Pathophysiology and Etiology of Lead Toxicity

The pharmacokinetics of lead (Pb) in humans is complex. Humans are in a state of positive lead balance from birth. In the United States, substantial progress has been made over the past four decades in reducing the number of children with elevated blood lead levels (BLLs). Data from the 1976–1980 cycle of the National Health and Nutrition Examination Survey (NHANES) indicated that an estimated 88% of children aged 1–5 years had BLLs ≥ 10 µg/dL. Since then, the percentage has fallen sharply, to 4.4% during 1991–1994, to 1.6% during 1999–2002, and to 0.8% during 2007–2010. National estimates of the geometric mean (GM) BLL for children aged 1–5 years declined significantly over time, from a 1976–1980 estimated GM BLL of 15 µg/dL to a 2015–2016 estimated GM BLL 0.82 µg/dL. ^{[1, 2]}

Gastrointestinal absorption

The percentage of lead absorption through the gastrointestinal (GI) tract is variable. Children are at greater risk for lead absorption than adults. Lead absorption is dependent on several factors, including the physical form of lead, the particle size ingested, the GI transit time, and the nutritional status of the person ingesting.

Lead absorption is inversely proportional to the particle size; the smaller the particle, the more completely the lead is absorbed. Thus, exposure to lead dust results in greater absorption than exposure to the equivalent amount of lead from chips of lead paint.

Lead absorption is augmented when iron, zinc, and/or calcium deficiency is also present. Lead absorption is also augmented by malnutrition, with lead absorption decreased if phosphorus, riboflavin, vitamin C, and vitamin E are in the diet. Low-energy (calorie) intake and high-fat intake have been associated with enhanced lead absorption.

Lead absorption is inversely proportional to chronologic age. In general, approximately 30–50% of lead ingested by children is absorbed, compared with approximately 10% of that ingested by adults.

Dermal absorption

Elemental and inorganic lead are not absorbed through intact skin.  Organic lead compounds (ie, tetraethyl lead) are absorbed through the skin. 

Inhalational absorption

If inhaled in a fine particulate state, lead may be absorbed directly through the lungs or may be carried by the mucociliary tree to the throat, where it is swallowed and absorbed via the GI system. The amount of absorption of particulate lead that occurs through the respiratory system depends on the particle size, the patient’s respiratory volume, the amount of deposition, and the mucociliary clearance of the lead inhaled. The majority (nearly 100%) of lead inhaled as fumes is absorbed directly through the lungs.

Distribution

Absorbed lead that is not excreted is exchanged primarily among the following 3 compartments:

• Blood

• Soft tissue (ie, liver, kidneys, lungs, brain, spleen, muscles, and heart)

• Mineralizing tissues (bones and teeth)

Blood

After absorption, lead enters the blood compartment. Lead in the blood is primarily found within red blood cells (RBCs). Although the blood generally carries only a small fraction of the total lead body burden, it serves as the initial receptacle of absorbed lead and distributes lead throughout the body, making it available to other tissues or for excretion. The elimination half-life of lead in adult human blood has been estimated to be 1 month, whereas in children it may be as long as 10 months.

Approximately 99% of the lead in blood is associated with RBCs; the remaining 1% resides in blood plasma, which transfers lead between the different compartments. Blood lead is also important because the BLL is the most widely used measure of lead exposure. The less sensitive erythrocyte protoporphyrin (EP) assay is also used as indirect confirmation of an elevated BLL. EP tests, however, do not measure total body burden and are elevated in other disease processes such as iron deficiency.

Soft tissue

Lead rapidly distributes in and out of soft tissues. The blood distributes lead to various organs and tissues. Animal studies indicate that the liver, lungs, and kidneys have the greatest soft-tissue lead concentrations immediately after acute exposure. The brain is a site of distribution as well. Children retain more lead in soft tissue than adults do. Selective brain accumulation may occur in the hippocampus. Lead in soft tissues has an approximate elimination half-life of 40 days.

Mineralizing tissue

Most retained lead in the human body is ultimately deposited in bones. The bones and teeth of adults contain more than 90% of their total lead body burden, and those of children contain approximately 75%. Lead in mineralizing tissues is not uniformly distributed, with accumulation in bone regions undergoing the most active calcification at the time of exposure.

Bone is viewed as a double compartment, with a relatively shallow labile compartment (trabecular bone), where the elimination half-life is 90 days, and a deep inert compartment (cortical bone), where the elimination half-life may be 10–30 years. The labile component readily exchanges bone lead with the blood, whereas lead in the inert component may be stored for decades. In times of physiologic stress, the body can mobilize lead stores in bone, thereby increasing the level of lead in the blood.

