Toxicity, Lead ?>

Toxicity, Lead

Toxicity, Lead


Introduction
Background

Lead is a natural compound that exists in elemental, inorganic, and organic forms. Lead is present in trace amounts in all soils, water, and foods. Lead is soft, malleable, blue-gray in color, and is highly resistant to corrosion. The melting point of lead is 327°C, and the vapor pressure of lead is 1000°C at 1.77 mm Hg. These properties, along with the poor ability of lead to conduct heat and electricity, probably contributed to the early discovery and persistent use of lead by humans. Lead pigments, for example, have been used in paints for more than 40,000 years, and lead utensils and artifacts, dating back 8000 years, have been recovered from Mediterranean excavation sites.

Currently, lead is used in more than 900 occupations and hobbies, including mining, smelting, refining, battery manufacturing, soldering, electrical wiring, home demolition and construction, painting, ceramic glazing, and the making of stained glass.

Lead toxicity has also been recognized for thousands of years. In the second century BCE, the Greek physician Dioscorides noted that lead makes the “mind give way.” In the first century BCE, Marcus Vitruvius Pollio, the father of architecture, recommended that clay replace all of the lead-based water pipeline system in the Roman Empire because “lead destroyed the vigor of the blood.”

Today, lead toxicity is well documented and is recognized as a major environmental health risk throughout the world. Lead affects humans and animals of all ages, but the effects of lead are most serious in young children.

Pathophysiology

Lead poisoning results from the interaction of the metal with biological electron-donor groups, such as the sulfhydryl groups, which interferes with a multitude of enzymatic processes. Lead also interacts with essential cations, particularly calcium, iron, and zinc; it interferes with the sodium-potassium-adenosine triphosphate (Na+/K+ -ATP) pump; and it alters cellular and mitochondrial membranes, thereby increasing cellular fragility. Additionally, lead inhibits pyrimidine-5′-nucleotidase and alters other nucleotide functions.

Lead interferes with many enzyme systems of the body, thereby affecting the function of virtually every organ. Clinical manifestations of lead toxicity include symptoms referable to the central nervous system, the peripheral nervous system, the hematopoietic system, the renal system, and the gastrointestinal systems. Children exposed to lead may experience devastating consequences because of the effects of lead on the developing brain.

Absorption

Lead poisoning occurs as a result of ingestion or inhalation of inorganic lead particles or through transdermal absorption of organic alkyl lead. The respiratory tract provides the most effective route of absorption because it only depends on the size of lead particles and the metabolic activity of the body. Airborne lead particles that are less than 0.5-1 microns in diameter are generally completely absorbed by the alveoli. Gastrointestinal absorption of lead is less effective and depends on a number of factors, eg, the presence of food in the stomach, the concentration of lead ingested, the nutritional status of the patient, and the age of the patient. Lead absorption rates may increase with iron, zinc, and calcium deficiencies.

Children are at the highest risk for toxicity because they absorb proportionately larger amounts of lead from either route. In the case of gastrointestinal absorption, children absorb as much as 40% of ingested lead, whereas adults only absorb 10%. Transdermal absorption is minimal for inorganic lead but may be substantial for alkyl lead.

Distribution

Once absorbed, 99% of lead binds to erythrocytes, and the remaining 1% is free to diffuse into soft tissues and bone, where it equilibrates with blood lead. Lead deposition in erythrocytes and soft tissues is responsible for most of the toxic effects of the metal. The half-life of lead differs for each of the compartments, ranging from 25-40 days in erythrocytes, 40 days in soft tissues, and as many as 28 years in bone.

Bone lead accounts for more than 95% of the lead burden in adults and 70% of the burden in children. Lead is commonly incorporated into rapidly growing bones, such as the tibia, femur, and radius, where it competes with calcium and may exert toxic effects on skeletal growth. Bone acts as a reservoir for lead in the same way that it acts as a reservoir for calcium. The body may mobilize its lead stores during periods of stress, fever, hyperthyroidism, prolonged immobilization, pregnancy, and lactation.

