Toxicology of Lead

TOXICOLOGY OF HEAVY METALS

LEAD

Lead poisoning is one of the oldest occupational and environmental diseases in the world. Despite its recognized hazards, lead continues to have widespread commercial application, including production of storage batteries (nearly 90% of US consumption), ammunition, metal alloys, solder, glass, plastics, pigments, and ceramics. Corrosion of lead plumbing in older buildings or supplylines may increase the lead concentration of tap water. Environmental lead exposure, ubiquitous by virtue of the anthropo-genic distribution of lead to air, water, and food, has declined con-siderably in the last three decades as a result of the elimination of lead as an additive in gasoline, as well as diminished contact with lead-based paint and other lead-containing consumer products, such as lead solder in canned food. Although these public health measures, together with improved workplace conditions, have decreased the incidence of serious overt lead poisoning, there remains considerable concern over the effects of low-level lead exposure. Extensive evi-dence indicates that lead may have subtle subclinical adverse effects on neurocognitive function and on blood pressure at low blood lead concentrations formerly not recognized as harmful. Lead serves no useful purpose in the human body. In key target organs such as the developing central nervous system, no level of lead exposure has been shown to be without deleterious effects.

Pharmacokinetics

Inorganic lead is slowly but consistently absorbed via the respiratory and gastrointestinal tracts. Inorganic lead is poorly absorbed through the skin. Absorption of lead dust via the respiratory tract is the most common cause of industrial poisoning. The intestinal tract is the primary route of entry in nonindustrial exposure (Table 57–1). Absorption via the gastrointestinal tract varies with the nature of the lead compound, but in general, adults absorb about 10–15% of the ingested amount, whereas young children absorb up to 50%. Low dietary calcium, iron deficiency, and ingestion on an empty stomach all have been associated with increased lead absorption.

Once absorbed from the respiratory or gastrointestinal tract, lead enters the bloodstream, where approximately 99% is bound to erythrocytes and 1% is present in the plasma. Lead is subse-quently distributed to soft tissues such as the bone marrow, brain, kidney, liver, muscle, and gonads; then to the subperiosteal surface of bone; and later to bone matrix. Lead also crosses the placenta and poses a potential hazard to the fetus. The kinetics of lead clearance from the body follows a multicompartment model, composed predominantly of the blood and soft tissues, with a half-life of 1–2 months; and the skeleton, with a half-life of years to decades. Approximately 70% of the lead that is eliminated appears in the urine, with lesser amounts excreted through the bile, skin, hair, nails, sweat, and breast milk. The fraction not undergoing prompt excretion, approximately half of the absorbed lead, may be incorporated into the skeleton, the repository of more than 90% of the body lead burden in most adults. In patients with high bone lead burdens, slow release from the skel-eton may elevate blood lead concentrations for years after expo-sure ceases, and pathologic high bone turnover states such as hyperthyroidism or prolonged immobilization may result in frank lead intoxication. Migration of retained lead bullet fragments into a joint space or adjacent to bone has been associated with the development of lead poisoning signs and symptoms years or decades after an initial gunshot injury.

Pharmacodynamics

Lead exerts multisystemic toxic effects that are mediated by mul-tiple modes of action, including inhibition of enzymatic function; interference with the action of essential cations, particularly cal-cium, iron, and zinc; generation of oxidative stress; changes in gene expression; alterations in cell signaling; and disruption of the integrity of membranes in cells and organelles.

A. Nervous System

The developing central nervous system of the fetus and young child is the most sensitive target organ for lead’s toxic effect. Epidemiologic studies suggest that blood lead concentrations even less than 5 mcg/dL may result in subclinical deficits in neurocog-nitive function in lead-exposed young children, with no demon-strable threshold for a “no effect” level. The dose response between low blood lead concentrations and cognitive function in young children is nonlinear, such that the decrement in intelligence associ-ated with an increase in blood lead from less than 1 to 10 mcg/dL (6.2 IQ points) exceeds that associated with a change from 10 to 30 mcg/dL (3.0 IQ points).

Adults are less sensitive to the central nervous system effects of lead, but long-term exposure to blood lead concentrations in the range of 10–30 mcg/dL may be associated with subtle, subclinical effects on neurocognitive function. At blood lead concentrations higher than 30 mcg/dL, behavioral and neurocognitive signs or symptoms may gradually emerge, including irritability, fatigue, decreased libido, anorexia, sleep disturbance, impaired visual-motor coordination, and slowed reaction time. Headache, arthral-gias, and myalgias are also common complaints. Tremor occurs but is less common. Lead encephalopathy, usually occurring at blood lead concentrations higher than 100 mcg/dL, is typically accompanied by increased intracranial pressure and may cause ataxia, stupor, coma, convulsions, and death. Recent epidemio-logical studies suggest that lead may accentuate an age-related decline in cognitive function in older adults. In experimental ani-mals, developmental lead exposure has been associated with increased expression of beta-amyloid, oxidative DNA damage, and Alzheimer’s-type pathology in the aging brain. There is wide inter-individual variation in the magnitude of lead exposure required to cause overt lead-related signs and symptoms.

