Lead exposure, toxicity, and poisoning in adults: Clinical manifestations and diagnosis

INTRODUCTION — 

Acute lead poisoning can present with severe symptoms of toxicity or with nonspecific signs and symptoms, depending in part on how much lead has been absorbed. In addition, chronic exposure to high, modest, or even low concentrations of lead may produce no symptoms but increase the risks for long-term development of adverse health outcomes.

The consequences of lead exposure may be reduced by taking an occupational and environmental health history to identify the exposures, recognizing the early signs and symptoms of elevated blood lead levels (BLLs) and lead poisoning, having a low threshold for suspecting asymptomatic lead exposure based on an occupational and environmental history or medical findings, and checking BLL in such cases to verify the diagnosis and provide appropriate advice and treatment. (See "Overview of environmental health".)

This topic will focus on identification of sources of lead exposure and the clinical manifestation and diagnosis of short-term and long-term lead toxicity in nonpregnant adults. The following related content is discussed separately:

●Management of lead exposure and poisoning in adults (see "Lead exposure and poisoning in adults: Management")

●Evaluation and prevention of lead exposure in pregnant adults and during breast feeding (see "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Lead' and "Childhood lead exposures: Exposure and prevention", section on 'Breastfeeding')

●Evaluation and management of lead nephropathy (see "Lead nephropathy and lead-related nephrotoxicity")

●Evaluation and management of lead poisoning in children (see "Childhood lead exposures: Exposure and prevention" and "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Childhood lead poisoning: Management")

DEFINITIONS — 

A blood lead level (BLL) remains the mainstay for assessing an individual's exposure to lead. However, ascribing a specific numeric BLL as a definition of adult lead toxicity is evolving as research continues to identify adverse health effects in association with lower levels of adult lead exposure.

To be consistent with the United States Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists (CSTE) [1,2], we use these terms:

●Blood lead reference value (BLRV) – An elevated BLRV for adults is defined as >3.5 mcg/dL (0.17 micromol/L). The Environmental Health Committee of the CSTE proposed this BLRV based on 2022 data from the National Health and Nutrition Examination Survey (NHANES) for lead [2]. The geometric mean BLL for adults was 0.855 mcg/dL (0.04 micromol/L) and the 97.5^th percentile BLL was calculated as 3.49 mcg/dL (0.17 micromol/L). This BLRV is not a toxicity threshold; rather, it is used to identify patients at the upper end of the population BLL distribution.

Previously, the case definition for an elevated BLL for an adult had been defined as ≥5 mcg/dL (0.24 micromol/L) by the National Institute for Occupational Safety and Health (NIOSH)/Centers for Disease Control and Prevention Adult Blood Lead Epidemiology and Surveillance (ABLES) program [1]. As the BLL considered to be potentially harmful has declined, some authors have started using units of micrograms per liter instead of micrograms per deciliter, emphasizing potential long-term adverse health effects below 5 mcg/dL (50 mcg/L) [3].

The reference BLL has been lowered from the previous concentrations of >10 mcg/dL (0.48 micromol/L), and, prior to that, ≥25 mcg/dL (1.21 micromol/L) based upon declining mean population BLLs [4].

●Adult lead toxicity – Lead toxicity in adults is a sufficiently elevated BLL such that there is inherent ability of the lead to cause harm. A mean chronic BLL ≥10 mcg/dL (0.48 micromol/L) is associated with an increase in some long-term risks (eg, increased blood pressure and cardiac adverse effects, excessive decline in kidney function, increased cognitive aging, and increased risk of essential tremor) [5]. There is some evidence that chronic lead exposure with BLL <5 mcg/dL (0.24 micromol/L) may also be associated with an increase in some long-term health risks [3]. (See 'Chronic and long-term exposure effects' below.)

●Adult lead poisoning – Lead poisoning occurs when an adult with lead toxicity has symptoms or signs. In pregnant individuals, some experts might identify lead poisoning even in the absence of symptoms or signs, because of considerations for both the mother's risks during pregnancy and the developing fetus. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Lead'.)

●Goal BLL – The US Department of Health and Human Services (HHS) recommends that BLLs among all adults be reduced to <10 mcg/dL (0.48 micromol/L), which is consistent with lower concentrations in the population as well as research concerning long-term effects of low-level exposures [1,5,6]. The US Occupational Health and Safety Administration's (OSHA) standard for lead exposure, which allows workers to continue working in a leaded environment with BLL up to 40 mcg/dL (1.93 micromol/L), is widely recognized as out of date and not adequately protective of health [1,7]. (See "Lead exposure and poisoning in adults: Management", section on 'OSHA and other governmental lead regulations'.)

EPIDEMIOLOGY — 

The full extent of adult lead poisoning and toxicity is difficult to ascertain because of limited data; existing data and research findings suggest that it remains an important environmental and public health problem [5,8-10]. In 2016, the estimated prevalence of blood lead levels (BLL) ≥10 mcg/dL (0.48 micromol/L) was 16 per 100,000 employed adults according to the United states (US) Centers for Disease Control and Prevention (CDC) Adult Blood Lead Epidemiology and Surveillance (ABLES) program, which monitors laboratory-reported elevated BLL among employed adults in 26 states [11].