Elimination

Lead that is not retained by the body is excreted unchanged in urine (65-75%) and in bile (25-30%). The urinary lead excretion rate depends on renal blood flow and glomerular filtration rate. Factors that affect either of these 2 functions affect blood lead concentrations. Small amounts of lead may be found in sweat and milk.

Hematologic effects

Perhaps the best-known and best-studied toxic effect of lead is the effect lead has on heme synthesis. Lead inhibits delta aminolevulinic acid dehydrase (delta-ALAD) and ferrochelatase (heme-synthetase). As a result, delta-ALAD cannot be converted into porphobilinogen nor can iron be incorporated into the protoporphyrin ring. Therefore, heme synthesis is reduced. Because heme is important for the function of the cytochrome system and cellular respiration, lead poisoning has tremendous impact on the entire organism. Lead also inhibits the Na+/K+ -ATP pump and attaches to the RBC membranes, leading to their lysis.

Neurologic effects

Lead affects the central nervous system by multiple different mechanisms, most of which are unexplored. In the brain, lead is known to alter the function of cellular calcium and inactivate the blood-brain barrier. These alterations result in leakage of proteinaceous fluid and brain edema, which affects all parts of the CNS, predominantly the cerebellum and the occipital lobes. Lead-induced cerebral edema is manifested initially by headaches, clumsiness, vertigo, and ataxia, followed by seizures, coma, mortality, or recovery with permanent neurologic loss. Lead also impairs the function of several protein kinases and neurotransmitters. In the peripheral nervous system, lead poisoning causes segmental demyelination of motor neurons and destruction of Schwann cells, resulting in motor neuron dysfunction.

Gastrointestinal effects

Lead causes contractions of the smooth muscle lining of intestinal walls, leading to severe, excruciating, colicky abdominal pains (lead colic); anorexia; diarrhea; and constipation.

Renal effects

Lead nephropathy develops because of the inhibitory effects of lead on cellular respiration. Lead causes a generalized dysfunction of proximal, tubular, energy-dependent functions, manifesting as a Fanconilike syndrome with aminoaciduria, glycosuria, and phosphaturia. Although this effect is generally limited and reversible by chelation, chronic industrial exposure to lead has been associated with an irreversible interstitial nephropathy. This chronic nephropathy may result in hyperuricemia with gout, called saturnine gout.

Other effects

Lead has negative effects on the reproductive system, causing low sperm count and abnormal sperm morphology in men and infertility, menstrual irregularity, spontaneous abortion, and stillbirths in women.

In children, lead impairs the release of human growth hormone and insulin growth factor and interferes with skeletal calcium and cyclic adenosine monophosphate (cAMP) functions, resulting in abnormalities of bone growth. Chronic exposure to lead also may result in reduced thyroid function. Rarely, acute lead poisoning results in hepatitis, pancreatitis, or cardiac dysfunction.
Frequency
United States

The most recent Adult Blood Level Epidemiology and Surveillance (ABLES) report indicated that the national prevalence rate of adults with blood lead levels (BLLs) greater than 25 mcg/dL was 7.5 per 100,000 in the employed population older than 16 years.1

In 2004, 3154 lead exposures were reported to US Poison Control Centers, with one fatality.

International

Lead toxicity is known to all cultures of the world, and efforts at reducing the prevalence of lead toxicity are common in industrialized countries. In France, more than 5% of adults and 2% of children aged 1-6 years have lead levels greater than 10 mcg/dL. Adults who live near smelter plants also have high blood lead levels. Leroyer et al reported that up to 30% of men living in the vicinity of smelter plants had blood lead levels that exceeded 10 mcg/dL.2

According to the Centers for Disease Control and Prevention (CDC), the prevalence of elevated blood lead levels among newly resettled refugee children (primarily children from Africa) is substantially higher than in children born in the United States.
Mortality/Morbidity

In humans, the acute ingestion of 15 grams of lead oxide has resulted in death. Survival generally depends on the adequacy of supportive care and the institution of chelation therapy. Chelation therapy combined with intensive therapy may reduce mortality rates from 65% to less than 5%.

