Understanding Lead Toxicity: Health Effects, Diagnosis, and Management

Acute lead poisoning may manifest with pronounced toxic symptoms or with nonspecific indicators, contingent upon the extent of lead absorption. Furthermore, prolonged exposure to elevated, moderate, or even minimal lead levels may not manifest symptoms but heighten the risk of long-term unfavorable health effects.

Mitigating the repercussions of lead exposure can be achieved by conducting a thorough occupational and environmental health history to pinpoint exposures, identifying the initial signs and symptoms of elevated blood lead levels (BLLs) and lead poisoning, maintaining a low threshold for suspecting asymptomatic lead exposure based on occupational and environmental history or medical findings, and measuring BLL in these instances to confirm the diagnosis and offer suitable guidance and treatment.

Definition of Lead Poisoning

A BLL is the primary method for evaluating an individual's lead exposure. Nonetheless, the designation of a specific numeric blood lead level as a criterion for adult lead poisoning is evolving as research increasingly uncovers detrimental health impacts linked to lower levels of adult lead exposure.

In alignment with established protocols and the guidelines set forth by the United States Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists (CSTE) [1,2], we employ these terminologies:

●Blood Lead Reference Value (BLRV) – An increased BLRV for adults is characterized as above 3.5 mcg/dL (0.17 micromol/L). The Environmental Health Committee of the CSTE recommended this BLRV based on 2022 data from the National Health and Nutrition Examination Survey (NHANES) about lead [2]. The geometric mean BLL for adults was 0.855 mcg/dL (0.04 micromol/L), whereas the 97.5th percentile BLL was determined to be 3.49 mcg/dL (0.17 micromol/L). This BLRV is not a toxicity threshold; instead, it serves to identify patients at the upper limit of the population BLL distribution.

The case definition for an elevated BLL in adults was previously established as ≥5 mcg/dL (0.24 micromol/L) by the National Institute for Occupational Safety and Health (NIOSH) and the CDC Adult Blood Lead Epidemiology and Surveillance (ABLES) program. With the reduction of the possibly dangerous BLL, certain authors have begun using micrograms per liter rather than micrograms per deciliter, highlighting potential long-term unfavorable health effects below 5 mcg/dL (50 mcg/L) [3].

Due to the decreasing mean population of BLLs, the reference BLL has been reduced from prior concentrations exceeding 10 mcg/dL (0.48 micromol/L) and≥25 mcg/dL (1.21 micromol/L) [4].

●Adult lead toxicity – Lead toxicity in adults occurs at a sufficiently elevated BLL that poses a risk of harm. A mean chronic BLL of ≥10 mcg/dL (0.48 micromol/L) correlates with heightened long-term hazards, including elevated blood pressure, severe cardiac consequences, significant deterioration in renal function, accelerated cognitive aging, and an increased likelihood of essential tremor. Evidence suggests that persistent lead exposure with a BLL of less than 5 mcg/dL (0.24 micromol/L) may be linked to an elevation in some long-term health concerns [3]. Adult lead poisoning manifests when an individual exhibits symptoms or indicators of lead toxicity. In pregnant persons, certain experts may detect lead poisoning even in the absence of symptoms due to concerns regarding the hazards to both the mother during pregnancy and the growing fetus. The US Department of Health and Human Services (HHS) advocates for the reduction of blood lead levels (BLLs) among all adults to below 10 mcg/dL (0.48 micromol/L), aligning with existing lower concentrations in the population and studies on the long-term effects of low-level exposures [1,5,6]. The US Occupational Health and Safety Administration's (OSHA) standard for lead exposure permits workers to remain in a lead-contaminated environment with a BLL of up to 40 mcg/dL (1.93 micromol/L). It is broadly regarded as outdated and insufficiently protective of health [1,7].

Epidemiology of lead poisoning

The comprehensive scope of adult lead poisoning and toxicity is challenging to determine due to insufficient data; current statistics and studies indicate that it continues to be a significant environmental and public health issue [5,8-10]. In 2016, the estimated prevalence of BLL ≥10 mcg/dL (0.48 micromol/L) was 16 per 100,000 employed adults, as reported by the CDC Adult Blood Lead Epidemiology and Surveillance (ABLES) program, which tracks laboratory-reported elevated BLL among employed adults in 26 states.