The prevalence of elevated BLLs is decreasing in the US general population, mostly from the elimination of lead in gasoline and leaded paint used in indoor dwellings [11,12]. The prevalence of BLL ≥25 mcg/dL (1.21 micromol/L) decreased from 14 to 2.8 per 100,000 employed adults from 1994 to 2016 [11]. There were also decreases in the percentage of adults with BLL ≥10 mcg/dL (0.48 micromol/L), from 3.1 to 0.7 percent for ages 20 to 59 years and from 6.5 to 0.7 percent for ages >60 years between 1991 and 1994 and between 1999 and 2002 [13].

The background mean BLL in the US adult population is now <1 mcg/dL (0.05 micromol/L). Available data from the US National Health and Nutrition Examination Survey (NHANES) showed that, from 2017 to 2018, average adult BLL was 0.855 mcg/dL (0.04 micromol/L) and the 95^th percentile BLL was 2.62 mcg/dL (0.13 micromol/L), with higher BLLs among adult males than females [4].

Other countries may experience higher population BLLs from continued use of lead paint and their sources. The World Health Organization estimated that, as of January 2024, only 48 percent of countries had legally binding controls on lead paint [14]. The United Nations Environment Programme (UNEP) banned the use of leaded gasoline in 2021. Studies have found that BLLs decrease when a country eliminates lead from gasoline [15].

LEAD SOURCES AND ABSORPTION

Sources of exposure — Among adults, the majority of lead exposure occurs in the workplace [6,12]. However, there are many other sources of exposure, including the home environment, hobbies, environmental exposure, and unintentional oral ingestion of material contaminated with lead (table 1).

Sources of exposure to lead include:

●Workplace exposure – Workplace exposure to lead can occur in numerous settings, including work that involves batteries, pigments or paint, paper-hanging, lead and ore mining, smelting and refining, welding, soldering, ammunitions, shooting ranges, car radiators, cable and wires, construction and demolition, some cosmetics, ceramics with lead glazes, plumbing, and tin cans [6,16].

●Paint – Lead paint exposure can occur occupationally or in the residence [17]. The lead content of paint was unregulated in the United States until 1977, so lead paint is widely dispersed in older homes as well as on five billion square feet of nonresidential surfaces in the United States (eg, most steel bridges) [18]. Construction workers, residents (especially children), and do-it-yourself home renovators in lead-painted homes can also sustain heavy exposure to lead [18,19]. There are also rare situations of lead poisoning occurring in adults and older children with autism spectrum disorder who have pica and eat lead paint or soil that may be contaminated with lead [20-22]. Lead from paint also increases soil lead concentrations when natural disasters (eg, hurricanes) destroy homes [23].

●Gasoline – Formerly, most lead in the air originated from automobile exhaust since lead was added to gasoline as an "anti-knocking" agent [6]. The introduction of lead-free gasoline in the 1980s contributed to a 99 percent decrease in air lead concentrations in the United States and consequently a decrease in average blood lead levels (BLLs) [24,25]. Use of leaded gasoline has declined worldwide, particularly in industrialized countries, but it is still used in aviation, racing cars, some farm equipment, and marine engines.

●Bullets – Leaded bullets can lead to lead toxicity through a variety of mechanisms. At firing ranges, exposure occurs due to dust generated from use of leaded bullets [26-28]. Leaching from bullets also raises BLLs in those who consume wild game that has been hunted using lead bullets [29] and in individuals with retained lead bullet fragments, especially when located in a body fluid compartment such as intra-articularly [30-32].

●Drinking water – Drinking water can be contaminated with lead both from external source contamination as well as from passage through lead or lead-soldered pipes with corrosion. In 1991, the US Environmental Protection Agency (EPA) established the Lead and Copper Rule, with subsequent updates to minimize lead and copper concentrations through various measures to reduce corrosivity, and established an action level for lead of 15 mcg/L, with an ideal maximum contaminant concentration goal of zero [6]. 15 mcg/L is not a health-based benchmark, but rather a concentration based upon the feasibility of public water systems to control corrosion in their distribution system.

In 2014 in Flint, Michigan, the source of municipal drinking water was switched from treated Lake Huron water to water from the Flint River, which was more corrosive (from high chloride content) and did not contain corrosion inhibitors, leading to more lead leaching from the city's aging metal service lines into the municipal water supply [33]. Drinking water lead concentrations varied widely, with multiple reports of water lead concentrations greater than 100 mcg/L [34].

After the switch, among children younger than age 5, there was an increase from 2.4 to 4.9 percent of children with BLL >5 mcg/dL (0.24 micromol/L) [35]. Among those tested, 10 children had BLL greater than 5 mcg/dL (0.24 micromol/L), 9 had BLLs between 5 to 9 mcg/dL (0.24 to 0.43 micromol/L), and one had a BLL between 10 to 14 mcg/dL (0.48 to 0.68 micromol/L) [36]. However, the impact of the exposure on BLL may be underestimated since there were no surveillance studies performed on formula-fed infants, pregnant individuals, or the general adult population. Of note, there were some children with even higher BLLs reported before the switch, most likely related to home (ie, paint) lead rather than water. (See "Childhood lead exposures: Exposure and prevention", section on 'Exposure'.)

