POISONING & DRUG OVERDOSE - LEAD

20250420R-WBIF-lead

page 253

LEAD
Michael J. Kosnett, MD, MPH

Lead is a soft, malleable metal that is obtained chiefly by the primary smelting and refiing  of natural ores or by the widespread practice of recycling and secondary smelting of scrap lead products. Recycling accounts for nearly 85% of domestic lead consumption, approximately 85% of which is used in the manufacture of lead acid batteries. Lead is used for weights and radiation shielding, and lead alloys are used in the manufacture of pipes; cable sheathing; brass, bronze, and steel; ammunition; and solder (predominantly electric devices and automotive radiators). Lead compounds are added as pigments, stabilizers, or binders in paints, ceramics, glass, and plastic. 
Although the use of lead in house paint has been curtailed since the 1970s, industrial use of corrosion-resistant lead-based paint continues, and high-level exposure may result from renovation, sandblasting, torching, or demolition. Corrosion of lead plumbing in older homes may increase the lead concentration of tap water. Young children are particularly at risk from repeated ingestion of lead-contaminated house dust, yard soil, or paint chips or from mouthing toy jewelry or other decorative items containing lead. Children may also be exposed to lead carried into the home on contaminated work clothes worn by adults. Regular consumption of game meat harvested with lead ammunition and contaminated with lead residues may increase blood lead above background levels, particularly in children.
Lead exposure may occur from the use of lead-glazed ceramics or containers for food or beverage preparation or storage. Certain folk medicines (eg, the Mexican remedies azarcon and greta, the Dominican remedy litargirio, and some Indian Ayurvedic preparations) may contain high amounts of lead salts.
Consumer protection legislation enacted in 2008 lowered the permissible concentration of lead in paint and other surface coatings for consumer use to 0.009%(90 ppm). By 2011, the lead content of children’s products must not exceed 100 ppm.

I. Mechanism of toxicity

A. The multisystem toxicity of lead is mediated by several mechanisms, including inactivation or alteration of enzymes and other macromolecules by binding to sulfhydryl, phosphate, or carboxyl ligands and interaction with essential cations, most notably calcium, zinc, and iron. Pathologic alterations in cellular and mitochondrial membranes, neurotransmitter synthesis and function, heme synthesis,
cellular redox status, and nucleotide metabolism may occur. Adverse impacts on the nervous, renal, GI, hematopoietic, reproductive, and cardiovascular systems can result.

B. Pharmacokinetics. Inhalation of lead fume or other fine, soluble particulate results in rapid and extensive pulmonary absorption, the major although not exclusive route of exposure in industry. Nonindustrial exposure occurs predominantly by ingestion, particularly in children, who absorb 45–50% of soluble lead, compared with approximately 10–15% in adults. After absorption, lead is distributed
via the blood (where 99% is bound to the erythrocytes) to multiple tissues, including trans-placental transport to the fetus, and CNS transport across the bloodbrain barrier. Clearance of lead from the body follows a multicompartment kinetic model, consisting of “fast” compartments in the blood and soft tissues (half-life,1–2 months) and slow compartments in the bone (half-life, years to decades).
Approximately 70% of lead excretion occurs via the urine, with smaller amounts eliminated via the feces and scant amounts via the hair, nails, and sweat. Greater than 90% of the lead burden in adults and more than two-thirds of the burden in young children occur in the skeleton. Slow redistribution of lead from bone to soft tissues may elevate blood lead concentrations for months to years after a patient
with chronic high-dose exposure has been removed from external sources. In patients with a high bone lead burden, pathologic states associated with rapid bone turnover or demineralization, such as hyperthyroidism and immobilization osteoporosis, have resulted in symptomatic lead intoxication.

