactivity, lassitude, or decreased activity. Some children may exhibit symptoms that are likely to result in diagnostic evaluation, such as delayed language or loss of developmental milestones.

Burton line (lead line). In individuals with chronic lead poisoning, Burton's line (also known as the Burton’s line, Burtonian line, or simply a "lead line") is a very thin, bluish-black line visible along the margin of the gums, at the base of the teeth (23; 124; 76).

Burton line is attributed to a reaction between circulating lead and sulfur ions released by bacterial activity in the mouth, resulting in the deposition of lead sulfide at the junction of the teeth and gums (124). It was originally described by British physician and chemist Henry Burton (1799-1848) in 1840:

Although not a sensitive marker of lead poisoning, it should not be overlooked.

Lead encephalopathy. Lead encephalopathy usually results with blood lead levels above 100 µg/dL. Lead encephalopathy presents with headache, altered sensorium, lethargy, seizures, and coma. Cerebral edema due to encephalopathy, which is more common in younger children, can be fatal.

In the past, lead encephalopathy was the typical presentation for a child with lead poisoning. With increased awareness of childhood lead poisoning and availability of screening programs, it is now uncommon for a child in the United States to present with life-threatening neurologic symptoms.

In utero exposure and neurodevelopmental outcomes. Lead exposure in utero adversely affects neurodevelopment independent of postnatal exposure (114; 65). Prenatal lead exposure at low levels is associated with poor intellectual developmental function (138). Blood lead concentrations as low as 6.4 µg/dL are associated with increased risks of behavioral problems such as pervasive developmental problems (99). Maternal lead exposure is also associated with an increased risk of miscarriages, prematurity, low birth weight.

Cognitive impairment. Cognitive impairment due to lead exposure is considered permanent. Even low blood lead levels are known to cause irreversible impaired cognitive function.

Behavioral changes. Hyperactivity and aggressive behavior have been noted in children with high blood lead levels and high bone lead content.

Cranial and peripheral neuropathies. Hearing loss and peripheral neuropathy with decreased nerve conduction velocities can occur at blood lead levels much lower than those that cause CNS toxicity (144). Children do not typically present with peripheral neuropathy, which is commonly seen in adults (148). Lead may produce changes in visual contrast sensitivity (103; 150).

Skeletal abnormalities. Lead accumulates in the metaphyses of growing bones, which are the most metabolically active zones; consequently, x-rays may show bands of increased density at the metaphyses.

Although lead toxicity can affect any metaphysis, involvement of the proximal fibula and distal ulnar metaphyses is highly suggestive of lead poisoning. X-rays may also show a "bone-in-bone" appearance (a descriptive term that is applied to bones that appear to have another bone within them). In addition, lead is an osteoclast-poison, so bone density is increased due to unopposed action of osteoblasts.

Blood lead levels are indicative of lead bound to erythrocytes and do not reflect the lead load in the body, as a significant amount of lead can be deposited in the bone. Bone lead is slowly released and is difficult to mobilize, unlike the lead bound to erythrocytes (bone lead has a longer half-life than erythrocyte-bound lead).

Hematologic abnormalities. Lead poisoning causes anemia by inhibiting hemoglobin synthesis and shortening erythrocyte survival.

Usually this is a microcytic hypochromic anemia with basophilic stippling.

Hypochromia and microcytosis are typically seen in iron-deficiency anemia, which often coexists with lead toxicity, and they are also seen in alpha-thalassemia. Assessing iron storage status (ferritin) in all cases of lead poisoning is important.

Lead antagonizes the enzymes porphobilinogen synthase and ferrochelatase, inhibiting the synthesis of heme and can ultimately cause elevation of free erythroprotoporphyrin. Lead also impedes the repair of cell membranes, leading to increased erythrocyte fragility. Lead in the blood can cause a range of hematologic abnormalities, ranging from reduction of hemoglobin synthesis to hemolysis (152). Overt anemia that is directly caused by lead poisoning is usually not seen until the blood lead level is over 60 µg/dL.

Renal abnormalities. Long-term exposure to lead (typically with blood lead levels higher than 100 µg/dL) leads to proximal renal tubular dysfunction, manifesting as Fanconi syndrome, which results in excess amounts of glucose, bicarbonate, phosphates, uric acid, potassium, and certain amino acids in the urine (100).

Gastrointestinal abnormalities. Gastrointestinal symptoms of lead poisoning usually present as lead colic with anorexia, abdominal pain, vomiting, and constipation. In some there may be x-ray evidence of lead particles in the gastrointestinal tract.

Pubertal development and reproductive capacity. Exposure to low levels of lead causes reduced semen volume, abnormal sperm morphology, and reduced sperm motility and viability (79). Delayed pubertal development and decreased height have been reported in girls (145).

Growth. Several studies have demonstrated diminished ponderal and linear growth in children with elevated blood lead levels (14; 143; 146).