A study including females of childbearing age in Flint found no evidence of a spike in BLL during the water crisis period compared with BLLs measured before and immediately after [37]. However, sample sizes were modest (<100) and the included individuals were different (ie, this was not a longitudinal study involving the same individuals), thus reducing the ability to draw conclusions from the comparisons. In a separate study of newborn cord BLL (which reflect maternal lead exposure) comparing Flint with Detroit populations, there was a higher prevalence of cord BLL >1 mcg/dL (0.05 micromol/L) in Flint compared with Detroit mothers [38]. However, the data were confined to births that occurred mostly after the Flint water crisis, limiting the ability to draw conclusions. Overall, although adults are known to absorb less dietary lead (including water) than children, it is likely that some adult lead exposure occurred, a concern given the increasing evidence of the impact of low-level exposure on adult health outcomes such as cardiovascular disease, as well as implications for fetal lead exposure. A report commissioned by the Governor of Michigan concluded that the exposure was "a story of government failure… unpreparedness, delay, inaction, and environmental injustice" [34].

For most adults, drinking water with elevations mildly above the United States Environmental Protection Agency (EPA) action level of 15 parts per billion (15 mcg/L) for lead may not contribute significantly to their overall BLL, but the risks may be greater for infants and small children given that their gastrointestinal absorption of dietary lead is typically substantially higher than that of adults. There is not a simple calculation to correlate lead in drinking water with BLL, since there may be various contributing factors.

There are measures that can be taken to reduce the risk of lead from drinking water, such as testing the water, using tap water filters certified for lead reduction, and drinking or cooking with water that comes from the tap cold [39]. In addition, individuals who repair or remove older leaded pipes (eg, plumbers, construction workers) may encounter considerable lead exposure and thus should use adequate personal protective measures.

●Cosmetics and personal care products – These products sometimes contain lead that can cause toxicity. Examples include litargirio (also known as litharge or lead monoxide), a lead-based powder used as an antiperspirant/deodorant, foot fungicide, burn/wound healing treatment, or for other purposes as a traditional remedy by individuals from the Dominican Republic [40]; and tiro, an eye cosmetic from Nigeria [41].

●Illegally distilled alcohol ("moonshine") – Sometimes made in stills with lead-containing solder, moonshine liquor can expose drinkers to lead. In one study comparing consumers of moonshine with nonconsumers, the median BLL was higher (11.0 versus 2.5 mcg/dL [0.53 versus 0.12 micromol/L]), and the percentage of patients with BLL ≥25 mcg/dL (1.21 micromol/L) was higher (26 versus 0 percent) [42].

●Herbal supplements and Ayurvedic medications – In one study, BLL was 10 percent higher among females who used herbal supplements compared with nonusers, although mean BLL was low in both male and female users (<2.0 mcg/dL [0.97 micromol/L]) [43]. BLL was also found to be higher among females reporting use of Ayurvedic [44] and/or traditional Chinese medicine herbs, as well as St. John's wort, compared with nonusers [45-47]. BLLs were found to be elevated in adult users of rasashastra Ayurvedic medications in New York City, and the medications when analyzed contained lead, mercury, and arsenic at concentrations above permissible limits [48]. There is also a case report of 31-year-old male in India taking many supplements for body building who developed lead poisoning [49].

●Others – Lead exposure can occur with other exposures as well [6,20,50], including the use of lead-glazed tableware or cookware [51,52] and the use of oral radiographic film that was stored in lead-lined boxes, where lead dust deposited on the film resulted in lead exposure during a dental radiograph [53]. Lead has also been found as an adulterant in marijuana [54], opium [55,56], candy [57], lipstick [58], cake-decorating products [59], cinnamon [60,61], turmeric [62], and other consumer products.

Living near a major source of occupational lead exposure can cause lead toxicity. For example, mass lead intoxication has been reported among people living around lead battery manufacturing and recycling plants or artisanal gold mines, particularly in resource-limited settings [63-67].

The Agency for Toxic Substances and Disease Registry and the EPA maintain lists of sources of lead exposure (including the home environment).

Lead absorption and distribution — Lead is absorbed into the body through the lungs, gastrointestinal tract, and to a lesser extent, the skin (figure 1).

●The respiratory tract is the most significant route of lead absorption in adults, with an average absorption rate of approximately 50 percent [26]. Respiratory exposures can occur with activities such as scraping, sanding, or burning paint from surfaces as well as with various smelting/burning/welding processes.

●The gastrointestinal tract is not the major route of absorption for adults, but can be a significant contributor, particularly for those working or eating in a lead-contaminated environment. Gastrointestinal absorption of lead in adults is typically <8 to 10 percent, however absorption increases during fasting and with diets deficient in calcium, iron, phosphorous, or zinc. In contrast to adults, the gastrointestinal tract is the predominant absorption route in children with absorption of about 50 percent [26]. (See "Childhood lead exposures: Exposure and prevention", section on 'Exposure'.)

●Skin absorption is not a common route of absorption among adults and typically occurs only with exposure to organic lead in the workplace (eg, organic tetraethyl lead in gasoline).

After absorption, lead is distributed to the blood, soft tissues, and bones (figure 1). Lead resembles and mimics calcium, iron, and zinc and enters cells through calcium channels and metal transporters [3]. One percent of blood lead is free in plasma to exchange with soft tissues (eg, kidney, brain, liver, bone marrow) and cross the placenta. In blood, 99 percent of lead is bound to heme in the erythrocyte.

