LEAD Toxicity

LEAD Toxicity

Lead has been mined and used in industry and in household products for centuries. The dangers of lead toxicity, the clinical manifestations of which are known as plumbism, have been known since ancient times. The twentieth century has seen both the greatest-ever exposure of the general population to lead and an extraordinary amount of new research on lead toxicity.

	Populations are exposed to lead chiefly via paints, cans, plumbing fixtures, and leaded gasoline. The intensity of these exposures, while recently decreased by regulatory actions, remains high in some segments of the population because of the deterioration of lead paint used in the past and the entrainment of lead from paint and vehicle exhaust into soil and house dust.
	Many other environmental sources of exposure exist, such as leafy vegetables grown in lead-contaminated soil, improperly glazed ceramics, lead crystal, and certain herbal folk remedies.
	Many industries, such as battery manufacturing, demolition, painting and paint removal, and ceramics, continue to pose a significant risk of lead exposure to workers and surrounding communities.

New research on lead toxicity has been stimulated by advances in toxicology and epidemiology as well as by a shift of emphasis in toxicology away from binary outcomes (life/death; 50 percent lethal dose) to grades of function, such as neuropsychological performance, indices of behavior, blood pressure, and kidney function.

Tests for levels of lead in blood have facilitated both research on lead and surveillance of individuals at risk. Measurement of the blood lead levels of children 6 months to 5 years of age is currently mandated by some states in U.S., and the U.S. Occupational Safety and Health Administration (OSHA) requires the testing of workers who may be exposed to lead in the course of their jobs.

METABOLISM

Elemental lead and inorganic lead compounds are absorbed through ingestion or inhalation. Organic lead (e.g., tetraethyl lead, the lead additive to gasoline) is absorbed to a significant degree through the skin as well. Pulmonary absorption is efficient, particularly if particle diameters are <1 um (as in fumes from burning lead paint). Children absorb up to 50 percent of the amount of lead ingested, whereas adults absorb only about 10 to 20 percent. Gastrointestinal absorption of lead is enhanced by fasting and by dietary deficiencies in calcium, iron, and zinc; such absorption is minimal, however, for lead in the form of lead sulfide, a common constituent of mining waste. Lead is absorbed into blood plasma, where it equilibrates rapidly with extracellular fluid, crosses membranes (such as the blood-brain barrier and the placenta), and accumulates in soft and hard tissues. In the blood, around 95 to 99 percent of lead is sequestered in red cells, where it is bound to hemoglobin and other components. As a consequence, lead is usually measured in whole blood rather than in serum. The largest proportion of absorbed lead is incorporated into the skeleton, which contains more than 90 percent of the body's total lead burden. Lead is excreted mainly in the urine (in a process that depends on glomerular filtration and tubular secretion) and in the feces. Lead also appears in hair, nails, sweat, saliva, and breast milk. The half-life of lead in blood is approximately 25 days; in soft tissue, about 40 days; and in the nonlabile portion of bone, more than 25 years. Thus, blood lead levels may decline significantly while the body's total burden of lead remains heavy.

The toxicity of lead is probably related to its affinity for cell membranes and mitochondria, as a result of which it interferes with mitochondrial oxidative phosphorylation and sodium, potassium, and calcium ATPases. Lead impairs the activity of calcium-dependent intracellular messengers and of brain protein kinase C. In addition, lead stimulates the formation of inclusion bodies that may translocate the metal into cell nuclei and alter gene expression.

CLINICAL FEATURES

Symptomatic lead poisoning in childhood generally develops at blood lead levels exceeding 3.9 umol/L (80 ug/dL) and is characterized by abdominal pain and irritability followed by lethargy, anorexia, pallor (resulting from anemia), ataxia, and slurred speech. Convulsions, coma, and death due to generalized cerebral edema and renal failure occur in the most severe cases. Subclinical lead poisoning [blood lead level >1.4 umol/L (> 30 u g/dL)] can cause mental retardation and selective deficits in language, cognitive function, balance, behavior, and school performance despite the lack of discernible symptoms. Epidemiologic studies and meta-analyses of studies regarding lead's effect on the intellectual function of children indicate that cognition is probably impaired in a dose-related fashion at blood lead levels well below 1.4 umol/L (30 ug/dL) and that no threshold for this effect is likely to exist above the lowest measurable blood lead level of 0.05 umol/L (1 ug/dL). The impact is greatest when the exposure is of long duration and when it takes place around the age of 2 years.

In adults, symptomatic lead poisoning usually develops when blood lead levels exceed 3.9 umol/L (80 ug/dL) for a period of weeks and is characterized by abdominal pain, headache, irritability, joint pain, fatigue, anemia, peripheral motor neuropathy, and deficits in short-term memory and the ability to concentrate. Encephalopathy is rare. A "lead line" sometimes appears at the gingiva-tooth border after prolonged high-level exposure. Some individuals develop these symptoms and signs at lower blood lead levels [1.9 to 3.9 umol/L (40 to 80 u g/dL)] and/or with briefer periods of exposure. Chronic subclinical lead exposure is associated with interstitial nephritis, tubular damage (with tubular inclusion bodies), hyperuricemia (with an increased risk of gout), and a decline in glomerular filtration rate and chronic renal failure. Epidemiologic evidence also suggests that blood lead levels in the range of 0.34 to 1.7 umol/L (7 to 35 ug/dL) are associated with increases in blood pressure, decreases in creatinine clearance, and decrements in cognitive performance that are too small to be detected as a lead effect in individual cases but nevertheless may contribute significantly to the causation of chronic disease.

An additional issue for both children and adults is whether lead that has accumulated in bone and lain dormant for years can pose a threat later in life, particularly at times of increased bone resorption such as pregnancy, lactation, and senile osteoporosis. Elevation of the bone lead level appears to be a risk factor for anemia and hypertension. Hyperthyroidism has been reported to cause lead toxicity in adults by mobilizing stores of bone lead acquired during childhood.

Genetic polymorphisms of the gene that codes for aminolevulinic acid dehydratase, a critical enzyme in the production of heme, may confer differences in susceptibility to lead retention and toxicity; 15 percent of Caucasians have a variant form of this gene. This issue is the focus of continued research.

LABORATORY FINDINGS

Regular measurement of blood lead in lead-exposed workers and the maintenance of blood lead levels below 1.9 umol/L (40 ug/dL) is advised.

	Lead-associated anemia is usually normocytic and normochromic and may be accompanied by basophilic stippling.
	Lead-induced peripheral demyelination is reflected by prolonged nerve conduction time and subsequent paralysis, usually of the extensor muscles of the hands and feet ("wrist and foot drop").
	An increased density at the metaphyseal plate of growing long bones ("lead lines") can develop in children and resemble those seen in rickets. Children with high-level lead exposure sometimes develop Fanconi's syndrome, pyuria, and azotemia.
	Adults chronically exposed to lead can develop elevated serum creatinine levels, decreased creatinine clearance rates, and chronic changes and intranuclear inclusion bodies (detected at renal biopsy).
	Deficits may be apparent in neuropsychometric tests of both children and adults; these abnormalities by themselves are not pathognomonic.
	X-ray fluorescence is being investigated as a method for estimating long-term accumulation of lead in bone.

TREATMENT

Treatment for lead toxicity involves the use of chelating agents, principally edetate calcium disodium (CaEDTA), dimercaprol, penicillamine, and succimer, which is given orally.

ARSENIC Toxicity

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