II. Toxic dose 

A. Dermal absorption is minimal with inorganic lead but may be substantial with organic lead compounds, which may also cause skin irritation. 
B. Ingestion. In general, absorption of lead compounds is directly proportional to solubility and inversely proportional to particle size. Gastrointestinal lead absorption is increased by iron deficiency and low dietary calcium. Absorption
can increase substantially in a fasted state.
1. Acute symptomatic intoxication is rare after a single exposure but may occur within hours after ingestion of gram quantities of soluble lead compounds or days after GI retention of swallowed lead objects, such as fishing weights and curtain weights.
2. Studies have not established a low-dose threshold for adverse subclinical effects of lead. Recent epidemiologic studies in children have observed effects of lead on cognitive function at blood lead concentrations of less than 5 mcg/dL, and other studies suggest that background levels of lead exposure in recent decades may have been associated with hypertension in some adults. The geometric mean blood lead concentration in the United States during 2003–2004 was estimated to be 1.43 mcg/dL; background dietary lead
intake may be in the range of 1–4 mcg/d.
3. The US Environmental Protection Agency (EPA) action level for lead in drinking water is 15 ppb (parts per billion). However, the maximum contaminant level (MCL) goal for drinking water is 0 ppb, and EPA has set no “reference dose” for lead because of the lack of a recognized low-dose threshold for adverse effects.
C. Inhalation. Unprotected exposure to the massive airborne lead levels (>2500 mcg/m3) encountered during abrasive blasting, welding, or torch cutting metal surfaces coated with lead-based paint poses an acute hazard and has resulted in symptomatic lead intoxication from within a day to a few weeks. The OSHA workplace permissible exposure limit (PEL) for inorganic lead dusts and fumes is 50 mcg/m3 as an 8-hour time-weighted average. The level considered immediately dangerous to life or health (IDLH) is 100 mg/m3
.
III. Clinical presentation. 

The multisystem toxicity of lead presents a spectrum of clinical findings ranging from overt, life-threatening intoxication to subtle, subclinical effects.
A. Acute ingestion of very large amounts of lead (gram quantities) may cause abdominal pain, anemia (usually hemolytic), toxic hepatitis, and encephalopathy.
B. Subacute or chronic exposure is more common than acute poisoning. 
1. Constitutional effects include fatigue, malaise, irritability, anorexia, insomnia,weight loss, decreased libido, arthralgias, and myalgias.
2. Gastrointestinal effects include cramping abdominal pain (lead colic), nausea, constipation, or (less commonly) diarrhea.
3. Central nervous system manifestations range from impaired concentration, headache, diminished visual-motor coordination, and tremor to overt encephalopathy (a life-threatening emergency characterized by agitated delirium or lethargy, ataxia, convulsions, and coma). Chronic low-level exposure in infants and children may lead to decreased intelligence and impaired neurobehavioral development, stunted growth, and diminished auditory acuity. Recent studies in adults suggest that lead may accentuate age-related decline in cognitive function.
4. Cardiovascular effects of chronic lead exposure include blood pressure elevation and an increased risk for hypertension. Recent studies have detected elevated cardiovascular mortality in populations whose long-term blood lead
concentrations were likely in the range of 10–25 mcg/dL.
5. Peripheral motor neuropathy, affecting mainly the upper extremities, can cause severe extensor muscle weakness (“wrist drop”).
6. Hematologic effects include normochromic or microcytic anemia, which may be accompanied by basophilic stippling. Hemolysis may occur after acute or subacute high-dose exposure.
7. Nephrotoxic effects include reversible acute tubular dysfunction (including Fanconi-like aminoaciduria in children) and chronic interstitial fibrosis. Hype ruricemia and gout may occur.
8. Adverse reproductive outcomes may include diminished or aberrant sperm production, increased rate of miscarriage, preterm delivery, decreased gestational age, low birth weight, and impaired neurologic development.
C. Repeated, intentional inhalation of leaded gasoline has resulted in ataxia, myoclonic jerking, hyperreflexia, delirium, and convulsions.
IV. Diagnosis. Although overt encephalopathy or abdominal colic associated with a suspect activity may readily suggest the diagnosis of severe lead poisoning, the nonspecific symptoms and multisystem signs associated with mild or moderate intoxication may be mistaken for a viral illness or another disorder. Consider lead poisoning in any patient with multisystem findings that include abdominal pain, headache, anemia, and, less commonly, motor neuropathy, gout, and renal insufficiency. Consider lead encephalopathy in any child or adult with delirium or convulsions (especially with coexistent anemia), and chronic lead poisoning in any child with neurobehavioral deficits or developmental delays. 