Lead in blood is excreted via the kidneys and cleared fairly quickly, with a mean half-life of about 30 days if kidney function is normal [68]. However, blood clearance can be slower in people with a long history of lead exposure that results in large bone stores of lead that serve as a reservoir that leaches lead into the blood over time during bone remodeling [69].

Bones contain up to 95 percent of the body burden of lead, with a half-life of decades [68]. However, lead can be released from the bone reservoir more quickly during times of accelerated bone turnover that occur, for example, with hyperthyroidism [70], bone fracture, immobilization, menopause, pregnancy [71,72], or breastfeeding [73].

CLINICAL MANIFESTATIONS — 

Lead is a toxic metal that adversely affects many physiologic functions and organ systems through multiple biochemical mechanisms [3,5-7,26,74]. Exposure produces adverse effects over a few weeks of exposure at high levels as well as over an extended duration. Some of the toxic effects of lead (such as lead colic and anemia) are reversible if lead poisoning is identified early and managed effectively. However, high blood lead levels (BLLs) or moderate BLLs over long periods can result in irreversible damage to the central and peripheral nervous systems, kidneys, and other organs [6,7,26,75].

These exposure effects are summarized in the table (table 2) and discussed in the sections below.

Acute and subacute signs and symptoms — Symptoms of lead poisoning can occur with days, weeks, or even months of sustained high lead exposure. There is a general correlation between health effects and BLLs, as shown in the table (table 2). However, manifestations of lead toxicity vary from individual to individual. Symptoms are also often nonspecific, making it difficult to identify lead as the etiology and emphasizing the importance of history taking to identify potential sources of lead exposure (table 1). (See 'Sources of exposure' above.)

Symptoms such as abdominal pain, myalgias, and anemia are most likely to occur in adults with BLL >80 mcg/dL (3.86 micromol/L). With BLL 40 to 80 mcg/dL (1.93 to 3.86 micromol/L), the symptoms are less severe, present to a more variable degree, and are more nonspecific (eg, fatigue, mild headache, myalgias, difficulty concentrating). Adults with BLL <40 mcg/dL (1.93 micromol/L) are usually asymptomatic and other explanations for symptoms should be sought.

Symptoms and signs of acute lead toxicity in adults include the following [6,7,74,76-79]:

●Gastrointestinal – Abdominal pain ("lead colic"), constipation, anorexia.

●Musculoskeletal – Joint pain/arthralgia, muscle ache/myalgia.

●General – Excessive fatigue, sleep disturbance, decreased libido.

●Neuropsychiatric – Headache, difficulty concentrating, deficits in short-term memory, irritability, depression.

Extremely high BLL (>100 mcg/dL [4.83 micromol/L] and more commonly >150 mcg/dL [7.24 micromol/L]) presents risks for more serious central nervous system effects such as encephalopathy (coma, seizures, delirium) as well as persistent cognitive impairment after recovery.

●Hematological effects – Anemia can occur as a subacute effect that usually reflects several months of lead exposures. While BLLs greater than 30 mcg/dL (1.45 micromol/L) over preceding months can result in inhibition of some of the enzymes of hemoglobin synthesis, frank anemia generally develops when BLL exceed 80 mcg/dL (3.86 micromol/L) [6,21,26,79-81]. When BLLs decline and return to normal, the hematological abnormalities typically correct. Anemia can also occur as a chronic exposure effect, as discussed below.

Chronic and long-term exposure effects — In addition to the manifestations of symptomatic acute lead poisoning, chronic prolonged elevated BLL (ie, over years), possibly as low as 5 to 10 mcg/dL (0.24 to 0.48 micromol/L), may have long-term effects on kidney, cardiovascular [10], cognitive [82], and other functions [5,7,26]. These effects, summarized in a table (table 2), may not be reversible with lowering of BLLs.

●Mortality – Elevated BLLs have been linked to increased mortality risk [10,83-85]. In one United States study, a BLL >10 mcg/dL (0.48 micromol/L) was associated with increased risks of all-cause mortality (relative risk [RR] 1.59, 95% CI 1.28-1.98), death due to cardiovascular disease (RR 1.55, 95% CI 1.16-2.07), and death due to cancer (RR 1.69, 95% CI 1.14-2.52) [86]. A similar increase in cardiovascular mortality was found after correcting for hemoglobin and adjusting for other factors [87]. There is no clear threshold BLL that identifies risk; even BLLs >2 to 5 mcg/dL (0.1 to 0.24 micromol/L) have been associated with increased mortality [10,84]. It is unclear if the increased risks are due to the low BLLs measured at the time of the study, or to much higher past exposures resulting in bone stores that continue to release lead into the blood over years.

Bone lead concentrations may be more closely associated with mortality risk. In a study of 868 lead-exposed males followed over nine years, a bone lead concentration in the highest tertile was associated with a higher risk of all-cause mortality (hazard ratio [HR] 2.5, 95% CI 1.2-5.4) and cardiovascular mortality (HR 5.63, 95% CI 1.7-18.3) [85].

On a molecular basis, the increased mortality due to lead may be mediated by its effects on deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) [88]. Some studies indicate that lead exposure may alter global DNA methylation [89,90]. Observational studies demonstrated an association between high lead exposure and telomere length shortening in Chinese battery manufacturing plant workers [91] and children [92]. A shortened telomere can result in genomic instability, which epidemiological investigations have linked to adverse outcomes such as decreased life expectancy, increased cancer risk, and cardiovascular diseases.