Prognosis and complications

Blood lead levels of 5 µg/dL are now the "action level" for intervention designated by the US Centers for Disease Control and Prevention (30). However, the term “blood lead level of concern” is no longer preferred because even low blood lead levels are associated with neurocognitive defects. Movement away from the term “blood lead level of concern” should place greater emphasis on primary prevention rather than action after detection of toxic blood lead levels. The proportion of children with "concerning" blood lead levels in the United States has been declining since at least the late 1990s, whichever threshold is used.

Decreased brain volume in adults with childhood lead exposure. In the Cincinnati Lead Study (CLS), an urban, inner-city cohort of individuals was recruited between 1979 and 1984, enrolling pregnant women who lived in neighborhoods with historically high rates of childhood lead poisoning (27). Detailed prenatal and postnatal histories of low-to-moderate lead exposure and behavioral outcomes were monitored over 25 years. Newborns were followed quarterly through 5 years of age, semiannually from ages 5 to 6.5 years, at age 10 years, and between ages 15 and 17 years. One hundred and fifty-seven participants between 19 and 24 years of age underwent brain imaging.

Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead levels (27).

Approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead level. The most affected regions included prefrontal gray matter and the anterior cingulate cortex responsible for executive functions, mood regulation, and decision-making. Areas of lead-associated gray matter volume loss were much larger and more significant in men than women, suggesting that lead-related atrophic changes have a disparate impact across sexes, or that there is a gender-related difference in exposures (eg, because of greater hand-to-mouth behavior at a young age, more active exploration of the environment, etc.).

Adverse cognitive and behavioral outcomes following lead exposure as a child may be related to lead’s effect on brain development producing persistent alterations in structure.

Cognition and IQ scores. According to a study of 488 cases, lead levels below 10 µg/dL result in significantly decreased standardized test scores, thus, affecting subsequent educational attainment (34). During the first 2 years of life, blood lead levels at or above 10 µg/dL are associated with poorer performance on developmental assessment scales (10; 111).

According to a study of 488 cases, lead levels below 10 µg/dL result in significantly decreased standardized test scores, thus, affecting subsequent educational attainment (34). During the first 2 years of life, blood lead levels at or above 10 µg/dL are associated with poorer performance on developmental assessment scales (10; 111).

The blood lead level at age 24 months used to be considered the best predictor of subsequent cognitive abilities and academic performance (111; 12). However, the lead level at 6 years of age is a more accurate predictor of later intellectual abilities (83).

Childhood lead poisoning is associated with lower IQ scores. A median IQ deficit of 6 points was demonstrated on the Wechsler Intelligence Scale for Children-Revised by first and second grade children who had elevated dentine (tooth) lead concentrations (116). This effect amounts to a decline of 3 IQ points for each 10 µg/dL blood level over 10 µg/dL (117). Follow-up studies on older school-aged children demonstrated that these deficits persist and result in ongoing school problems (185; 11).

Intellectual impairment caused by blood levels below 10 µg/dL has also been recognized. Canfield and colleagues showed that IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 µg/dL (25). Children's neurodevelopment is inversely related to their blood lead levels even in the range of less than 10 µg/dL (156).

Children with elevated blood lead levels frequently demonstrate impaired language development, both receptive and expressive. Verbal comprehension, verbal processing, and sentence repetition are some of the skills affected (109). Lead has also been shown to have an adverse effect on auditory processing abilities (49).

Attentional and behavioral problems. Modest levels of lead may compromise a child's attention span, fueling a debate about whether low levels of lead "cause" ADHD. A careful reading of the literature, however, permits a distinction between lead effects and typical ADHD. Whereas teacher rating scales document similar behaviors (164), children exposed to lead have impairment of "focus-execute," the ability to select and respond to critical information, and "shift," the ability to appropriately and adaptively shift focus from one stimulus to another (09). In contrast, children with ADHD make significant errors of omission and commission on continuous performance tests (101), demonstrating impairment of "encode," the ability to process auditory information, or "sustain," the ability to maintain focus over time (ie, vigilance) (113). A study of 43 boys, 8 to 12 years old, with elevated levels of lead by hair analysis demonstrated slower reaction time and impaired flexibility of attention (112).

In a large study, teachers who were blinded to their students' dentine lead levels consistently identified a higher frequency of maladaptive behaviors in those children with elevated lead levels (116). Examples of these behavior problems included hyperactivity, impaired attention span, impulsivity, daydreaming, and inability to follow directions. A clear dose-response relationship was demonstrated by these data, with those children with higher lead levels manifesting a higher frequency of behavioral difficulties (116).

Lead interrupts midbrain dopamine circuitry (40), which is also involved in ADHD (118; 134). Early reports confirmed that lead influences the symptoms of ADHD although typically at levels greater than 10µg/dl (62; 147; 159; Centers for Disease Control and Prevention 2005b). However, studies have established a relation between attentional difficulties and low lead exposures (less than 5 µg/dl) that are typical in the United States and Western Europe populations (56; 29; 37; 119; 120; 151). The first study involved 150 children aged 8 to 17 years from a community sample exposed to average lead levels (119). There was a non-ADHD control group and an ADHD group, diagnosed by clinical criteria. The maximum lead level in the sample was 3.4 µg/dl, and the blood lead levels were significantly higher in the ADHD group in comparison with the non-ADHD control group. A subsequent study confirmed the association using a different representative sample of 236 children aged 6 to 17 years (120). The maximum lead level of the sample was 2.2 µg/dl, and the levels were higher in the ADHD group than in the non-ADHD control group. This is the lowest lead level to be associated with ADHD (120). The studies confirm that lead, a neurotoxicant, is a plausible influence on ADHD even at low levels (119; 120).