Bone-to-blood lead mobilization increases during periods of pregnancy, lactation, menopause, physiologic stress, chronic disease, hyperthyroidism, kidney disease, fractures, and advanced age, and is exacerbated by calcium deficiency. Consequently, the normally inert pool poses a special risk because it is a potential endogenous source of lead that can maintain BLLs long after exposure has ended.

Teeth also are considered part of the terminal compartment. Lead acculumulates in teeth over the long term, specifically in the dentine of children's teeth, which can allow measurements of cumulative lead exposure. ^[3]

Excretion

Most of the lead absorbed into the body is excreted either through renal clearance or through biliary clearance in the feces. The percentage of lead excreted and the timing of excretion depend on a number of factors. Significant drops in a person’s BLL may take several months, or sometimes years, even after complete removal from the exposure sources. It is important for clinicians evaluating a patient with potential lead poisoning to examine potential current and past lead exposures and look for other factors that affect the biokinetics of lead (eg, poor nutrition).

Maternal-fetal kinetics

Lead readily crosses the placenta, with the fetus retaining lead cumulatively throughout gestation. Specific health problems, such as malnutrition and iron deficiency, may result in greater lead absorption in the mother. Elevated maternal lead levels subsequently result in greater lead distribution to the fetus.

Lead has no physiologic role in the human body. Lead exerts numerous adverse mechanisms of toxicity. Lead has a high affinity for sulfhydryl groups. It is therefore particularly toxic to multiple enzyme systems, including those required in heme synthesis (ie, ferrochelatase) and antioxidants (ie, superoxide dismutase, catalase, glutathione peroxidase).

Many of lead’s toxic effects also result from its inhibition of cellular function requiring calcium. Lead binds to calcium-activated proteins with much greater (105 times) affinity than calcium. The interaction of lead and calcium with cellular sites depends on the concentration of free ions present (ie, Pb²⁺ and Ca²⁺). Pb²⁺ and Ca²⁺ compete at the plasma membrane for transport systems, which affect their entry or exit (ie, Ca²⁺ channels and the Ca²⁺ pump.) Intracellular Ca²⁺ is buffered by proteins, endoplasmic reticulum, and mitochondria; Pb²⁺ disturbs this intracellular Ca²⁺ homeostasis. A (Ca²⁺)-(Pb²⁺) interaction at the mitochondria has been described. Pb²⁺ interacts with a number of Ca²⁺-dependent effector mechanisms, such as calmodulin, protein kinase C, Ca²⁺-dependent K⁺ channels in the plasma membrane, and neurotransmitter release.

It is suggested that lead induces more oxidative stress in females and more upregulation of genes responding to oxidative stress, while males have more proteolytic destruction; in both cases, there is generation of altered/denatured self-constituents causing inflammation and loss of homeostasis of neuronal and immune functions. ^[4]  

Encephalopathy

The development of encephalopathy is considered the most detrimental lead health hazard. The microvasculature of a child’s developing brain is uniquely susceptible to high-level lead toxicity, characterized by cerebellar hemorrhage, increased blood-brain barrier permeability, and vasogenic edema. Previous studies on the toxic effects of lead on the brains of young animals have shown damage to the blood-brain barrier, which in severe forms appears as a hemorrhagic encephalopathy.

Neuropathy

The cellular, intracellular, and molecular mechanisms of lead neurotoxicity are numerous. ^[5] Lead affects many biologic activities at different levels of control, including the voltage-gated channels and the first, second, and third messenger systems. Lead also affects the postnatal reorganization of the brain through the following recognized mechanisms:

• Decreased oligodendrite density

• Myelin deposition

• Cortical synaptogenesis

• Induction of precocious glial cell differentiation

• Blockage of voltage-sensitive calcium channels

• Interference with neurotransmitters

• Disorganized synaptic pruning

• Interference with protein kinases

One study found that chronic occupational exposure led to atrophy and increased white matter lesions years after termination of the exposure in a cohort of workers. ^[6] Total brain volume, frontal and total gray matter volume, and parietal white matter volume were found to be decreased. Higher measured bone levels were also associated with regionally diminished volumes in the cingulate gyrus and insula.

Lead also impacts the auditory nervous system. Lead exposure affects conduction in the distal auditory nerve and the auditory pathway in the lower brainstem. Subtle impairments of auditory processing could have profound effects on learning.