On a pathophysiologic basis, there is evidence that the increased cardiovascular mortality due to lead may be mediated specifically by its impact on hypertension (see below) and ischemic heart disease [93].

●Neurologic/psychiatric – Chronic (cumulative) lead exposure at a level as low as BLL 5 mcg/dL (0.24 micromol/L) has been associated with neuropsychiatric effects. These include:

•Declines in neurocognitive functioning [82,94-96]

•Anxiety, depressive symptoms, or irritability [97-100]

•Distal motor (especially of extremity extensor muscle groups) and less commonly sensorimotor neuropathy after many years, usually of very high exposure [75]

•Decreases in hearing acuity [101]

•Tremor [5]

•Brain structural changes including white matter lesions, loss of brain volume [102], and increased brain gliosis [103]

Bone lead, which remains for decades, has been shown to be a better predictor than BLL of long-term effects on cognitive function [94,104]. In a cohort of workers followed over a 22-year period, bone lead concentration predicted lower cognitive performance, particularly in workers older than age 55, whereas BLL showed no association [94].

Although evidence is inconclusive, other studies found that cumulative lead exposure may increase the risk of Parkinson disease and worsen cognitive function among patients with Parkinson disease [105,106]. Whether lead increases the risk of amyotrophic lateral sclerosis (ALS) is controversial because of limitations and biases in the studies, as well as the possibility of reverse causality, because ALS decreases limb movement, leading to bone demineralization and potential release of lead [26,107]. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Risk factors' and "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Risk factors'.)

Several biochemical mechanisms may contribute to the neurotoxic effects of lead. Lead may compete with another divalent cation, calcium, in several biologic systems, such as mitochondrial respiration and various nerve functions. Lead's interference with several calcium-dependent processes has been implicated as a contributing mechanism in lead neurotoxicity and other adverse health effects [26,79]. Additionally, lead alters permeability of the blood-brain barrier and accumulates in astroglia cells essential for maintenance of the neuronal environment [108].

●Anemia/hematologic – Anemia can develop with subacute exposure to very high BLL, usually >80 mcg/dL (3.86 micromol/L), as discussed above.

In addition, other studies, including one modeling study examining the relationship between BLL and hematocrit in Taiwanese factory workers, suggest that more chronic low level exposure may be associated with increased risk of anemia [109-111].

Lead can cause anemia by a number of processes [21,26]:

•Lead inhibits enzymes such as delta-aminolevulinic acid dehydratase (delta-ALAD) and ferrochelatase that are critical to hemoglobin synthesis [21,26,79]. Inhibition of ferrochelatase inhibits the insertion of iron into the porphyrin ring and leads to creation of free erythrocyte protoporphyrin (FEP) as well as zinc protoporphyrin (ZPP) when zinc is inserted instead of iron. An excess of FEP can usually be measured in blood when BLL rises above 30 mcg/dL (1.45 micromol/L) [79]. Lead poisoning and iron deficiency act synergistically to produce very high FEP and ZPP and more severe microcytic anemia [21].

•Additionally, lead causes increased red cell membrane fragility, which leads to a shorted lifespan and resultant hemolysis [21,26].

•Some studies have also found lower erythropoietin concentrations associated with elevated BLL and low hemoglobin [26] that has been attributed to lead accumulation in the proximal tubule of the kidney where cells produce erythropoietin.

•Lead also inhibits pyrimidine 5' nucleotidase, causing degradation of RNA in red blood cells that can manifest as basophilic stippling on a peripheral blood smear. However, basophilic stippling is an inconsistent and nonspecific sign of lead poisoning (picture 1) [112,113]. (See "Evaluation of the peripheral blood smear", section on 'Basophilic stippling'.)

●Hypertension – An association between elevated BLLs and both elevated blood pressure and risk of hypertension has been found in numerous studies [3,114-119]. Although the magnitude of this effect is uncertain, the alignment of toxicological studies supporting the effect, the potential associated mechanisms, and the consistency of findings in epidemiologic studies prompted a 2007 systematic review to conclude that the association between lead exposure and hypertension is causal [115]. This was further confirmed during the 2013 Integrated Science Assessment of lead toxicity conducted by the US Environmental Protection Agency (EPA) [120], which also concluded that the relationship is causal.

As examples, in a meta-analysis of studies in the general population and in individuals with occupational exposure to lead, a twofold increase in BLL was associated with a small increase in blood pressure (1.0/0.6 mmHg) [114]. In a subsequent study including 12,000 lead-exposed Korean workers, even among those with BLL below 10 mcg/dL (0.48 micromol/L), increasing systolic and diastolic blood pressures were positively associated with higher BLLs, and a BLL of ≥6.87 mcg/dL (0.33 micromol/L) was associated with hypertension [121].

Studies in the general population have also found associations between BLLs and hypertension at levels of BLL below 10 mcg/dL (0.48 micromol/L), including studies using data from the United States National Health and Nutrition Examination Survey (NHANES) [122,123] as well as studies in low- to middle-income countries such as Haiti [124].

Bone lead, reflecting cumulative lead exposure, may be more closely associated than BLL with development of hypertension [117,119]. As an example, in the Normative Aging Study, an increase from the lowest to the highest quintile of tibial lead was an independent risk factor for developing hypertension (odds ratio [OR] 1.5); however, BLL was not an independent risk factor [117,125]. In the same population, bone lead was also found to be associated with widening of pulse pressure (the difference between systolic and diastolic blood pressure), a marker of arterial stiffening [126]. Bone lead has also been associated with an increased risk of resistant hypertension [127]. (See "Definition, risk factors, and evaluation of resistant hypertension", section on 'Definitions'.)