Morbidity remains high; nearly 85% of patients who survive encephalopathy eventually develop permanent and obvious neurologic sequelae, including seizures and cognitive deficits. Additionally, lead toxicity has chronic deleterious effects on the peripheral nervous system, the hematopoietic system, the renal system, and the gastrointestinal tract.

As stated above, in 2004, 3154 lead exposures were reported to the US Poison Control Centers with only one fatality. However, 94 patients were reported to have moderate-to-severe toxicity.
Race

According to the 1999-2002 NHANES study, nonHispanic black and Mexican American children living in inner-city, old, dilapidated buildings are at the highest risk for developing lead toxicity because of socioeconomic factors. The prevalence of blood lead levels higher than 10 mcg/dL in children aged 1-5 years is estimated to be 1.4% in African American children and 1.5% in Mexican American children, compared with 0.5% in nonHispanic white children.
Sex

In adults, lead toxicity is most commonly caused by occupational exposure, and men are generally at higher risk than are women.

Lead has adverse effects on follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in both men and women.

Lead has direct toxic effects on spermatogenesis, resulting in a decreased sperm count and an increase in the number of abnormal sperm.

Lead readily crosses the placenta and may adversely affect the outcome of a pregnancy and the fetus. Lead poisoning has been associated with an increased risk of spontaneous abortion, preterm delivery, and stillbirth and an increased incidence of infant mortality.

Age

Infants and children absorb lead more readily than adults and deposit only 70% of the lead burden into bone, compared with 95% in adults. This leaves 30% of the lead burden to be deposited in soft tissue, particularly the brain, kidneys, bone marrow, and liver.

According to the CDC, 1.98% of children tested for lead toxicity in 2004 were found to have elevated blood lead levels.3

Clinical
History

Because lead is a multiorgan toxin, consider the diagnosis of lead poisoning in patients presenting with multisystem disease. The combination of abdominal pain, hemolytic anemia, and neurologic dysfunction, including headache, should raise suspicion of lead toxicity.

Chronic exposure to low levels of lead may present with nonspecific abdominal symptoms, such as anorexia, fatigue, abdominal pain, vomiting, constipation, diarrhea, and neurobehavioral abnormalities such as headache, inability to concentrate and perform complex tasks, tremors, irritability, mood disorders, depression, and decreased libido. More severe chronic exposures are associated with microcytic anemia, motor neuropathies, hypertension, hyperuricemia, aminoaciduria, and renal failure.

Acute massive lead poisoning is very rare. In children, massive lead poisoning is generally due to the cumulative effects of continued exposure to small amounts of lead, culminating in an acute life-threatening presentation. Blood lead levels are generally greater than 100 mcg/dL in children with severe life-threatening illness. Most commonly, patients present with a history of nonspecific multiorgan symptoms similar to those seen in mild toxicity, but progress to acute life-threatening encephalopathy. Symptoms include headache, vomiting, bizarre behavior, loss of developmental skills, lethargy alternating with lucid intervals, clumsiness, vertigo, and ataxia, followed by delirium, seizures, and coma. Abdominal pain is intense. Vomiting and diarrhea may be severe enough to result in hypovolemic shock. Anemia due to hemolysis and iron deficiency is common, as is renal failure.

In the US, lead encephalopathy is rarely reported in adults and is most commonly associated with the ingestion of “moonshine.” It is manifested by headache, confusion, convulsions and coma. Blood lead levels are generally greater than 150 mcg/dL. Patients may also present with peripheral neuropathies, optic neuritis, severe abdominal pain, anemia as well as nephropathy.
Physical

Similar to the history, the physical examination findings in a patient with lead toxicity attest to multiorgan involvement. The CNS, gastrointestinal, hematologic, and renal systems are the most seriously affected. Patients with moderate chronic toxicity may appear uncomfortable due to abdominal pain, pale due to anemia, with an elevated blood pressure due to renal insufficiency. CNS effects are manifested by tremors, hyperreflexia, weakness of upper extremity, and peripheral neuropathies (especially wrist drop). Other physical findings of chronic lead toxicity include the following:

Gingival lead lines (purple-blue lines consisting of lead sulfide precipitates within the gingival tissue)
Buccal stains
Macular gray stains

Severe and acute lead poisoning presents with lead encephalopathy, hemolysis, renal failure, and/or circulatory collapse. Lead encephalopathy, which may or may not be associated with cerebral edema, is manifested by changes in behavior, stupor, coma, or convulsions. The presence of papilledema, hypertension, and bradycardia should prompt the consideration of cerebral edema. The abdomen may be rigid. Vomiting and diarrhea may be so severe so as to cause circulatory collapse. Shock may also be due to severe hemolysis, which also results in significant anemia and pallor.

Causes

Lead is used in paints because of its luster and durability. Lead dusts are produced when these paints are old and chipped; thus, the environment becomes contaminated with the dust. Children also may ingest lead paint chips, which taste sweet. Lead-based industries, such as lead smelting, lead refining, and battery manufacturing, constitute another major environmental source of lead poisoning. Vapors, fumes, and powders generated by these industries contaminate the soil, food, and water supply of the communities surrounding them. Vehicle exhaust may be a significant environmental source of lead in countries that continue to use lead as an antiknock agent in their gasoline, a practice that has been banned in the United States since 1976.
Leaded paints: Historically, leaded paints have been considered to be among the highest quality paints and are desirable for their durability, their water resistance, and their bright colors. Prior to 1955, lead constituted as much as 40% of the dry weight in these paints that commonly were used around households. In 1955, the American Standards Association limited the lead concentration in paints to 1%. In 1978, the Consumer Product Safety Commission banned paints containing more than 0.06% of lead from use around households. People, especially children, living in homes built prior to World War II that were painted prior to 1955 are at high risk for lead toxicity. Children are most often poisoned by nibbling on paint chips and by mouthing objects contaminated by the dust emanating from old paints.
Contaminated waters: Water channeled through old water distribution systems also may contain high levels of lead. In these systems, water with high oxygen and low salt contents, such as spring water and rainwater, carries a higher risk for lead toxicity because of the formation of a water-soluble lead oxide, which is carried through the pipeline. The presence of calcium salts (carbonates and sulfates), on the other hand, creates an insoluble lead salt film covering the internal aspect of the pipeline, thus reducing the leaching of lead into the water.
Contaminated food supply: Food may be contaminated by lead dust and leaded soils, as well as by the leaching of lead from leaded utensils. Although lead may be resistant to most acids in its massive state, acids as weak as fruit juices, ciders, tomato juice, and vinegar corrode it when it is in small quantities. Foods canned outside the United States may also be a source of contamination, as lead is used to solder these cans. In the United States, this practice was abolished in 1991.
Contaminated alcohol and substances of abuse: Moonshine, a whiskey that is illicitly distilled in lead-containing automobile pipes and radiators, may be the source of substantial lead poisonings in the population with alcoholism. Traces of lead are occasionally found in street drug samples of heroin and cocaine, and most recently in marijuana samples.4
Hobbies: Some hobbies, such as painting, making the glaze for ceramics, and making stained glass, use lead-based substances and may expose the artist to high concentrations of lead.
Occupations: Lead poisoning may also occur through chronic occupational exposure. Lead is used extensively in the electrical, printing, ammunitions, plumbing, and automobile industries. Poisoning may occur through the chronic inhalation of these industrial emissions. Populations living in the proximity of these industries also are at higher risk for exposure through the inhalation of industrial emissions.
Leaded gasoline: Outside the United States, organic lead, an alkyl form of the metal used mainly as an antiknock additive to gasoline, may be an important source of lead. In the United States, however, leaded gasoline has been banned since 1976.
Other: Recently, high levels of lead were found in toys imported from China, leading to a number of massive product recalls in the United States. Lead has also been found in many folk remedies from around the world (Asian, Middle-Eastern, Ayurvedic, Hispanic). Retained lead bullets may also cause toxicity, especially when the bullet is in contact with serous membranes.

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