Traditionally, the neuromuscular disorder associated with lead poisoning has been purely a motor neuropathy. The classic form of lead neuropathy consists of weakness that primarily involves the wrist and finger extensors but which later spreads to other muscles. ^[7]  The motor neuropathy is more likely to develop following relatively short-term exposure to high lead concentrations and evolves in a subacute fashion. Patients may also rarely note sensory and autonomic neuropathic features. It has been proposed that the traditional motor syndrome associated with subacute lead poisoning is more likely to be a form of lead-induced porphyria rather than a direct neurotoxic effect of lead.

Before 1925, toxic neuropathy caused by lead was a frequent phenomenon. In modern times, it is a distinct rarity.

Compromised enzyme function

Lead has an effect on heme biosynthesis, causing anemia at high blood levels; however, at low levels, Pb²⁺ causes microcytosis (ie, decreased mean corpuscular volume [MCV] and mean corpuscular hemoglobin [MCH]) and a compensatory increase in the number of RBCs.

Lead irreversibly binds to the sulfhydryl group of proteins, causing impaired function without any discernible threshold. The enzymes delta-aminolevulinic acid dehydratase, which catalyzes the formation of the porphobilinogen ring, and ferrochelatase, which catalyzes the incorporation of iron into the protoporphyrin ring, are both compromised by lead.

The inhibition of these enzymes may begin with lead levels as low as 5 µg/dL. If ferrochelatase is inhibited (as with lead toxicity) or inadequate iron is present, zinc is substituted for iron and zinc protoporphyrin concentrations increase. The major consequence of this effect is the reduction of circulating levels of hemoglobin. Basophilic stippling of erythrocytes may be present.

Nephropathy

Lead poisoning inhibits the proximal tubular lining cells. Abnormalities that may be seen with lead toxicity include aminoaciduria, phosphaturia, and glycosuria (Fanconi syndrome). These effects are reversible. This acute form of nephropathy is more frequently reported in children. Gout secondary to lead-induced nephropathy is typically a long-term complication of occupational lead exposure (referred to as saturnine gout).

Chronic lead nephropathy, a chronic tubulointerstitial nephritis on biopsy, occurs in the setting of long-term lead exposure and is often associated with hypertension and gout. Diagnosis of chronic lead nephropathy is more difficult since the laboratory abnormalities seen with acute lead intoxication are not present with chronic lead exposure.

Increased blood pressure

In a meta-analysis focusing on an epidemiologic reappraisal of the association between blood pressure and blood lead, Nawrot et al. found that this association was similar in men and women. ^[8] In the combined studies, a 2-fold increase in blood lead concentration was associated with a 1 mmHg rise in systolic pressure and a 0.6 mmHg increase in diastolic pressure. This study suggests that there is a weak association between blood pressure and blood lead.

Altered reproductive function

Lead toxicity has been associated with decreased fertility. Males with elevated lead levels have been found to have reduced sperm counts and impaired sperm motility. In females, increased infertility, stillbirths, and miscarriages have been reported in association with lead toxicity, as has reduced birth weight. Lead poisoning has also been associated with menstrual irregularity.

Bone abnormalities

The accumulation of lead in bone cells may have toxic consequences for bone status itself. Skeletal development and the regulation of skeletal mass are ultimately determined by the 4 different types of cells: osteoblasts, lining cells, osteoclasts, and osteocytes. These cells, which line and penetrate the mineralized matrix, are responsible for matrix formation, mineralization, and bone resorption, under the control of both systemic and local factors.

Systemic components of regulation include parathyroid hormone, 1,25-dihydroxyvitamin D-3, and calcitonin. Local regulators include numerous cytokines and growth factors. Lead intoxication directly and indirectly alters many aspects of bone cell function.

First, lead may indirectly alter bone cell function through changes in the circulating levels of those hormones, particularly 1,25-dihydroxyvitamin D-3, which modulates bone cell function.

Second, lead may directly alter bone cell function by inhibiting the ability of bone cells to respond to hormonal regulation. For example, the 1,25-dihydroxyvitamin D-3 stimulated synthesis of osteocalcin, a calcium-binding protein synthesized by osteoblastic bone cells, is inhibited by low levels of lead. Impaired osteocalcin production may inhibit new bone formation as well as the functional coupling of osteoblasts and osteoclasts.

Third, lead may impair the ability of cells to synthesize or secrete other components of the bone matrix, such as collagen.