Lead may affect blood pressure by promoting generation of superoxide and hydrogen peroxide in endothelial and vascular smooth muscle cells [128].

●Cardiovascular disease – Lead exposure is associated with an increased risk of atherosclerosis through mechanisms related to nitric oxide inactivation, increased formation of hydrogen peroxide, prevention of endothelial repair, impaired angiogenesis, and thrombosis stimulation [3]. Lead exposure is also associated with an increased risk of death from cardiovascular disease, even at BLLs <5 mcg/dL (0.24 micromol/L) [3,10].

●Lead nephropathy – Lead nephropathy is a potential complication of prolonged high-level lead exposure. Even chronic low levels of lead exposure (ie, resulting in BLL <10 mcg/dL [0.48 micromol/L]) have the potential for lead-related nephrotoxicity with decrease in kidney function over time. Kidney effects of lead can occur without elevation of serum creatinine, which does not increase substantially until kidney function is reduced more than 50 percent. (See "Lead nephropathy and lead-related nephrotoxicity".)

●Effects on sperm – Effects on sperm have been seen in some studies of males with chronic lead exposure with BLL between 40 and 70 mcg/dL (1.93 to 3.38 micromol/L). The percent of sperm with abnormal morphology increased, and there were decreases in sperm concentration, total sperm count, and total motile sperm count [129-131] as well as alterations of male endocrine function [132].

●Other effects – Elevated BLL and lead accumulated in bone from low-level lead exposure typically experienced by United States adults appear to be associated with increased risk of age-related diseases such as cataract formation [133], tooth loss [134], and frailty [135] as well as with nephrolithiasis [136] and gout [137]. Elevated BLLs have been associated with electrocardiographic conduction delays [138].

Although the data are not conclusive, "lead and lead compounds" are listed as "reasonably anticipated to be human carcinogens" by the National Toxicology Program of the US Department of Health and Human Services [139]. Epidemiological studies have demonstrated mixed results regarding whether lead increases the risk of cancer, and the studies lack information about quantitative exposure, contributions from smoking, and exposures to other metals. Some animal studies have found that inorganic lead is carcinogenic, particularly for kidney tumors [6,139]. In 2006, the International Agency for Research on Cancer (IARC) found limited evidence for carcinogenicity of inorganic lead compounds in humans and gave inorganic lead compounds a probably carcinogenic to humans (Group 2A) rating [140].

Common genetic polymorphisms may predispose to less favorable responses to lead exposure, though study results vary. In one study, an allele for hemochromatosis (C282Y or H63D), even in heterozygous carriers not at risk for clinical hemochromatosis, was associated with worse cognitive declines given the same cumulative exposure to lead [141]. However, other studies have shown inconsistent polymorphism relationships [142,143]. Assessment of these genetic polymorphisms is not used in clinical practice.

DIAGNOSTIC EVALUATION — 

Because lead poisoning often presents with nonspecific symptoms and signs, the diagnosis must be suspected based on exposure history and other associated symptoms (eg, nonspecific abdominal pain, headache and difficulty concentrating) and signs (eg, anemia) and then confirmed by laboratory testing.

Initial assessment — The clinician should perform a thorough history and physical examination that focuses on identifying (or recognizing) potential sources of lead exposure (see 'Sources of exposure' above), presence of medical issues that might put a person at increased risk of lead toxicity (such as kidney impairment), and symptoms of lead toxicity (see 'Clinical manifestations' above). Specifics of any history of lead poisoning during childhood should also be obtained. Unexplained gastrointestinal, neurologic, psychiatric, constitutional symptoms, and/or dysfunction of lead-targeted organs should prompt the clinician to include lead poisoning on the differential diagnosis.

In the United States (US), medical surveillance for construction workers as part of the lead standard of the Occupational Health and Safety Administration (OSHA) includes the following (this is a reasonable baseline assessment for anyone working with or concerned about lead exposure, although other organizations may have different requirements) [144] (see "Lead exposure and poisoning in adults: Management", section on 'OSHA and other governmental lead regulations'):

●Thorough physical examination (with particular attention to teeth, gums, hematologic, gastrointestinal, kidney, cardiovascular, neurologic systems, and pulmonary status if respiratory protection is to be used) (see 'Clinical manifestations' above)

●Blood pressure measurement

●Blood lead level (BLL; venous) (see 'Blood lead levels' below)

●Complete blood count with differential (anemia from lead toxicity is often associated with microcytosis and sometimes basophilic stippling)

●Blood urea nitrogen and serum creatinine

●Urinalysis with microscopic examination

●Zinc protoporphyrin (see 'Additional testing' below)

When lead poisoning is suspected, certain aspects of the physical examination may identify potential manifestations, although these findings are generally seen only with very high, prolonged lead exposure (eg, with BLL >60 mcg/dL [2.9 micromol/L]) and are frequently absent even in people with BLL >60 mcg/dL (2.9 micromol/L). Such findings include:

●Gastrointestinal – Presence of diffuse abdominal tenderness in the absence of palpable organomegaly, mass, or rebound tenderness.