Motor abilities. Motor coordination may be impaired. Dietrich and colleagues administered a comprehensive neuromotor assessment battery to 245 6-year-old children enrolled in the Cincinnati Lead Study (48). Suspecting that tests of motor coordination may be less influenced by cultural and socioeconomic factors in this predominantly poor, inner-city, African-American cohort, the authors found a dose-effect relationship between life-time postnatal lead dose and fine motor coordination. In this cohort, lead levels peaked at 2 years of age and slowly tapered off by the time of neuromotor assessment at 6 years of age. Other studies have demonstrated a significant relationship between postnatal lead levels and standing balance (16) and reaction time (73).

Biological basis

Etiology and pathogenesis

Lead is a metal that has no physiologic function in the human body. Lead exposure starts in utero and continues for life. Lead exists as organic and inorganic compounds. As a divalent ion, lead functions as a surrogate for calcium in most biological systems. Many clinically relevant effects relate to the role of lead as a high potency surrogate in disrupting calcium homeostasis and in interfering with calcium-dependent intracellular functions.

Childhood lead poisoning is caused by inhalation or ingestion of lead particles, which then enter the bloodstream to be distributed throughout the body and permeate bone cells; the lead is then stored long-term within the bone cells. In addition to household dust and paint chips, lead gets into the body through inhalation of vapor (eg, from heat stripping of lead-containing paints).

Sources of lead exposures. There are multiple potential sources of exposure to lead pollution and many resultant potential adverse health effects.

Lead paint and other residential exposures. There are multiple residential sources for childhood lead exposure (36).

In the United States, the UK, and France, the most common current source of lead in childhood lead poisoning is lead-based paint (43; 123; 87; 174; 175). Peeling or chipping paint from houses built before 1960 can contaminate the dust inside the house and the soil around the outside of the house (39; 172; 43; 174). Lead-based paint was sometimes used after the manufacturing ban in 1978. Improper lead abatement techniques can cause lead poisoning in children in the house being abated or in neighboring houses (38; 106). Remodeling or renovation of older homes may also produce lead dust or spread existing lead dust into the air where it may settle onto contact surfaces. Children living in homes built before the 1978 ban on lead-based residential paint may also be exposed to lead from drinking water service lines made from lead, lead solder, or plumbing materials containing lead (21).

A study of lead exposure pathways in Michigan from 2017 to 2021 studied 429 children in 345 homes; 53 had blood lead levels of 5 ug/dl or greater (174). Blood lead levels were directly predicted by lead in settled (ie, on the floor) house dust, the age of the child, season, and mouthing behavior and indirectly predicted by windowsill and trough dust lead, bare soil lead, proportion of floors with carpets, and exterior building deteriorations. Paint lead was also an indirect predictor of blood lead levels through the soil and settled dust pathways. This study reinforces earlier studies from the 1990s. Before that, the main direct and indirect pathways of lead exposure for most children in older housing remained paint and the contaminated dust and soil it generates.

A retrospective cohort study in England studied cases of lead exposure in children reported to the UK Health Security Agency between 2014 and 2020 via surveillance (43). Inclusion criteria were children under 16 years of age, residing in England, with an elevated blood lead concentration (BLC) level of 0.48 μmol/L (10 µg/dL) or greater and referred for public health management; 266 children met the inclusion criteria. After adjusting for reporting source, housing age, and type, cases residing in housing built before 1976 had a BLC of 0.32 µmols/L higher than cases living in housing built after this time. Housing age and type are a proxy for lead exposure risk through exposure to leaded paint, lead water pipes, and lead-contaminated dust from indoor and outdoor sources.

Older infants and toddlers are at risk for ingestion of lead as they engage in developmentally normal oral exploration of their environment. They may crawl on floors covered with dust that contains lead and subsequently put toys in their mouth or suck their thumb. Children at this age are particularly susceptible to the effects of lead poisoning because of rapid brain development. Furthermore, some children exhibit higher rates of hand-to-mouth behaviors than other children, which puts them at higher risk for lead poisoning. Children with pica may eat dirt, paint chips, and other substances that are contaminated with lead (110; 43); however, a history of pica is absent in most children with lead poisoning, so the absence of a history of pica should not dissuade clinicians from testing for lead poisoning.

Children may develop lead poisoning following ingestion of lead curtain weights, fishing weights, and bullets (58).

The canned food industry in the United States stopped using lead-soldered cans in 1991. In 1995, the Food and Drug Administration issued a final rule prohibiting the use of lead solder in all food cans, including imported products.

Occupational lead exposures transferred to the home. Lead has been deposited in soil from leaded gasoline and from industrial sources, such as lead smelters or battery recycling facilities, including some units that are operated as in-home occupations (46; 186).