Finally, lead may directly affect or substitute for calcium in the active sites of the calcium messenger system, resulting in loss of physiologic regulation.

Compartmental analysis indicates that the kinetic distribution and behavior of intracellular lead in osteoblasts and osteoclasts occurs by perturbation of the calcium and cyclic adenosine monophosphate (cAMP) messenger systems in these cells.

A lead line refers to the metaphyseal line of increased radiodensity that occurs in lead poisoning. The histologic lesion consists of impaired resorption of calcified metaphyseal cartilage, depressed bone deposition on cartilaginous surfaces, and the accumulation of numerous multinucleate giant cells, some containing lead inclusions.

The lead line is the result of a lead-induced inability of cartilage-resorbing cells to degrade mineralized matrix, with a resultant impairment of metaphyseal cartilage resorption. The radiodensity of the lead line is due to persistent mineralized metaphyseal cartilage and not to a primary osseous change or lead itself.

Other abnormalities

Lead may also cause other signs and symptoms. Lead colic is a symptom of chronic lead poisoning and is associated with obstinate constipation. The Burton line or gingival lead line is a dark blue line along the gums that signifies lead poisoning. It occurs typically when lead poisoning is associated with poor oral hygiene.

Lead causes activation of protein kinase C (PKC) ^[9]  and binds to PKC more avidly than Ca²⁺, its physiologic activator. This further compounds the problem with neurotransmitter release described above. Alteration of PKC function also compromises second-messenger systems within the cell, leading to further changes in gene expression and protein synthesis.

At higher blood levels, Pb²⁺ disrupts the function of endothelial cells in the blood–brain barrier. This may lead to hemorrhagic encephalopathy, characterized by seizures and coma.

All causes of lead poisoning are environmental, however, the sources of lead are quite varied. Lead-based paint remains the single most significant source of lead exposure to children in the United States. Although lead in paint has been recognized as a source of neurotoxic effects for a century, it wasn't until 1977 that the Consumer Product Safety Committee mandated lead would no longer be added to residential paint. However, this did not address problems of deteriorating paint in older homes and the use of leaded paint for exterior surfaces or artistic endeavors.

Flaking, dusting, and peeling lead paint is by far the number one source of lead exposure in children. However, other sources of lead in a child’s environment may result in acute lead poisoning or contribute to an already elevated blood lead level. ^[10]

Work environment

Adults may become exposed or bring lead dust home from their job on clothes, hands, hair, and shoes. Occupations with exposure to lead include the following: house painting or wallpapering, home renovation4,furniture refinishing, lead smelting or mining, ^[11]  firearms instruction, automotive repair, battery manufacturing or recycling, ^[12]  or construction of bridges, tunnels, or elevated highways.

Hobbies

Certain hobbies may contaminate the home with lead dust or fumes or contaminate the patient's clothes, hands, hair, or shoes. Examples include melting lead for homemade musket balls or fishing tackle, target shooting, making stained glass (artists may use lead solder and solid lead came, which wraps around pieces of glass and frames the artwork), and ceramics.

Soil

Though lead was completely phased out of gasoline by 1995 in the United States, lead particles emitted in engine exhaust still persist in some soil near major roadways. In addition, deteriorating exterior lead paint may contaminate the soil around old homes. Children who play in bare soil risk exposure to lead, and family members may track contaminated soil into the home on their shoes. ^[13]  Cities that were previous locations of lead smelters may still have lead-contaminated soil. 

Ceramics

Lead is used in some ceramic glazes because it produces certain colors and helps prevent cracking. Improperly fired glazes and deteriorating glazes may leach lead into food and beverages, especially if contact is prolonged or if the food is hot or acidic. The US Food and Drug Administration (FDA) has established leachable lead limits on commercially made or imported products, but handmade items are not regulated. Ceramics bought in foreign countries and items not intended for food use may also leach high levels of lead.

Folk remedies

Some Hispanic, Indian, Asian, and Middle Eastern folk medicine practices consider heavy metals to be therapeutic. Certain folk remedies for digestive ailments have been found to contain very high levels of lead. Remedy names include Azarcon, Alarcon, Coral, Pay-loo-ah, and Greta. The product is likely a capsule or an orange or yellow powder that is ingested.

Lead solder

Soldering creates tiny fragments and dust-sized particles of lead, as well as lead fumes. Solders with varying concentrations of lead are used in the electronics industry and in making stained glass. Some people may use them to make fishing tackle or in home plumbing projects, although this is illegal. Homemade moonshine stills may be soldered with lead, which can result in lead leaching into the drink. ^[14]

In 1995, the FDA banned lead-soldered food cans, but some may still occasionally be imported illegally into the United States, especially to ethnic grocery stores.