Elevated blood lead levels are declining in the US general population, mostly due to the removal of Lead from gasoline and lead-based paint in residential environments [11,12]. The incidence of BLL ≥25 mcg/dL (1.21 micromol/L) diminished from 14 to 2.8 per 100,000 employed individuals between 1994 and 2016 [11]. The percentage of persons with BLL ≥10 mcg/dL (0.48 micromol/L) decreased from 3.1% to 0.7% for individuals aged 20 to 59 years and from 6.5% to 0.7% for those over 60 years between 1991 and 1994, and again between 1999 and 2002 [13].

The average background blood lead level in the United States adult population is less than 1 mcg/dL (0.05 micromol/L). Data from the US National Health and Nutrition Examination Survey (NHANES) indicated that, from 2017 to 2018, the average adult BLL was 0.855 mcg/dL (0.04 micromol/L), while the 95th percentile BLL was 2.62 mcg/dL (0.13 micromol/L), with elevated levels observed in adult males compared to females [4].

Other nations may encounter elevated population blood lead levels due to the ongoing utilization of lead-based paint and its sources. The World Health Organization projected that, by January 2024, only 48 percent of nations will have legally enforceable regulations on lead paint. In 2021, the United Nations Environment Programme (UNEP) prohibited the utilization of leaded gasoline. Research indicates that blood lead levels diminish when a nation abolishes leaded gasoline.

LEAD Sources AND ABSORPTION

The workplace is the predominant source of lead exposure among adults. Nonetheless, additional sources of exposure exist, such as the domestic environment, recreational activities, environmental factors, and inadvertent oral intake of lead-contaminated materials.

Potential sources of lead exposure encompass:

Workplace exposure to Lead can transpire in various environments, including occupations related to batteries, pigments or paint, paper-hanging, Lead and ore mining, smelting and refining, welding, soldering, ammunition manufacturing, shooting ranges, automotive radiators, cables and wires, construction and demolition, certain cosmetics, ceramics with lead glazes, plumbing, and tin cans.

1.    Lead paint exposure may occur in work settings or residential environments.

Until 1977, the lead content in paint remained unregulated in the United States, resulting in the widespread presence of lead paint in older homes and on five billion square feet of nonresidential surfaces, such as most steel bridges. Construction workers, residents—particularly children—and non-professional home renovators in lead-painted residences may experience significant lead exposure. Rare instances of lead poisoning can occur in adults and older children with autism spectrum disorder who exhibit pica and ingest Lead paint or lead-contaminated soil [20-22]. Lead from paint elevates soil lead concentrations when natural disasters, such as hurricanes, demolish homes [23].

2.    Gasoline

Historically, most airborne lead emissions were derived from automotive exhaust, as Lead was incorporated into gasoline as an "anti-knocking" additive. The implementation of lead-free petrol in the 1980s resulted in a 99 percent reduction in air lead concentrations in the United States, leading to a decline in average blood lead levels (BLLs) [24,25]. The utilization of leaded gasoline has diminished globally, especially in developed nations; nonetheless, it remains in use in aircraft, racing vehicles, certain agricultural machinery, and marine engines.

3.    Leaded bullets

Leaded bullets can cause lead poisoning through multiple routes. At shooting ranges, exposure arises from dust produced by lead-containing ammunition [26-28]. Leaching from bullets increases blood lead levels (BLLs) in those who consume wild species hunted with lead bullets and in those with retained lead bullet fragments, particularly when situated in a bodily fluid compartment, such as intra-articularly.

4. Drinking water

Drinking water may be contaminated with Lead due to external sources or through the corrosion of Lead or lead-soldered pipes. In 1991, the US Environmental Protection Agency (EPA) instituted the Lead and Copper Rule, implementing subsequent revisions to mitigate Lead and copper levels through various strategies aimed at reducing corrosivity, and set an action level for Lead at 15 mcg/L, with an optimal maximum contaminant concentration goal of zero. 15 mcg/L is not a health-oriented standard; instead, it is a concentration determined by the capability of public water utilities to manage corrosion within their distribution networks.

In 2014, Flint, Michigan, altered its municipal drinking water source from treated Lake Huron to Flint River water. The latter was more corrosive due to elevated chloride levels and lacked corrosion inhibitors, resulting in increased lead leaching from the city's deteriorating metal service lines into the municipal water supply. Lead concentrations in drinking water exhibited significant variability, with numerous reports indicating levels exceeding 100 mcg/L [34].