Blood lead levels were markedly higher among children in a Vietnamese battery recycling craft village (46) than among children from Ho Chi Minh City (74).

Even the car seats in the family automobiles of workers who work with lead have caused contamination leading to increased lead levels in children and infants (31).

Lactation. Lactation can mobilize maternal lead stores. Cross-sectional studies involving three countries at three separate times have shown that longer duration of breastfeeding is associated with increased lead levels in infants (102).

Air. Lead can be released directly into the air as suspended particles. Historic major sources of lead air emissions were motor vehicles and industrial sources. Motor-vehicle emissions have been reduced by the phasing out of leaded gasoline, but lead is still used in general-aviation gasoline for piston-engine aircraft. Ambient air lead levels are a predictor of blood lead levels greater than 10 µg/dL when controlling for other known contributors (19). Since the late 1970s, elimination of tetraethyl lead in gasoline and lead in paints has dramatically reduced lead pollution in the United States. However, much of the lead that was released from leaded gasoline in the past remains in the environment, especially in the soil near major roadways.

Less common sources. Less common sources of lead include lead pipes or lead solder in copper pipes, lead in crystal and lead-glazed pottery used as food containers, and lead-adulterated food products or ingredients (168).

Children can also be exposed to lead dust from indoor shooting ranges and from parental activities such as welding, construction, or pottery. In addition, lead continues to be used as a folk remedy in some cultures (eg, China) (07; 183).

Spices, herbal remedies, ceremonial powders, and imported cookware have also been identified as potential sources of lead (03).

Widespread lead contamination has been noted in 60% of imported low-cost jewelry and in cosmetics (171).

Effects on the brain. Biological effects of lead on the CNS are pervasive and complex (40; 57).

Very high blood levels, sufficient to cause seizures and obtundation, are associated with an acute hemorrhagic encephalopathy and cerebral edema. This is related to lead's ability to disrupt the normal capillary function of the endothelial cells in the blood-brain barrier (64) by interfering with calcium's regulatory effect on endothelial cells (17). More importantly, lead may have a greater effect on astrocytes, which surround the microvessels. Astrocytes appear to be more sensitive to the toxic effects of lead at low concentrations (81), sequestering lead within the endoplastic reticulum away from mitochondria (160) to protect neurons from excitotoxic injury and apoptosis (184).

Studies on adrenal chromaffin cells, which are similar to neurons in the central nervous system, showed that lead inhibits the inactivation of voltage-gated calcium channels, removing the cellular "safety switch" and permitting excessive influx of calcium. In calcium-dependent potassium channels, lead prolongs the presynaptic action potential, also permitting calcium influx. Additionally, through its action on phospholipase C (discussed below), lead facilitates the release of calcium from intracellular pools into the cytosol, further compromising cell survival.

Calcium has a critical role in exocytosis and release of neurotransmitters from presynaptic terminals. Because lead is a more potent cation than calcium in this role, it stimulates neurotransmitter release at much lower concentrations, resulting in an increase in basal release of neurotransmitters. At the same time lead effectively competes with calcium released during excitation, resulting in a decrease in evoked release of neurotransmitters. This enhanced basal release and decrement in evoked release creates significant "noise" in neurotransmitter systems. This is particularly relevant during early brain development, when redundant interneuronal pathways are "pruned" in response to the presence or absence of neurotransmitter activity, laying the foundation for the final synaptic network of the adult brain. In a developing brain exposed to lead, there may be a qualitative difference in the normal process of synaptic pruning (22; 64; 90). Permanent damage to the tertiary synaptic structure of the brain during the formative stages is postulated to result from the abnormal synaptic pruning process.

The mechanism for lead's disruptive action in neurotransmitter release is related to its activation of synaptotagmin, a synaptic vesicle protein necessary for exocytosis. This protein has two regulatory domains (C1 and C2) and two catalytic domains (C3 and C4). The C2 regulatory domain has two binding sites for calcium, one of which binds lead at nanomolar (10-9 M) concentrations, whereas calcium typically binds to stimulate neurotransmitter release at micromolar (10-6 M) concentrations (Pevsner, personal communication). This C2 regulatory domain occurs in dozens of proteins, many of which are associated with neurotransmitter release. Prominent among these is phosphokinase C, which, when activated by lead, exacerbates the problem with neurotransmitter release and affects the body's "second messenger system" (107; 18). Animal studies have shown that the vascular adrenergic system and nitric oxide pathway change in short-term and subchronic phases of lead poisoning. An initial increase in blood pressure with decreased levels and nitrates was followed by a reversal of the metabolite levels with blood pressure maintained at high levels (80).

Hematologic effects. Lead binds to enzymes in the heme synthesis pathway. Inhibition of ferrochelatase results in the increased levels of protoporphyrin in the erythrocyte. Protoporphyrin is chelated by lead instead of iron, thus, inhibiting heme formation. Erythrocyte protoporphyrin accumulation results in toxicity independent of lead levels. The rise and fall of erythrocyte protoporphyrin is not related to blood lead levels (98).