A. Specific levels. The whole-blood lead level is the most useful indicator of lead exposure. Relationships between blood lead levels and clinical findings generally have been based on subacute or chronic exposure, not on transiently high values that may result immediately after acute exposure. In addition, there may be considerable interindividual variability. Note: Blood lead samples must
be drawn and stored in lead-free syringes and tubes (“trace metals” tube or royal blue stopper tube containing heparin or EDTA).
1. Blood lead levels are less than 5 mcg/dL in populations without occupational or specific environmental exposure. Levels between 1 and 25 mcg/dL have been associated with subclinical decreases in intelligence and impaired neurobehavioral development in children exposed in utero or in early childhood. The dose-response for IQ decrement is log-linear, such that IQ loss per mcg/dL is
steepest at low dose. Studies in adults indicate that long-term blood lead concentrations in the range of 10–25 mcg/dL (and possibly lower) pose a risk for hypertension and may possibly contribute to age-related decline in cognitive function.
2. Blood lead levels of 25–60 mcg/dL may be associated with headache, irritability, difficulty concentrating, slowed reaction time, and other neuropsychiatric effects. Anemia may occur, and subclinical slowing of motor nerve conduction may be detectable.
3. Blood levels of 60–80 mcg/dL may be associated with GI symptoms and subclinical renal effects.
4. With blood levels in excess of 80 mcg/dL, serious overt intoxication may occur, including abdominal pain (lead colic) and nephropathy. Encephalopathy and neuropathy usually are associated with levels over 100 
B. Elevations in free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZPP) (>35 mcg/dL) reflect lead-induced inhibition of heme synthesis. Because only actively forming and not mature erythrocytes are affected, elevations typically lag lead exposure by a few weeks. High blood levels of lead in the presence of a normal FEP or ZPP level therefore suggests very recent exposure. Protoporphyrin elevation is not specific for lead and may also occur with iron deficiency. Protoporphyrin levels are not sensitive for low-level exposure (blood lead <30 mcg/dL).
C. Urinary lead excretion increases and decreases more rapidly than blood lead. In the CDC’s “Fourth National Report on Human Exposure to Environmental Chemicals” (http://www.cdc.gov/exposurereport), the geometric mean urinary lead concentration of subjects age 6 and older was 0.6 mcg/L. Normal, baseline urinary lead excretion for the general population is less than 5 mcg/d. Several
empiric protocols that measure 6- or 24-hour urinary lead excretion after calcium EDTA challenge have been developed to identify persons with elevated body lead burdens. However, because chelatable lead predominantly reflects lead in soft tissues, which in most cases already correlates satisfactorily with blood lead, chelation challenges are seldom indicated in clinical practice.
D. Noninvasive in vivo x-ray fluorescence measurement of lead in bone, a test predominantly available in research settings, may provide the best index of longterm cumulative lead exposure and total body lead burden.
E. Other tests. Nonspecific laboratory findings that support the diagnosis of lead poisoning include anemia (normocytic or microcytic) and basophilic stippling of erythrocytes, a useful but insensitive clue. Acute high-dose exposure sometimes may be associated with transient azotemia (elevated BUN and serum creatinine) and mild to moderate elevation in serum aminotransferases. Recently ingested
lead paint, glazes, chips, or solid lead objects may be visible on abdominal radiographs. CT or MRI of the brain often reveals cerebral edema in patients with lead encephalopathy. Because iron deficiency increases lead absorption, iron status should be evaluated.
V. Treatment
A. Emergency and supportive measures 1. Treat seizures (p 22) and coma (p 18) if they occur. Provide adequate fluids to maintain urine flow (optimally 1–2 mL/kg/h) but avoid overhydration, which may aggravate cerebral edema. Avoid phenothiazines for delirium, as they may lower the seizure threshold. 
2. Patients with increased intracranial pressure may benefit from corticosteroids (eg, dexamethasone, 10 mg IV) and mannitol (0.25–1.0 g/kg IV as a 20–25% solution).
B. Specific drugs and antidotes. Treatment with chelating agents decreases blood lead concentrations and increases urinary lead excretion. Although chelation has been associated with relief of symptoms and decreased mortality, controlled clinical trials demonstrating efficacy are lacking, and treatment recommendations have been largely empiric.
1. Encephalopathy. Administer IV calcium EDTA (p 481). Some clinicians initiate treatment with a single dose of BAL (p 453), followed 4 hours later by concomitant administration of calcium EDTA and BAL.
2. Symptomatic without encephalopathy. Administer oral succimer (DMSA, p 553) or parenteral calcium EDTA (p 481). Calcium EDTA is preferred as initial treatment if the patient has severe GI toxicity (eg, lead colic) or if the blood lead concentration is extremely elevated (eg, >150 mcg/dL). Unithiol (p 558) may be considered as an alternative to DMSA.