●Neurologic – Behavioral and psychological disturbances (eg, irritability), memory impairment, abnormal gait and coordination, tremor, muscle weakness, especially of extensor muscle groups of all extremities. If the patient reports memory or concentration difficulties, we will sometimes administer a screening cognitive test, such as the Montreal Cognitive Assessment (MoCA) or Mini-Mental State Examination (MMSE). (See "Evaluation of cognitive impairment and dementia", section on 'Cognitive testing'.)

●Oral mucosa – Although rarely present, there may be a Burton line, which is bluish gingival pigmentation at the gum-tooth line due to reaction of lead with bacteria in dental plaque that causes formation of lead sulfide (picture 2 and picture 3). However, a Burton line may not be present even in severe lead poisoning if good oral hygiene is practiced and there is no plaque.

Blood lead levels — A BLL should be obtained to follow up on a lead exposure history, particularly if it is ongoing or if there are associated signs or symptoms. We also measure a BLL as part of the evaluation and periodic follow-up of an individual with a retained lead bullet [32]. BLL is the key test to determine how much lead a patient has absorbed and reflects ongoing or recent exposure to exogenous lead sources as well as release of endogenous lead from bone and soft tissue stores. We have encountered elevated BLLs of 10 to 25 mcg/dL (0.48 to 1.21 micromol/L) from solely previous exposures without ongoing exposure. In rare cases involving increased bone turnover (eg, hyperthyroidism), BLLs of 40 to 50 mcg/dL (1.93 to 2.41 micromol/L) may occur from the large release of lead from bone stores [70].

In many workplaces in the US, federal and/or state regulations mandate that lead exposure is documented and, when air concentrations meet a certain threshold, that workers undergo surveillance BLL monitoring. (See "Lead exposure and poisoning in adults: Management", section on 'OSHA and other governmental lead regulations'.)

Other individuals who are not subject to workplace mandates but who are known to be at risk for lead exposure (eg, painters, construction workers) should have BLL measured at regular intervals (eg, every one to two months during the time a painter might be scraping off paint from houses built before 1978). Surveillance of BLL for patients found to have it elevated is described separately. (See "Lead exposure and poisoning in adults: Management", section on 'Monitoring blood lead levels'.)

BLL, along with symptoms and exposure assessment, are used to guide management and treatment decisions. In interpreting the results and determining appropriate interventions, it is important to use BLLs appropriate to adults, rather than to children.

For routine monitoring of occupational exposure to lead, venous blood is preferable to capillary blood because even after the skin is cleaned with an alcohol wipe, skin contamination with lead can result in false elevations in BLL measured using capillary blood [145]. Although it is still sometimes used to assess lead in children, it is not used for adults. (See "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Laboratory evaluation'.)

Additional testing — For patients with lead exposure, additional testing may be warranted to assess end-organ effects (table 2).

In addition to occupational medical surveillance, measurement of free erythrocyte protoporphyrin or zinc protoporphyrin may be warranted to assess potential lead exposure that might have occurred months previously, especially if the BLL is not sufficiently elevated to explain the patient's symptoms.

●Erythrocyte protoporphyrin or zinc protoporphyrin – Erythrocyte protoporphyrin (EPP), typically assayed as zinc protoporphyrin (ZPP), is no longer used for screening for lead exposure. It is sometimes mandated by regulations (eg, OSHA) or by the workplace.

ZPP may be used to evaluate suspected lead toxicity in a patient with a BLL that is not high enough to account for the symptoms, particularly if there is suspicion that BLL may have been higher during the preceding three or four months. Lead inhibits enzymes involved in hemoglobin synthesis. With high BLLs (usually at least 30 mcg/dL [1.45 micromol/L]), free erythrocyte protoporphyrin increases due to inhibition of hemoglobin synthesis resulting in the production of porphyrin rings not containing iron. BLLs ≤25 mcg/dL (1.21 micromol/L) typically do not inhibit the enzymes of hemoglobin synthesis sufficiently to result in much increase in ZPP. Due to the average 120-day lifespan of erythrocytes, ZPP can assess lead exposure over the preceding three or four months.

If ZPP is elevated more than approximately 1.5 above a normal value of 36 mcg/dL (1.74 micromol/L), lead exposure in the recent three to four months may have been higher than the current BLL indicates. However, an elevation in ZPP is not diagnostic for lead exposure, because it is also elevated in the presence of iron deficiency anemia as well as jaundice and sickle cell anemia. If BLL is ≤25 mcg/dL (1.21 micromol/L) and ZPP is not more than about 1.5 times above normal, the measured BLL is likely representative of the actual BLL over the past few months. Iron deficiency and lead poisoning can act synergistically to cause a very elevated ZPP and more severe microcytic anemia [21].

Other tests to assess for the presence of lead are either not as accurate as BLL or are used primarily in research, not in clinical practice.

●Measurement of lead concentrations in urine, hair, or other media – Measurement of lead in fluids or tissues other than blood is not as accurate or reliable as BLL and does not correlate as well with adverse health effects.

●X-ray fluorescence – X-ray fluorescence (XRF) measures bone lead concentration, which reflects cumulative lead exposure because lead has a half-life of up to 30 years in bone [146-148]. XRF is a rapid noninvasive technique, and interpretation is increasingly standardized, but XRF equipment is available only in a few research centers and is used primarily for research [149,150].