Eukaryotic pyrimidine 5'-nucleotidase type 1 (P5N-1) catalyzes dephosphorylation of pyrimidine 5'-mononucleotides. The structure of lead-inhibited P5N-1 revealed that lead binds within the active site and compromises the function of the cationic cavity, which is required for the recognition and binding of the phosphate group of nucleotides. Deficiency of P5N-1 activity in red blood cells results in nonspherocytic hemolytic anemia. The enzyme deficiency is either familial or can be acquired through lead poisoning (15).

Gene expression and protein synthesis. Lead may alter gene expression, and protein synthesis (33).

Developmental lead exposure produces epigenetic effects on DNA methylation mediated at least in part through dysregulation of methyltransferases, even at the lowest levels of exposure (140). Studies of rats exposed to lead demonstrate increased histone acetylation in the hippocampus and increased locomotor activity (104). Even brief postnatal lead exposure produces significant changes in expression of various genes in the hippocampus (139).

In rats, maternal lead exposure can permanently alter the hypothalamic-pituitary-adrenal axis, altering the production of some corticosteroids (167).

Epidemiology

In the United States, the toxic reference blood lead level is currently 5 µg/dL as determined by the Centers for Disease Control and Prevention (CDC). This reference level reflects the lead blood levels of children aged 1 to 5 years in the United States who are in the highest 2.5%. Data regarding childhood blood lead levels in the United States come from the second and third National Health and Nutrition Examination Surveys, conducted by the National Center for Health Statistics/Centers for Disease Control and Prevention. The first blood lead level surveillance occurred during NHANES II (1976 to 1980) and the first part of NHANES III (1988 to 1991) (20). Between these two surveys of mean blood lead level in the overall United States population, there was a 78% decrease, from 12.8 to 2.8 µg/dL. Among children aged 1 to 5 years, the mean blood lead level decreased from 13.7 to 3.2 µg/dL for non-Hispanic white children and from 20.2 to 5.6 µg/dL for black children. Despite this decrease, 8.9% of children 1 to 5 years of age still have blood lead levels greater than 10 µg/dL (127).

The number of children aged less than 5 years with newly confirmed blood lead levels of 70 μg/dL or greater from the U.S. Childhood Blood Lead Surveillance System decreased somewhat from 2009 to 2014 (131).

Based on data from the U.S. Childhood Blood Lead Surveillance System, the percentage of children aged less than 5 years with blood lead levels from 5 to 9 μg/dL declined over the interval from 2009 to 2014 (131). For children less than 1 year old, the rate of blood lead level 5 to 9 μg/dL declined from 448 per 100,000 children in 2010 to 149 per 100,000 children in 2014. For children 1 to 4 years of age, the rate of blood lead level 5 to 9 μg/dL declined from 806 per 100,000 children in 2010 to 444 per 100,000 children in 2014.

Three factors contribute to this decline in mean blood lead levels: (1) removal of tetraethyl lead as an additive to gasoline in the United States between 1976 and 1990, (2) phasing out of lead soldering in food cans by 1991, and (3) a mandate in 1977 by the Consumer Product Safety Commission restricting the allowed amount of lead in paint for household use to less than 0.07% by weight. Although this last action has prevented the use of lead-based paint in newer homes, it did not address the problems of deteriorating paint in older homes, continued use of older stores of leaded interior paint, and use of leaded paint on exterior surfaces such as porches.

Although the overall decline in childhood blood lead levels is a positive trend, children aged 1 to 2 years continue to demonstrate the highest prevalence of elevated blood lead levels. Approximately 450,000 children in the United States are above the 5 µg/dL reference value for blood lead levels and are, therefore, at risk for adverse developmental consequences.

Elevated lead levels are most common among urban rather than rural children, children living in older housing, and low-income children (132). National data are of limited usefulness, however, because local prevalence varies substantially. Norman and colleagues found that children living in rural areas of North Carolina were at significantly higher risk of lead exposure than urban children were (122). Of 114,000 North Carolina children screened over a 2-year period, between 1992 and 1994, more than 20.9% had lead levels greater than 10 µg/dL (121).

A study highlighted the problem of lead toxicity in immigrant refugee populations (29). Malnutrition often compounds the problem. Anemia can enhance lead absorption and, thus, can increase risk for elevated blood lead levels, even in housing with minimal lead exposure hazards. Blood lead levels became elevated after resettlement for nearly 30% of refugee children with two tests, suggesting that lead exposure for these children occurred in the United States. Investigations revealed several risk factors for lead poisoning: living in old homes, the presence of lead hazards, behaviors that could increase the chance of ingesting lead, a lack of awareness of the dangers of lead, and evidence of chronic and acute malnutrition (165).

Lead levels have a seasonal component (182; 71; 92; 95; 129; 130; 131).

The variation of dust lead levels on the floor, windowsills, and carpets are consistent with the variation of blood lead levels, showing the highest levels in the hottest months of the year, June, July, and August (92).

Prevention

In childhood lead poisoning, primary prevention refers to prevention of lead exposure and maintenance of medically acceptable blood lead levels (less than 5 µg/dL). Secondary prevention refers to the identification of a child with an elevated lead level through periodic screening, with subsequent effort to prevent further lead exposure to the child.