After the transition, the prevalence of children under five with blood lead levels exceeding 5 mcg/dL (0.24 micromol/L) rose from 2.4 to 4.9 percent [35]. Of the children tested, 10 exhibited BLL over 5 mcg/dL (0.24 micromol/L), 9 had BLLs ranging from 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]. The effect of exposure on blood lead levels may be underestimated due to the absence of surveillance studies conducted on formula-fed infants, pregnant individuals, or the general adult population. Notably, some children exhibited much higher blood lead levels before the transition, possibly attributable to lead exposure from home sources, such as paint, rather than water. A study including female childbearing age in Flint found no evidence of a spike in BLL during the water crisis compared with BLLs measured before and immediately after [37]. However, sample sizes were modest (<100), and the included individuals were different (i.e., this was not a longitudinal study involving the same individuals), thus reducing the ability to conclude from the comparisons. In a separate survey of newborn cord BLL (which reflects 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]. Nevertheless, the data were restricted to births predominantly occurring post-Flint water crisis, constraining the capacity to formulate conclusions. Although adults are known to absorb Less dietary Lead (including from water) than children, it is probable that some adult lead exposure has occurred, raising concerns due to the mounting evidence of the effects of low-level exposure on adult health outcomes, including cardiovascular disease, and the implications for fetal lead exposure. A report commissioned by the Governor of Michigan said that the exposure represented "a narrative of governmental failure… unpreparedness, delay, inaction, and environmental injustice." [34]

For most adults, consuming water with lead concentrations slightly exceeding the United States Environmental Protection Agency (EPA) action level of 15 parts per billion (15 mcg/L) is unlikely to significantly affect their overall BLL. However, the risks are heightened for infants and small children, as their gastrointestinal absorption of dietary Lead is generally considerably greater than that of adults. A straightforward calculation correlating Lead in drinking water with BLL is not feasible due to multiple contributing factors.

Measures to mitigate the risk of Lead in drinking water include testing the water, utilizing tap water filters certified for lead reduction, and consuming or cooking with cold tap water. Furthermore, individuals repairing or removing antiquated lead pipes (e.g., plumbers and construction workers) may face significant lead exposure and should, therefore, implement appropriate personal protective measures.

5. Cosmetics and personal care items

These goods may occasionally contain Lead, which can induce poisoning. For instance, litargirio (also referred to as litharge or lead monoxide), a lead-derived powder utilized by certain communities as an antiperspirant/deodorant, foot fungicide, burn/wound healing treatment, or for various other traditional remedies, and tiro, an eye cosmetic from Nigeria, have resulted in lead toxicity.

6. Illegally produced alcohol ("moonshine")

Moonshine liquor, occasionally produced in stills using lead-containing solder, might expose consumers to lead. A study comparing moonshine consumers to nonconsumers revealed a higher median BLL of 11.0 mcg/dL (0.53 micromol/L) against 2.5 mcg/dL (0.12 micromol/L), with a greater percentage of individuals exhibiting BLL ≥25 mcg/dL (1.21 micromol/L) at 26 percent compared to 0 percent [42].

7. Herbal supplements and Ayurvedic treatments:

A study indicated that BLL were 10 percent elevated in females utilizing herbal supplements compared to non-users. However, the average BLL remained low for both male and female users (<2.0 mcg/dL [0.97 micromol/L]) [43]. BLL was elevated in females utilizing Ayurvedic and/or traditional Chinese medicinal herbs, as well as St. John's wort, compared to non-users. Blood lead levels (BLLs) were seen to be increased in adult consumers of rasa shastra Ayurvedic remedies in New York City, and the examined medications included Lead, mercury, and arsenic at amounts exceeding legal limits [48]. A case report describes a 31-year-old male in India who, after consuming numerous bodybuilding supplements, got lead poisoning [49].

Lead exposure may also arise from various sources, including using lead-glazed tableware or cookware and handling oral radiographic film stored in lead-lined containers, where lead dust accumulation on the film leads to exposure during dental radiography. Lead has been identified as an adulterant in marijuana, opium, sweets, lipstick, cake-decorating items, cinnamon, turmeric, and various other consumer goods.

Proximity to a significant source of occupational lead exposure can result in lead poisoning. Mass lead poisoning has been documented among individuals residing near lead battery manufacturing and recycling facilities or artisanal gold mining, especially in resource-constrained environments [63-67].

The Agency for Toxic Substances and Disease Registry and the EPA compile inventories of lead exposure sources, including residential environments.

Lead absorption and distribution 

Lead uptake and dissemination: Lead is assimilated into the body via the lungs, gastrointestinal tract, and, to a lesser degree, the skin.

1.    The respiratory system is the primary pathway for lead absorption in adults, with an average absorption rate of about 50 percent [26]. Respiratory exposures may arise from scraping, sanding, or incinerating leaded paint from surfaces and various smelting, combustion, or welding procedures.