Overt peripheral neuropathy may appear after chronic high-dose lead exposure, usually following months to years of blood lead concentrations higher than 100 mcg/dL. Predominantly motor in character, the neuropathy may present clinically with painless weakness of the extensors, particularly in the upper extremity, resulting in classic wrist-drop. Preclinical signs of lead-induced peripheral nerve dysfunction may be detectable by elec-trodiagnostic testing.

B. Blood

Lead can induce an anemia that may be either normocytic or microcytic and hypochromic. Lead interferes with heme synthesis by blocking the incorporation of iron into protoporphyrin IX and by inhibiting the function of enzymes in the heme synthesis path-way, including aminolevulinic acid dehydratase and ferrochelatase. Within 2–8 weeks after an elevation in blood lead concentration (generally to 30–50 mcg/dL or greater), increases in heme precur-sors, notably free erythrocyte protoporphyrin or its zinc chelate, zinc protoporphyrin, may be detectable in whole blood. Lead also contributes to anemia by increasing erythrocyte membrane fragil-ity and decreasing red cell survival time. Frank hemolysis may occur with high exposure. Basophilic stippling on the peripheral blood smear, thought to be a consequence of lead inhibition of the enzyme 3’,5’-pyrimidine nucleotidase, is sometimes a suggestive— albeit insensitive and nonspecific—diagnostic clue to the presence of lead intoxication.

C. Kidneys

Chronic high-dose lead exposure, usually associated with months to years of blood lead concentrations greater than 80 mcg/dL, mayresult in renal interstitial fibrosis and nephrosclerosis. Lead neph-ropathy may have a latency period of years. Lead may alter uric acid excretion by the kidney, resulting in recurrent bouts of gouty arthritis (“saturnine gout”). Acute high-dose lead exposure some-times produces transient azotemia, possibly as a consequence of intrarenal vasoconstriction. Studies conducted in general popula-tion samples have documented an association between blood lead concentration and measures of renal function, including serum creatinine and creatinine clearance. The presence of other risk fac-tors for renal insufficiency, including hypertension and diabetes, may increase susceptibility to lead-induced renal dysfunction.

D. Reproductive Organs

High-dose lead exposure is a recognized risk factor for stillbirth or spontaneous abortion. Epidemiologic studies of the impact of low-level lead exposure on reproductive outcome such as low birth weight, preterm delivery, or spontaneous abortion have yielded mixed results. However, a well-designed nested case-control study detected an odds ratio for spontaneous abortion of 1.8 (95% CI 1.1–3.1) for every 5 mcg/dL increase in maternal blood lead across an approximate range of 5–20 mcg/dL. Recent studies have linked prenatal exposure to low levels of lead (eg, maternal blood lead concentrations of 5–15 mcg/dL) to decrements in physical and cognitive development assessed during the neonatal period and early childhood. In males, blood lead concentrations higher than 40 mcg/dL have been associated with diminished or aberrant sperm production.

E. Gastrointestinal Tract

Moderate lead poisoning may cause loss of appetite, constipation, and, less commonly, diarrhea. At high dosage, intermittent bouts of severe colicky abdominal pain (“lead colic”) may occur. The mecha-nism of lead colic is unclear but is believed to involve spasmodic contraction of the smooth muscles of the intestinal wall, mediated by alteration in synaptic transmission at the smooth muscle-neuro-muscular junction. In heavily exposed individuals with poor dental hygiene, the reaction of circulating lead with sulfur ions released by microbial action may produce dark deposits of lead sulfide at the gingival margin (“gingival lead lines”). Although frequently men-tioned as a diagnostic clue in the past, in recent times this has been a relatively rare sign of lead exposure.

F. Cardiovascular System

Epidemiologic, experimental, and in vitro mechanistic data indi-cate that lead exposure elevates blood pressure in susceptible indi-viduals. In populations with environmental or occupational lead exposure, blood lead concentration is linked with increases in systolic and diastolic blood pressure. Studies of middle-aged and elderly men and women have identified relatively low levels of lead exposure sustained by the general population to be an indepen-dent risk factor for hypertension. In addition, epidemiologic stud-ies suggest that low to moderate levels of lead exposure are risk factors for increased cardiovascular mortality. Lead can also elevate blood pressure in experimental animals. The pressor effect of lead may be mediated by an interaction with calcium mediated con-traction of vascular smooth muscle, as well as generation of oxida-tive stress and an associated interference in nitric oxide signaling pathways.