3. Asymptomatic children with elevated blood lead levels. The CDC recommends treatment of children with levels of 45 mcg/dL or higher. Use oral succimer (DMSA, p 553). A large randomized, double-blind, placebo-controlled trial of DMSA in children with blood lead concentrations between 25 and 44 mcg/dL found no evidence of clinical benefit.
4. Asymptomatic adults. The usual treatment is removal from exposure and observation. Consider oral succimer (DMSA, p 553) for patients with markedly elevated levels (eg, >80–100 mcg/dL).
5. Although D-penicillamine (p 531) is an alternative oral treatment, it may be associated with more side effects and less efficient lead diuresis.
6. Blood lead monitoring during chelation. Obtain a blood lead measurement immediately before chelation and recheck the measurement within 24–48 hours after starting chelation to confirm that levels are declining. Recheck measurements 1 day and from 7 to 21 days after chelation to assess the extent of rebound in blood lead level associated with redistribution of lead from high bone stores and/or the possibility of reexposure. Additional courses of treatment and further investigation of exposure sources may be warranted.
C. Decontamination (p 46)
1. Acute ingestion. Because even small items (eg, a paint chip or a sip of lead-containing glaze) may contain tens to hundreds of milligrams of lead, gut decontamination is indicated after acute ingestion of virtually any lead containing substance.
a. Administer activated charcoal (although efficacy is unknown).
b. If lead-containing material is still visible on abdominal radiograph after initial treatment, consider whole-bowel irrigation (p 52).
c. Consider endoscopic or surgical removal of lead foreign bodies that exhibit prolonged GI retention.
2. Lead-containing buckshot, shrapnel, or bullets in or adjacent to a synovial space or a fluid-filled space, such as a paravertebral pseudocyst or a subscapular bursa, should be surgically removed if possible, particularly if associated with evidence of systemic lead absorption.
D. Enhanced elimination. There is no role for dialysis, hemoperfusion, or repeatdose charcoal. However, in anuric patients with chronic renal failure, limited study suggests that calcium EDTA combined with hemofiltration or high-flux hemodialysis may increase lead clearance.
E. Other required measures. Remove the patient from the source of exposure and institute control measures to prevent repeated intoxication. Other possibly exposed persons (eg, co-workers or siblings or playmates of young children) should be evaluated promptly.
1. Infants and children. The CDC no longer recommends universal blood lead screening for low-income or Medicaid-eligible children, but instead urges state and local officials to target screening toward specific groups of children in their area at higher risk for elevated blood lead levels. Detailed guidelines for case management of children with elevated blood lead levels are found at the following CDC Web site: www.cdc.gov/nceh/lead/CaseManagement/ caseManage main.htm. The 2005 CDC statement “Preventing Lead Poisoning in Young Children” (www.cdc.gov/nceh/lead/publications/PrevLeadPoison ing.pdf) maintained 10 mcg/dL as a blood lead level of concern but acknowledged adverse impacts at lower levels and called for primary prevention.
2. Adults with occupational exposure a. Federal OSHA standards for workers exposed to lead provide specific guidelines for periodic blood lead monitoring and medical surveillance (www.osha-slc.gov/OshStd toc/OSHA Std toc 1910.html). Under the general industry standard, workers must be removed from exposure if a single blood lead level exceeds 60 mcg/dL or if the average of three successive levels exceeds 50 mcg/dL. In construction workers, removal is required if a single blood lead level exceeds 50 mcg/dL. Workers may not return to work until the blood lead level is below 40 mcg/dL and any clinical manifestations of toxicity have resolved. Prophylactic chelation is prohibited. OSHA standards mandate that workers removed from work because of elevated blood lead levels retain full pay and benefits. 

b. Medical removal parameters in the OSHA standards summarized above were established in the late 1970s and are outdated based on current background blood levels and recent concern about the hazards of lower-level exposure. The standards explicitly empower physicians to order medical removal at lower blood lead levels. It may now be prudent and feasible for employers to maintain workers’ blood lead levels below 20 mcg/dL and possibly below 10 mcg/dL. In 2005, the Association of Occupational and Environmental Clinics (www.aoec.org) approved “Medical Management Guidelines for Lead-Exposed Adults,” which call for worker protection more stringent than current OSHA standards. Under EPA regulations effective in 2010, contractors performing renovation, repair, and painting projects that disturb lead-based paint in homes, child care facilities, and schools built before 1978 must be certified and must follow specific work practices to prevent lead contamination.
c. The CDC recommends that pregnant women with blood lead concentrations of 5 mcg/dL or higher undergo exposure reduction, nutritional counseling, and follow-up testing, and that pregnant women with blood lead concentrations of 10 mcg/dL or higher be removed from occupational lead exposure.