2.    The gastrointestinal system is not the primary pathway for absorption in adults. However, it can be an important factor, especially for individuals engaged in labor or consumption in a lead-contaminated setting. The gastrointestinal absorption of Lead in people is generally between 8 to 10 percent; however, this absorption increases while fasting and with diets lacking calcium, iron, phosphorus, or zinc. Unlike adults, the gastrointestinal system serves as the primary absorption pathway in children, with an absorption rate of approximately 50 percent [26].

3.    Skin absorption is an uncommon pathway for adults and generally occurs solely with occupational exposure to organic Lead, such as tetraethyl lead in gasoline.

Following absorption, lead is disseminated to the bloodstream, soft tissues, and skeletal system. Lead resembles and imitates calcium, iron, and zinc, infiltrating cells via calcium channels and metal transporters [3]. One percent of blood lead is unbound in plasma, allowing for exchange with soft tissues (e.g., kidney, brain, liver, and bone marrow) and the ability to traverse the placenta. Ninety-nine percent of Lead in the blood is linked to heme within erythrocytes.

The kidneys eliminate blood lead and clear it rapidly, with an average half-life of approximately 30 days, assuming normal kidney function [68]. Blood clearance may be diminished in individuals with a prolonged history of lead exposure, leading to substantial lead accumulation in bone reserves that gradually releases Lead into the bloodstream during bone remodeling.

Bones harbor up to 95 percent of the body's lead accumulation, which has a half-life of decades. Lead can be released from the bone reservoir more rapidly during periods of heightened bone turnover, such as those associated with hyperthyroidism, bone fractures, immobilization, menopause, pregnancy, or nursing.

Clinical presentation of lead poisoning

Lead is a hazardous element that negatively impacts various physiological functions and organ systems via multiple biochemical mechanisms [3,5-7,26,74]. Exposure has detrimental consequences after a few weeks at elevated levels and over prolonged periods. Certain toxic effects of Lead, such as lead colic and anemia, are reversible if lead poisoning is promptly recognized and adequately controlled. Nevertheless, elevated blood lead levels (BLLs) or moderate BLLs sustained over extended durations can cause irreparable harm to the central and peripheral neurological systems, kidneys, and other organs [6,7,26,75].

Possible consequences of lead exposure in adults

The effects of exposure are encapsulated in Fig 2 and further upon in the subsequent sections.

Symptoms of acute and subacute lead exposure

Symptoms of lead poisoning may manifest within days to weeks of prolonged high lead exposure. A broad association exists between health impacts and blood lead levels, as illustrated in Fig 2. Nonetheless, manifestations of lead poisoning differ among individuals. Symptoms frequently lack specificity, complicating the identification of Lead as the causative agent and underscoring the significance of thorough history collection to ascertain potential sources of lead exposure.

Symptoms such as stomach pain, myalgia, and anemia are most probable in individuals with a blood lead level exceeding 80 mcg/dL (3.86 micromol/L). A BLL of 40 to 80 mcg/dL (1.93 to 3.86 micromol/L), symptoms are less severe, exhibit greater variability, and are more nonspecific (e.g., fatigue, moderate headache, myalgia, difficulty concentrating). Adults with a BLL below 40 mcg/dL (1.93 micromol/L) are typically asymptomatic, necessitating the investigation of other causes for any symptoms.

The manifestations and indicators of acute lead toxicity in adults encompass the following [6,7,74,76-79]:

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

●Musculoskeletal – Arthralgia, myalgia.

●General – Profound weariness, sleep disruption, diminished libido.

●Neuropsychiatric – headache, impaired concentration, short-term memory impairments, irritability, depression.

Severely elevated BLL over 100 mcg/dL [4.83 micromol/L] and more frequently beyond 150 mcg/dL [7.24 micromol/L], provide significant risks for severe central nervous system consequences, including encephalopathy (coma, seizures, delirium) and enduring cognitive deficits post-recovery.

●Hematological consequences – Anemia may manifest as a subacute consequence, typically indicating several months of lead exposure. Blood lead levels (BLLs) over 30 mcg/dL (1.45 micromol/L) over previous months may impede certain enzymes involved in hemoglobin synthesis; nevertheless, overt anemia often occurs when BLLs surpass 80 mcg/dL (3.86 micromol/L) [6,21,26,79-81]. When BLLs decrease and normalize, the hematological anomalies are generally rectified. Anemia may also manifest as a consequence of prolonged exposure, as elaborated below.