Because the major source of lead exposure for children in the United States is lead-based paint, preliminary prevention strategies should focus on housecleaning techniques that will remove lead-contaminated dust (28), or relocating the child, if necessary, during lead abatement. Vacuuming and sweeping both disperse significant amounts of dust, so families are encouraged to use damp-cleaning techniques on all surfaces. A high-phosphate detergent, (eg, powdered automatic dishwasher detergent), should be employed, because the phosphate forms a chemical bond with the lead. A high-efficiency particle accumulator vacuum cleaner (HEPA-VAC) may be used to trap lead-containing dust particles too small to be captured by common household vacuum cleaners.

When a house is abated, the lead paint is permanently removed or encapsulated, thereby rendering the house "lead-free" or "lead-safe." Abatement and renovation should only be carried out by professionals certified to perform lead abatement, and all adults, children, and pets must vacate the premises until the work is complete. Furniture and all of the family's belongings must be stored or protected from dust particles during this time. It is not uncommon for children to suffer acute elevations in blood lead level if they are living in or near a house that is being renovated or abated by untrained persons who have not taken proper precautions (38).

During infant and toddler years, hand-to-mouth behavior is common. Parent education about sources of lead in and around the home and frequent hand washing and fingernail clipping are important preventive measures. In an uncontrolled study, such counseling was effective in reducing mean blood lead level in 78 children from 15 to 8 µg/dL (94). In addition, toys should be washed to remove lead-contaminated dust, and antique toys, often painted with lead-based paint, should not be given to infants and toddlers.

Good nutrition practices are essential to prevent childhood lead poisoning (135). Hand washing effectively removes lead and should be encouraged prior to hand to mouth feeding. Regular feedings are important because gastrointestinal absorption of lead is increased when the stomach is empty. Lead competes with calcium and iron; hence, a diet rich in iron and calcium needs to be promoted. Children with iron deficiency or low calcium stores absorb and retain more lead than those children who are not deficient. Indeed, longitudinal studies demonstrate that iron deficiency is associated with lead poisoning (177).

Differential diagnosis

Confusing conditions

Clinical findings associated with mildly or moderately elevated lead levels are typically subtle and nonspecific. Chronic lead intoxication should be considered in the differential diagnosis of developmental delay, disorders or attention, learning disability, visual-motor incoordination, auditory perceptual deficits, autistic and other behavioral problems, language disorders, speech problems, and mental retardation. Clinical findings associated with significantly elevated lead levels (eg, lassitude, headache), seizures, increased intracranial pressure, and coma are like those found in a other causes of encephalopathy. Similarly, colicky pain, anorexia, constipation, and failure-to-thrive may suggest various gastrointestinal problems.

Because children with chronic lead exposure typically come from the lower socioeconomic strata, questions are occasionally raised about whether the neurodevelopmental impairment evident in a lead-exposed child is attributable to the effects of lead or to confounding variables, such as nutrition or family history. A study of German school-aged children, for example, demonstrated that visual-motor integration and reaction time were adversely affected in lead-exposed children only if they were socially disadvantaged (176). Therefore, a clinician's suspicion of lead intoxication should be greater in children from lower socioeconomic environments.

Diagnostic workup

Targeted blood-lead testing of the populations at high risk for lead poisoning, an approach to secondary prevention, is the current strategy. Children living in or visiting buildings built before 1950 or built before 1978 but renovated in the past 6 months as well as those who have a sibling with lead poisoning are considered at high risk. Risk factors differ by community and no risk questionnaire developed at the national level should be applied across communities to target screening (45). Nevertheless, it is worth addressing the following three questions:

Except under particular circumstances (eg, pregnancy, lactation), bone lead stores have low turnover; therefore, (1) it is possible to have significant deposit of lead deposition in bone with meager blood lead levels; and (2) blood lead level may not reflect total lead stores in the body. Regardless of these caveats, the venous blood lead level is currently the best available screening test for lead poisoning.

Clinical testing for lead exposure is necessary to identify those children for whom primary prevention measures have failed (02). Testing will often occur during routine well-child care (as recommended by the American Academy of Family Physicians and the American Academy of Pediatricians).

CDC recommendations for blood lead level include the following:

In addition, a blood lead level should also be considered for children with excessive pica or hand-to-mouth activity.

Confirmation of suspected elevation in blood level should be obtained from a venous blood sample because capillary blood samples ("fingersticks") are frequently contaminated by lead dust on the skin and may yield false-positive results (137; 141). Free erythrocyte protoporphyrin is not consistently elevated until the blood lead level is above 40 µg/dL, so it should not be used to screen for lead poisoning (47). At a blood lead level of 35 to 40 µg/dL, only 50% of children will have an elevated free erythrocyte protoporphyrin; when the blood lead level reaches 50 to 55 µg/dL, 95% of children will have an elevated free erythrocyte protoporphyrin. In addition, free erythrocyte protoporphyrin may be elevated by other medical conditions such as iron deficiency. Free erythrocyte protoporphyrin may serve as an indirect indicator of exposure acuity: if the lead level is markedly elevated but free erythrocyte protoporphyrin remains relatively normal, the child most likely has had an acute ingestion; if both lead level and free erythrocyte protoporphyrin are elevated, the child most likely has chronic lead exposure. Free erythrocyte protoporphyrin elevation usually lags slightly behind the blood lead level elevation that causes it.

