Etiology
Toxicity results almost exclusively from inhalation or ingestion of lead particles from environmental sources, food, or water. Organic lead compounds are now rare except where leaded gasoline is available and inhaled.
Sources of exposure include the following:
Houses built before 1950: multiple surveys have indicated that most cases of home lead exposure occur in pre-1950 housing, although lead was not banned from use in household paints until 1978.
Deteriorating paint surfaces: there is a strong association between the condition of paint in older homes and lead exposure. Deteriorating surfaces chip and peel. Deteriorating paint surfaces contaminate dust in the home and soil around the home.[6]
Occupational exposure: people who work in certain industries (e.g., battery production, heavy construction, mining, automotive repair, metal/electronic recycling) are at high risk of exposure to airborne lead.[12] Small-business workers such as painting contractors and plumbers are also at risk.[9][13]
Hobbies: constructing stained glass items that are soldered with lead materials, and making bullets and fishing sinkers in the home, often expose the hobbyist to high levels of airborne lead.[6][13]
Bullet firing ranges: lead exposure occurs due to inhalation of airborne lead or lead contamination of clothing and other objects. It is primarily a risk for instructors and others working in the range. Exposure can be limited by good air exchange and filtration, appropriate use of protective clothing, and restrictions on eating and drinking in the range.[14]
Folk medications: Mexican folk remedies (e.g., azarcon and greta), pay-loo-ah (a Hmong folk remedy), and Ayurvedic medicines.[10][11][15][16] A detailed list of exposure sources is available from the US Centers for Disease Control and Prevention (CDC).[6]
Lead-contaminated water: lead pipes and lead-soldered copper pipes present a significant risk for exposure when acidic (aggressive) water sits in contact with the lead.[17] The lead content in the water supply declines significantly with running water and with increasing pH. In most developed countries, using lead solder in home and commercial building water supplies is not allowed, and lead supply pipes are being replaced.[18][19][20]
Toys and other objects: lead in household objects and toys is a considerable concern because they may present a hazard to children. Although multiple cases of such exposures have been reported in the US and elsewhere, they account for a minority of significant exposures.[6]
Retained bullet or shrapnel fragments: these may form a persistent source of lead exposure.[9]
Fetal exposure: maternal lead stores are mobilized to the fetus during pregnancy. This mobilization is a risk factor for fetal loss and subsequent neurologic impairment in the infant after delivery.[21]
Pathophysiology
Small lead particles are well absorbed from the lungs. Ingested particles are absorbed less well. Lead absorption is inversely proportional to the exposure particle size.[22]
Diets low in minerals, especially calcium and iron, or high in fat, likely increase absorption of lead. Preexisting iron deficiency and other mineral deficiencies also increase the absorption of lead from the gastrointestinal tract.[23]
Most circulating lead is bound to red blood cells (99%), with only a small fraction in the plasma (1%).[22] Saturable binding of lead to red blood cell proteins contributes to a curvilinear relationship between blood lead concentration and plasma lead concentration (so that at higher exposure levels, a small change in whole-blood lead concentration corresponds to a relatively larger change in plasma lead concentration). The lead in the plasma fraction is slowly distributed to tissues, with most excreted in urine. Because this process is slow, clinical toxicity generally requires long-term exposure over months to years. Bone is a major repository of lead, containing the vast majority of body lead burden (>90%). Lead resides in bone for decades, representing a source that can continue to target tissues even exposure has ceased and/or chelation therapy has been given.[24]
The proportion distributed to target organs, particularly the nervous system, bone marrow, and kidneys, is responsible for the observed toxicity. Lead is also a potent toxin to the proximal renal tubules in the kidneys, with accumulation of intracellular lead inclusions at high levels of exposure. This can result in a renal Fanconi syndrome, with phosphaturia, glucosuria, and aminoaciduria.[25] It produces a range of cardiovascular toxicities in adult patients. The key toxicity is hypertension, but coronary artery disease, increased stroke mortality, and peripheral artery disease are also seen. The etiology of these effects is unknown. Some studies suggest renal causes due to decreased glomerular filtration rates or stimulation of the renin-angiotensin system. Other proposed hypotheses suggest a more direct effect on vascular tone.[26]
Lead toxicity produces neurodevelopmental dysfunction in children, although any dose-response relationship is nonlinear.[27][28][29][30] Blood lead levels in children peak at age 18 to 24 months.[6] This is a critical period of neurologic development with rapid acquisition of skills and high levels of activity. It is also a period of rapid synaptogenesis. In vivo and cell culture models suggest that lead exposure alters synaptogenesis.[31][32]
The exact pathophysiology is unclear. Lead competes with other minerals, particularly calcium and zinc, in cellular and subcellular systems. It therefore inhibits several calcium- and zinc-dependent processes.
Lead interferes with mitochondrial function in vitro by interfering with calcium uptake.[33]
Protein kinase C is a calcium-dependent enzyme critical to brain function, and its inhibition by lead may contribute to neurotoxicity.
Lead interferes with calcium-dependent control of neurotransmitter function at presynaptic nerve terminals.[34][35]
Lead inhibits two key enzymes of heme synthesis by competing with zinc. This may lead to diffuse effects on a variety of heme-dependent processes.[36]
Some studies suggest that lead may induce epigenetic modifications that may influence lead-induced toxicity.[37][38]
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