Chronic exposure impacts—Beyond the symptoms of acute lead poisoning, sustained increased blood lead levels (BLL), potentially as low as 5 to 10 mcg/dL (0.24 to 0.48 micromol/L), may adversely affect renal, cardiovascular, cognitive, and other physiological processes. The effects, outlined in Fig 2, may not be reversible despite a reduction in BLLs.

Elevated blood lead levels (BLLs) have been associated with an increased risk of mortality. A study conducted in the United States found that a BLL exceeding 10 mcg/dL (0.48 micromol/L) correlated with heightened chances of all-cause mortality (relative risk [RR] 1.59, 95% CI 1.28-1.98), mortality from cardiovascular disease (RR 1.55, 95% CI 1.16-2.07), and mortality from cancer (RR 1.69, 95% CI 1.14-2.52) [86]. A comparable rise in cardiovascular mortality was observed following adjustments for hemoglobin and other variables [87]. No definitive BLL threshold delineates risk; even BLLs exceeding 2 to 5 mcg/dL (0.1 to 0.24 micromol/L) have been linked to heightened mortality [10,84]. The source of the heightened hazards remains ambiguous; it may stem from the low blood lead levels recorded during the trial or from significantly higher prior exposures that have led to bone storage perpetually releasing Lead into the bloodstream over the years.

Bone lead concentrations may be more strongly correlated with mortality risk. A study involving 868 males exposed to Lead over nine years revealed that a bone lead content in the highest tertile correlated with an increased 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].

The heightened mortality associated with Lead may be attributable to its impact on deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) [88]. Certain studies suggest that lead exposure may modify global DNA methylation [89,90]. Observational research indicated a correlation between elevated lead exposure and telomere length reduction in Chinese battery production plant workers and children. A shorter telomere can lead to genetic instability, which epidemiological studies have associated with negative outcomes, including reduced life expectancy, heightened cancer risk, and cardiovascular disorders.

Pathophysiologically, evidence suggests that the elevated cardiovascular mortality associated with lead exposure may be specifically mediated by its effects on hypertension and ischemic heart disease [93].

Chronic lead exposure, even at a blood lead level of 5 mcg/dL (0.24 micromol/L), has been linked to neuropsychiatric consequences. These encompass: •Deteriorations in neurocognitive functioning [82,94-96]

•Psychiatric manifestations (phobic anxiety, sadness, and hostility) [97,98]

•Distal motor neuropathy, and less frequently sensory neuropathy, typically manifests after prolonged exposure, often of significant intensity [75]

•Diminutions in auditory acuity [99]

Tremor [5]

•Alterations in brain structure, encompassing white matter lesions, reduction in brain volume [100], and heightened gliosis [101]

For decades, bone lead has been a superior predictor to BLL for long-term cognitive function impacts [94,102]. In a cohort of workers monitored over a 22-year, bone lead concentration was a predictor of diminished cognitive performance, especially in individuals over 55, although blood lead levels showed no correlation.

While data remains equivocal, several studies indicate that cumulative lead exposure may elevate the likelihood of Parkinson's disease and exacerbate cognitive performance in persons with the condition [103,104]. The association between lead exposure and the risk of amyotrophic lateral sclerosis (ALS) remains contentious due to methodological flaws and biases in the research, as well as the potential for reverse causality, wherein ALS-induced reduction in limb movement may result in bone demineralization and subsequent lead release.

Multiple biochemical pathways may underlie the neurotoxic effects of Lead. Lead may rival calcium, another divalent cation, in numerous biological systems, including mitochondrial respiration and various neural activities. Lead's disruption of many calcium-dependent processes has been identified as a significant factor in lead neurotoxicity and other detrimental health effects [26,79]. Furthermore, Lead modifies the permeability of the blood-brain barrier and accumulates in astroglial cells, which are crucial for maintaining the neuronal environment [106].

As mentioned, anemia may arise from subacute exposure to elevated blood lead levels, typically exceeding 80 mcg/dL (3.86 micromol/L).

Furthermore, additional research, including a modeling study investigating the correlation between blood lead levels and hematocrit in Taiwanese factory workers, indicates that prolonged low-level exposure may be linked to a heightened risk of anemia [107-109].