Drinking water

Most public water sources are routinely tested and do not exceed the Environmental Protection Agency (EPA) lead limits of less than 15 parts per billion (ppb). (For bottled water, the limit is less than 5 ppb.) However, water may become contaminated if it encounters old lead-soldered pipes or lead-containing faucets inside old buildings. Lead levels are highest in water left standing in pipes for more than a few hours and in hot or acidic water.

In the early 2000s, lead levels in the Washington, DC, drinking water supply were found to be above EPA standards. ^{[15, 16]} The cause was uncertain but may have been due to a change in water purification techniques. More recent assessments have recorded lead levels that comply with EPA standards. 

In 2014–2015, residents of Flint, Michigan were exposed to lead in the drinking water due to a switch in the water source and lack of proper corrosion control. Due to this exposure, the percentage of children with elevated BLLs increased significantly from 3.1% to 5%. ^{[17, 10]}

Fishing tackle

Lead weights and sinkers are small and smooth and easily swallowed by curious children, especially when they are imitating adults who use their teeth to manipulate the tackle.

Costume/toy jewelry

Cheap jewelry marketed to children, often sold in vending machines, has been the source of several documented cases of acute lead poisoning. Children readily chew or suck on these items or unintentionally swallow them. Toy jewelry containing lead is a banned hazardous substance, however, such items may remain on the market. Imported jewelry is especially suspect. There was a death in 2006 from lead poisoning after ingestion of a charm from a pair of sneakers that went unrecognized, illustrating the challenges to identifying and managing lead-poisoning cases. ^[18]   

Curtain weights

Some curtain weights are made of lead and are of swallowable size. They are sewn into the hem of curtains or drapes.

Artist oil paint

One color of fine art oil paint, so-called flake white, contains lead carbonate. Many artists feel that there is no substitute for this product, which enhances a painting’s durability. Artists successfully lobbied for the exemption of flake white from the US Consumer Product Safety Commission’s 1977 ban on lead paint.

Vinyl miniblinds

Vinyl miniblinds made before 1997 may contain lead. Over time, exposure to heat and sunlight deteriorates the vinyl and lead dust forms on the surface. Blinds made with lead were recalled and banned by the Consumer Product Safety Commission in 1997, but by that time millions of these blinds had already been sold. It is likely that they are still in many US homes.

Pool cue chalk

The use of lead as a coloring agent in pool cue chalk is often denied by the industry. Nevertheless, a study from 1996 did conclude that 3 of 23 brands of pool cue chalk tested contained lead, 1 of them as much as 7000 parts per million (ppm).

Antique toys

The Consumer Product Safety Commission continually screens newly produced toys for hazardous substances including lead or lead paint. Antique toys, however, may contain lead, especially toy cars, planes, or trucks, painted toys, and toy soldiers or other figurines.

Glassware (leaded crystal)

Like ceramics, leaded crystal can leach lead into food or beverages, especially if there is prolonged contact or if the beverage is acidic. Experts advise against storing beverages in a lead crystal container or drinking from crystal routinely. Leaded crystal baby bottles should never be used.

Kohl

Kohl is an ancient black cosmetic still used by some women in the Middle East, Asia, and Africa. It often contains ground galena, a metallic mineral and source of lead. Some cultures also put kohl on the umbilical stump of newborns, or use it to decorate the eyes and faces of children. Although kohl is illegal in the United States, it may be found in some ethnic shops or may be available for purchase online. Travelers may bring kohl home to the United States unaware of its dangers.

Mexican candies

Studies have found high levels of lead in many Mexican candies, especially those with tamarind or chili powder as an ingredient. The ink used to print the wrappers has also been shown to contain dangerous amounts of lead.

Projectiles (eg, bullets)

Lead has been used to make projectiles since the mid-15th century. Its widespread availability, malleability, and high density continue to make it ideal for this purpose. Today, most bullets for shotguns, handguns, and rifles are made of a lead core surrounded by a copper or steel jacket to protect the lead from changing shape at high speeds. Economical solid lead bullets are also available, as are traditional lead musket balls.

Curious young children will readily swallow projectiles. Buckshot (small balls of lead used by hunters) may remain in cooked game and be unintentionally eaten. Also, lead from projectiles that remain lodged in the acidic synovial fluid of joints can be absorbed into the blood.