Radiographs of long bones (hands and knees) may show lead lines in the metaphysis suggestive of long-term lead exposure. Recently ingested paint chips may be seen in plain radiographs of the abdomen. Bone lead stores can be assessed by x-ray fluorescence (82; 84), but this is not done routinely and is only available in research centers.

A lead mobilization test has been used to identify children with lead that may be mobilized by chelation therapy. The test is done by measuring urine lead levels following administration of a single dose of adequacy of iron stores, a chelating agent (eg, calcium sodium EDTA). The test is of limited use and, therefore, is not recommended (108).

Additional blood tests are helpful in evaluating children with lead poisoning, including the following: (1) complete blood count (including hemoglobin, mean corpuscular volume, and red blood cell distribution width; (2) review of the blood smear; (3) serum iron and ferritin; (4) BUN and creatinine. Adequacy of iron stores is important because it is difficult to lower the blood lead level in a child who has chronic iron deficiency anemia. In most cases, concomitant treatment with therapeutic doses of iron will enhance the body's ability to excrete lead.

Neuroimaging typically does not play a pivotal role in the diagnosis of lead poisoning, except in cases of overt lead encephalopathy. Cerebral edema, presumably a consequence of vascular changes, may be seen in early stages in selected cases (157). With long-standing exposure, calcifications may be seen on CT, appearing patchy, punctate, or linear along the border of cortical and subcortical zones. Calcifications may also be seen on MRI as T2 hypointensities, occasionally surrounded by a hyperintense margin, likely due to an albuminoid matrix into which calcium salts are imbedded (96). Hyperintense lesions may sometimes be seen in periventricular regions (161). MR imaging findings, affecting predominantly the cerebral gray-white matter junction and the subcortical white matter, often resolve after chelation therapy (06).

Management

A fundamental principle of lead poisoning management is the removal of the source of lead exposure, without which chelation will have only transient ameliorative effects.

Childhood lead poisoning is currently classified by a system outlined in 1991 by Centers for Disease Control and Prevention. The venous blood lead level determines the recommended interventions. A blood lead level less than or equal to 5 µg/dL whole blood is considered medically acceptable (13). The complete classification system is as follows:

Venous blood lead levels of 45 µg/dL or more require chelation therapy. Chelation is the process by which a metal is chemically bound in a form that is easily excreted by the human body. In 1991 meso 2,3-dimercaptosuccinic acid (succimer) was approved for use in children. This water-soluble oral chelating agent is an analogue of British anti-lewisite but is more selective for lead, less toxic, and does not mobilize essential trace elements. Succimer, which can be used on an inpatient basis or in a "lead-safe" outpatient environment, is usually given for a period of 19 to 28 days. It is the preferred treatment regimen for children with blood lead levels between 45 and 70 µg/dL, although it is contraindicated in children with G6PD deficiency. The impact of treatment with succimer on developmental outcome of children with moderately elevated blood lead levels (20 to 44 µg/dL) has not yet been established. Chelation therapy with concomitant use of a cathartic removes the lead present in the intestine and prevents further absorption.

Another commonly used chelating agent for children with blood lead levels between 45 and 70 µg/dL is calcium disodium versenate, which is given intramuscularly twice a day for 5 days. This medication can be used for the small number of children who are unresponsive to succimer or who are allergic to sulfa drugs. It is less metal-specific, and will also chelate zinc, copper, and iron from the body (38). The 5-day course may be repeated after a 3-day rest period during which supplementation of the other chelated metals can be given.

Lead levels above 70 µg/dL are considered medical emergencies, whether neurologic symptoms are present or not (28); children with such levels require therapy with two chelating agents for more than one course. At these levels the risk of developing acute encephalopathy is high, especially if the child is already neurologically compromised or the blood lead level is rising quickly. Among those children with blood lead levels higher than 70 µg/dL and no evidence of encephalopathy calcium sodium EDTA combined with dimercaptosuccinic acid or British anti-Lewisite may be used, whereas those with evidence of encephalopathy require a combination of calcium sodium EDTA and British anti-Lewisite. British anti-Lewisite and penicillamine are associated with neutropenia. In a child with symptomatic lead poisoning, chelation will shorten the period of morbidity and can be lifesaving. Fluid intake must be closely monitored to ensure adequate urine flow without overhydration. A benzodiazepine is recommended for the initial treatment of seizures in this setting (126).

Any child receiving chelation therapy must be under close medical surveillance and should undergo frequent monitoring for renal, hepatic, and hematologic side effects (63), as all the above chelation agents utilize renal excretion. British anti-lewisite utilizes some hepatic excretion.