Lead can induce anemia through various mechanisms [21,26]:

Lead obstructs enzymes, including delta-aminolevulinic acid dehydratase (delta-ALAD) and ferrochelatase, essential for hemoglobin formation [21,26,79]. The inhibition of ferrochelatase obstructs the incorporation of iron into the porphyrin ring, resulting in the formation of free erythrocyte protoporphyrin (FEP) and zinc protoporphyrin (ZPP) when zinc is substituted for iron. An elevated level of FEP can typically be detected in the blood when the BLL exceeds 30 mcg/dL (1.45 micromol/L) [79]. Lead toxicity and iron deficiency interact synergistically to result in elevated levels of FEP and ZPP, exacerbating microcytic anemia.

Furthermore, Lead induces heightened fragility of red cell membranes, resulting in a reduced lifespan and subsequent hemolysis [21,26].

•Certain studies have identified diminished erythropoietin levels correlated with increased BLL and reduced hemoglobin, which has been ascribed to lead deposition in the proximal tubule of the kidney, where erythropoietin is synthesized. •Lead additionally obstructs pyrimidine 5' nucleotidase, resulting in RNA degradation in erythrocytes, which may present as basophilic stippling on a peripheral blood smear. Nonetheless, basophilic stippling is an unreliable and nonspecific indicator of lead poisoning [110,111].

Numerous studies have identified a correlation between elevated blood lead levels (BLLs) and increased blood pressure, as well as a heightened risk of hypertension [3,112-117]. The extent of this effect remains ambiguous; however, the convergence of toxicological studies endorsing the effect, the plausible mechanisms involved, and the uniformity of results in epidemiological studies led to a 2007 systematic review to determine that the relationship between lead exposure and hypertension is causal [113]. This conclusion was further confirmed in the 2013 Integrated Science Assessment of lead toxicity conducted by the US Environmental Protection Agency (EPA) [118], which also determined that the relationship is causal.

A meta-analysis of studies involving the general population and those with occupational lead exposure revealed that a twofold increase in BLL correlated with a modest rise in blood pressure (1.0/0.6 mmHg) [112]. A subsequent study involving 12,000 Korean workers exposed to Lead revealed that, even among individuals with BLL below 10 mcg/dL (0.48 micromol/L), a positive correlation existed between increasing systolic and diastolic blood pressures and higher BLLs. Furthermore, a BLL of ≥6.87 mcg/dL (0.33 micromol/L) was linked to hypertension [119].

Research conducted in the general population has identified associations between blood lead levels (BLLs) and hypertension at concentrations below 10 mcg/dL (0.48 micromol/L). These findings are supported by studies using data from the United States National Health and Nutrition Examination Survey (NHANES) and investigations conducted in low—to middle-income countries, such as Haiti.

Bone lead, indicative of cumulative lead exposure, may have a stronger correlation with the onset of hypertension than BLL [115,117]. In the Normative Aging Study, an elevation from the lowest to the highest quintile of tibial Lead was identified as an independent risk factor for hypertension (odds ratio [OR] 1.5); conversely, BLL was not an independent risk factor [115,123]. In the same population, bone lead was found to correlate with an increase in pulse pressure (the disparity between systolic and diastolic blood pressure), an indicator of arterial stiffness [124]. Bone Lead has been linked to a heightened risk of resistant hypertension [125].

Lead may influence blood pressure by facilitating the production of superoxide and hydrogen peroxide in endothelial and vascular smooth muscle cells [126].

Cardiovascular disease: Lead exposure correlates with an elevated risk of atherosclerosis via pathways involving nitric oxide inactivation, enhanced hydrogen peroxide production, inhibition of endothelium repair, compromised angiogenesis, and promotion of thrombosis [3]. Lead exposure is linked to a heightened risk of mortality from cardiovascular disease, even at blood lead levels below 5 mcg/dL (0.24 micromol/L) [3,10].

Lead nephropathy is a possible problem caused by extended exposure to elevated lead levels. Chronic exposure to low lead levels (i.e., blood lead levels <10 mcg/dL [0.48 micromol/L]) may also lead to nephrotoxicity, resulting in a gradual decline in renal function. Lead can adversely affect the kidneys without a corresponding increase in serum creatinine, which typically rises significantly only after kidney function declines by over 50 percent.

●Impact on sperm—Some studies have observed effects on sperm in males with chronic lead exposure exhibiting BLL between 40 and 70 mcg/dL (1.93 to 3.38 micromol/L). The percentage of sperm exhibiting abnormal sperm morphology increased, whereas sperm concentration, total sperm count, and total motile sperm count decreased, alongside abnormalities in male endocrine function.