●Cumulative blood lead index – In research studies, a cumulative blood lead index (CBLI), a time-weighted average of BLL measured regularly over a period of high (eg, occupational) exposure, is sometimes calculated to assess cumulative lead exposure [150]. The test is highly correlated with bone lead concentration, which has been shown to be a better predictor than BLL for the risk for several chronic diseases. CBLI tends not to be used in clinical practice because it does not influence clinical decision-making, but it arguably could be, particularly with known prolonged exposures and multiple blood lead test results.

●Provoked challenge urine testing – Post-chelator challenge urinary metal testing (also called "urine mobilization test") is a test in which DMSA (2,3-dimercaptosuccinic acid, succimer) or calcium disodium ethylenediaminetetraacetic acid (EDTA) chelation therapy is administered, and subsequent urinary excretion of lead is compared with reference ranges calculated from urine specimens from a nonchallenged normal population. This mobilization test has been proposed to indirectly measure lead body burden to determine if chelation therapy is indicated, but studies have failed to establish correlations among lead exposure, post-challenge results, and symptoms [151]. The American College of Medical Toxicology (ACMT) does not support post-challenge testing [152]. However, some alternative medical practices assess "high body burden" of lead by post-challenge testing and then interpret results and offer treatments that are not based upon scientific evidence.

Some experts will perform post-challenge testing to assess for chronic lead exposure as part of the evaluation of lead nephropathy, which is discussed in detail separately. (See "Lead nephropathy and lead-related nephrotoxicity", section on 'Diagnosis'.)

●Abdominal or long-bone radiographs – Abdominal radiographs are generally not used to assess lead in adults because exposure is more commonly via inhalation rather than oral intake (except in occasional circumstances) that may be visualized radiographically. However, abdominal radiographs are often useful in children to look for evidence of recent oral lead ingestion and could be used in the less common situation of suspected oral ingestion of lead by an adult. Long-bone radiographs are not useful in adults since lead lines occur at the end of growing bones. (See "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Diagnostic imaging'.)

Diagnosis — Lead exposure or poisoning in adults is diagnosed based on the BLL and presence of symptoms or secondary health effects.

●Lead exposure – Lead exposure is diagnosed in a patient with a BLL >3.5 mcg/dL (0.17 micromol/L) without clinical symptoms or acute biomarker changes (eg, anemia, elevated EPP or ZPP, severe tremor, kidney impairment). The BLL can reflect either or both ongoing lead exposure and distribution from bone stores from prior exposure (even in the absence of ongoing exposure).

●Lead poisoning – Lead poisoning is diagnosed in a patient with an elevated BLL (typically >40 mcg/dL [1.93 micromol/L]) and consistent clinical symptoms (eg, abdominal pain, headache, difficulty concentrating, irritability, weakness, tremor) or acute biomarker changes.

SPECIAL POPULATIONS

Pregnancy — Elevated blood lead levels (BLLs) are associated with pregnancy complications. Additionally, lead readily crosses the placenta; thus, even slight elevations in BLL during pregnancy are of high concern because the developing fetus is more susceptible to lead's toxic effects.

Clinicians should have a low threshold to obtain a BLL in pregnant patients. Whether to screen a pregnant patient (or a female contemplating pregnancy) for elevated BLL; follow-up testing; management of lead exposure during pregnancy; and effects of lead on reproduction and development are described in detail separately [153]. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Lead' and "Childhood lead poisoning: Management", section on 'Prenatal exposure'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lead and other heavy metal poisoning".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Lead poisoning (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview of lead exposure and toxicity – Lead exposure and toxicity remains an important environmental health problem, particularly as the adverse health effects of even low levels of toxicity have been demonstrated. A blood lead level (BLL) remains the mainstay for assessing an individual's exposure to lead, although ascribing a specific numeric BLL as a definition of adult lead toxicity is evolving as research continues to identify adverse health effects in association with lower levels of adult lead exposure. (See 'Definitions' above and 'Epidemiology' above and 'Chronic and long-term exposure effects' above.)

●Common sources of lead exposure – Among adults, the majority of lead exposure occurs in the workplace. Other sources include hobbies, environmental exposure, and unintentional oral ingestion of material contaminated with lead (table 1). (See 'Sources of exposure' above.)

●Clinical manifestations of lead toxicity – Clinical manifestations of lead toxicity are varied and may be nonspecific (table 2). (See 'Clinical manifestations' above.)

•Acute toxicity – Manifestations of acute toxicity may include abdominal pain ("lead colic"), joint/muscle aches, fatigue, decreased libido, headaches, difficulty concentrating, short-term memory deficits, and irritability. These symptoms may also occur with long-term exposure of over one year. (See 'Acute and subacute signs and symptoms' above.)

•Chronic toxicity – Additionally, long-term exposure may produce decline in neurocognitive function, lead nephropathy or impaired kidney function, tremor, hypertension, and increased risks for adverse cardiovascular events. (See 'Chronic and long-term exposure effects' above.)

●Elevated BLL in pregnancy – For pregnant patients, elevated BLL is associated with pregnancy complications. Lead readily crosses the placenta, and the developing fetus is more susceptible to lead's toxic effects. (See 'Pregnancy' above and "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Lead'.)

●Management of adults with elevated BLL – Management is discussed separately. (See "Lead exposure and poisoning in adults: Management".)