Among divalent cations, the ionophore monensin shows high activity and selectivity for the transport of lead ions (Pb2+) across phospholipid membranes. On co-administration to rats that were receiving meso-dimercaptosuccinate for treatment of lead intoxication, monensin significantly increased the amount of lead removed from femur, brain, and heart. Monensin may act by co-transporting lead and hydroxide ions out of cells, in exchange for external sodium ions. The net effect would be to shuttle intracellular lead to extracellular dimercaptosuccinic acid thereby enhancing its effectiveness. Thus, monensin may be useful for the treatment of lead intoxication when applied in combination with hydrophilic lead chelators (72).

Children with elevated blood levels of lead are at risk for poor nutrition and should ideally receive a diet consistent with the 2010 dietary guidelines recommended by the U.S. Food and Drug Administration (44). Given similar structural properties between lead and calcium, children at risk for lead poisoning should receive adequate amounts of calcium in their diet.

Special considerations

Pregnancy

Lead can cross the placenta and deposit in fetal tissues. Though mobilization of bone lead stores has been reported during pregnancy the maternal blood lead levels tend to remain relatively constant over the duration of the pregnancy, provided there is no increase in maternal lead exposure or ingestion (10; 26). Maternal blood lead levels may rise during later trimesters in pregnancy (105). Because the central nervous system develops rapidly throughout fetal life, it may be especially vulnerable to toxins. The lowest fetal blood lead threshold for adverse effects has not been established (26) and probably does not exist, meaning that any lead exposure will convey some adverse effect of fetal development. Infant neurodevelopment is adversely affected by exposure to lead independent of postnatal blood lead levels.

Lead also interacts with other metals to influence neurocognitive development. For example, there is a dose-dependent interaction between lead and cadmium exposure at 6 months of age (93). Cadmium levels below the median maternal blood level are antagonistic to lead during early pregnancy. At median levels of cadmium the interaction with lead is minimal. However, levels of cadmium above the median result in a synergistic modification of effect between prenatal cadmium and lead exposures, to the detriment of neurocognitive development.

Although blood lead is a marker for recent exposure, bone lead is an indicator of chronic exposure. Bone lead is both a depot for cumulative lead and a source of exposure with bone turnover. Bone lead is mobilized during pregnancy and lactation, (154; 70). During pregnancy, maternal bone lead increases blood lead from 9% to 65% (69). Chronic exposure produces reactive oxygen species (01; 04), which interfere with DNA methylation (166). There is an inverse relationship between maternal bone lead and DNA methylation of umbilical cord samples (125), which suggests that the maternal lead influences the epigenome of the developing fetus, producing disease vulnerability throughout the lifetime. In addition, blood lead affects homocysteine levels, which have been linked to decreases in DNA methylation (181), likely from suppression of DNA methyltransferases (42; 88).

Maternal bone lead is associated with adverse birth outcomes (66) and neurodevelopmental consequences (65). Maternal lead exposure can cause spontaneous abortions and stillbirths, and lead was used as an abortifacient prior to the 20th century (142; 115). Fetal death and premature birth have been associated with maternal occupational lead exposure; consequently, this has led to occupational hygiene measures as well as laws that excluded pregnant women from lead-related work (115). No clear pattern of congenital anomalies associated with fetal lead exposure has been reported, although available studies are limited (142).

Prenatal lead exposure is associated with neurodevelopmental deficits in young children (10; 85; 97; 67). Measurement of cord blood levels, monoamine concentrations, and neurodevelopmental outcome in 244 newborns in Paris demonstrated a negative correlation between both 5-HIAA concentration and sociability at age 9 months, leading to speculation that variance of serotonergic activity may mediate some behavioral consequences of elevated levels of lead (153).

DNA methylation, which regulates gene expression by suppression of transposons (173), is susceptible to environmental modification (52). In animals, environmental exposures during early life may influence DNA methylation, causing phenotype changes that produce a lifetime of disease vulnerability (170; 50; 51; 179). In addition, transgenerational inheritance of the phenotype is possible through environmental alterations on the germline of the epigenome (05; 35; 89). Investigations about early-life lead exposures using rodents and monkey models have demonstrated effects in the regulation of the amyloid precursor protein, reduction in the DNA methyltransferase activity, and susceptibility to Alzheimer disease in later life (08; 178).

Lead has affinity for calcium-binding sites (136), and calcium deficiency promotes intestinal lead absorption (75) and retention (149). In pregnancy and lactation, when there is an increased calcium demand (128), maternal bone lead is mobilized into the circulation (70; 105; 155). Increased milk consumption during pregnancy is associated with lower maternal and umbilical cord lead levels in postpartum women (78). In the United States, the recommended dietary intake of calcium for pregnant and lactating women is 1,000 mg to 1,300 mg/day (86). Studies have shown that lactating women who had a daily intake of 1,200 mg of calcium had a reduced maternal blood lead by 15% to 20% (77) and breast milk lead by 5% to 10% (54) throughout the course of lactation. In pregnancy, 1,200 mg of daily calcium supplementation was associated with an average reduction of 11% in blood lead level relative to placebo (53). Dietary calcium supplementation is a cost-effective means to lower lead exposure of the developing fetus and the breastfeeding infant.