Other effects: Elevated BLL and lead accumulation in bone due to low-level lead exposure commonly encountered by adults in the United States are correlated with an increased risk of age-related diseases, including cataract formation, tooth loss, frailty, nephrolithiasis, and gout. Increased blood lead levels have been linked to electrocardiographic conduction delays [136].

While the findings are inconclusive, the National Toxicology Program of the US Department of Health and Human Services categorizes "lead and lead compounds" as "reasonably anticipated to be human carcinogens" [137]. Epidemiological studies have yielded inconclusive findings on the association between lead exposure and cancer risk, and they are deficient in quantitative exposure data, smoking factors, and exposure to other metals. Certain animal investigations have demonstrated that inorganic Lead is carcinogenic, especially for renal malignancies [6,137]. In 2006, the International Agency for Research on Cancer (IARC) identified minimal evidence of the carcinogenicity of inorganic lead compounds in humans, assigning them a probable carcinogenic classification (Group 2A).

Common genetic variants may predispose individuals to suboptimal responses to lead exposure; however, study outcomes differ. In research, an allele for hemochromatosis (C282Y or H63D), even in heterozygous carriers not predisposed to clinical hemochromatosis, was linked to worse cognitive impairment with equivalent cumulative lead exposure [139]. Notwithstanding, additional investigations have demonstrated inconsistent associations regarding polymorphism [140,141]. The evaluation of these genetic polymorphisms is not employed in clinical practice.

DIAGNOSTIC ASSESSMENT OF LEAD POISONING

Due to the vague nature of lead poisoning symptoms and indications, the diagnosis should be inferred from exposure history and accompanying symptoms (e.g., nonspecific abdominal discomfort, headache, and difficulty concentrating) and signs (e.g., anemia), subsequently verified through laboratory testing.

The clinician must conduct a comprehensive history and physical examination to identify potential sources of lead exposure, assess medical conditions that may elevate the risk of lead toxicity, such as renal impairment, and recognize symptoms of lead toxicity.

Details regarding any history of lead poisoning in childhood should be acquired. Unexplained gastrointestinal, neurologic, mental, and constitutional symptoms and/or malfunctioning of lead-targeted organs should cause the clinician to consider lead poisoning in the differential diagnosis.

In the United States, medical surveillance for construction workers under the lead standard of the Occupational Safety and Health Administration (OSHA) encompasses the following: a reasonable baseline assessment for individuals engaged with or concerned about lead exposure, despite potential variations in requirements from other organizations.

●Comprehensive physical assessment (focusing specifically on dental health, gingival condition, hematologic, gastrointestinal, renal, cardiovascular, neurological systems, and pulmonary state if respiratory protection is required)

●Measurement of blood pressure

●Venous BLL

Complete blood count with differential (anemia due to lead toxicity is frequently linked to microcytosis and occasionally to basophilic stippling).

Blood urea nitrogen and serum creatinine levels

Urinalysis accompanied by microscopic inspection

Zinc protoporphyrin

In cases of suspected lead poisoning, specific elements of the physical examination may reveal potential manifestations; however, these findings typically occur only with significantly elevated and prolonged lead exposure (e.g., BLL >60 mcg/dL [2.9 micromol/L]) and are often absent even in individuals with BLL >60 mcg/dL (2.9 micromol/L). The findings encompass:

●Gastrointestinal - Diffuse abdominal soreness observed without visible organomegaly, mass, or rebound tenderness.

Neurologic—Behavioral and psychological abnormalities (e.g., irritability), memory deficits, aberrant gait and coordination, tremors, and muscle weakness, particularly in the extensor muscle groups of all extremities. Should the patient indicate challenges with memory or focus, we may occasionally perform a screening cognitive assessment, such as the Montreal Cognitive Assessment (MoCA) or the Mini-Mental State Examination (MMSE).

●Oral mucosa—Although infrequently observed, a Burton line may manifest as bluish gingival pigmentation at the gum-tooth junction. This line results from the interaction of Lead with bacteria in dental plaque, leading to the creation of lead sulfide. Notwithstanding, a Burton line may be absent even in cases of severe lead poisoning if proper dental hygiene is maintained and plaque is nonexistent.

Blood lead concentrations: A BLL test should be conducted to monitor lead exposure history, especially if it is persistent or accompanied by related signs or symptoms. During the evaluation, W further assesses a BLL and regularly monitors an individual with a retained lead bullet [32]. The BLL test is essential for assessing the extent of lead absorption in a patient, indicating both current or recent exposure to external lead sources and the mobilization of endogenous Lead from bone and soft tissue reserves. We have observed high blood lead levels (BLLs) ranging from 10 to 25 mcg/dL (0.48 to 1.21 micromol/L) resulting exclusively from prior exposures without current exposure. In uncommon instances of heightened bone turnover (e.g., hyperthyroidism), blood lead levels (BLLs) of 40 to 50 mcg/dL (1.93 to 2.41 micromol/L) may arise due to significant lead release from skeletal reserves [70].

In numerous workplaces in the US, federal and/or state regulations require the documentation of lead exposure and mandate that workers undergo blood lead level monitoring when air concentrations exceed a specified threshold.

Individuals not subject to workplace mandates but identified as at risk for lead exposure (e.g., painters, construction workers) should have their blood lead levels measured regularly (e.g., every one to two months when painters may be scraping paint from houses constructed before 1978). The monitoring of BLL for patients identified with elevated levels is detailed separately.

Blood Lead Levels (BLL), symptomatology, and exposure evaluation inform management and therapy strategies. When analyzing the results and identifying suitable therapies, it is crucial to utilize blood lead levels pertinent to adults rather than those applicable to children.

Venous blood is preferred over capillary blood for routine monitoring of occupational lead exposure, as skin contamination with Lead, despite cleansing with an alcohol wipe, can lead to erroneous increases in blood lead levels assessed by capillary blood [143]. Although it is occasionally employed to evaluate lead levels in children, it is not utilized for adults.

Supplementary testing—For individuals with lead exposure, further evaluation may be necessary to identify end-organ effects (Fig 2).

Furthermore, assessing free erythrocyte or zinc protoporphyrin may be necessary if lead toxicity is anticipated due to recent significant exposures, even if the current blood lead level is not sufficiently elevated to account for symptoms.

Erythrocyte protoporphyrin (EPP), commonly measured as zinc protoporphyrin (ZPP), is no longer utilized for lead exposure screening, although regulations (e.g., OSHA) or workplace policies may occasionally require it.

ZPP can be utilized to assess potential lead toxicity in a patient whose BLL is insufficient to explain the symptoms, especially if there is concern that the BLL may have been elevated in the past three to four months. Lead obstructs enzymes essential for hemoglobin production. Elevated blood lead levels (often a minimum of 30 mcg/dL [1.45 micromol/L]) lead to an increase in free erythrocyte protoporphyrin due to the suppression of hemoglobin synthesis, leading to the formation of iron-deficient porphyrin rings. BLLs ≤25 mcg/dL (1.21 micromol/L) generally do not substantially inhibit the enzymes involved in hemoglobin production to cause a significant increase in ZPP. The average lifespan of erythrocytes is 120 days so that ZPP can evaluate lead exposure over the first three to four months.

If ZPP exceeds approximately 1.5 above the typical range of 36 mcg/dL (1.74 micromol/L), recent lead exposure within the last three to four months may have been greater than the present BLL suggests. An increase in ZPP does not indicate lead exposure, as it can also be increased in cases of iron deficiency anemia, jaundice, and sickle cell anemia. If the BLL is ≤25 mcg/dL (1.21 micromol/L) and the zinc protoporphyrin (ZPP) is no more than approximately 1.5 times the usual value, the assessed BLL is likely indicative of the true BLL over the preceding months. Iron deficiency and lead poisoning can synergistically result in significantly higher ZPP levels and more severe microcytic anemia [21].

Alternative tests for detecting lead present are either less accurate than BLL assessments or are predominantly utilized in research rather than therapeutic settings.

●Assessment of lead concentrations in urine, hair, or other matrices—The assessment of Lead in fluids or tissues, excluding blood, is less precise and dependable than BLL and exhibits a lower correlation with negative health outcomes.

X-ray fluorescence (XRF) quantifies bone lead content, indicating cumulative lead exposure due to Lead's half-life of up to 30 years in bone. XRF is a swift, noninvasive method with growing standardization in interpretation; nonetheless, the XRF apparatus is limited to certain research institutions and is predominantly utilized for research purposes [147,148].

●Cumulative Blood Lead Index — In research investigations, a cumulative blood lead index (CBLI), which is a time-weighted average of BLL recorded consistently throughout significant exposure (e.g., occupational), is occasionally computed to evaluate cumulative lead exposure [148]. The test exhibits a strong correlation with bone lead concentration, which has proven to be a superior predictor compared to blood lead levels for the risk of several chronic diseases. CBLI is rarely utilized in clinical practice as it does not affect clinical decision-making; nonetheless, it could be relevant, especially in cases of known protracted exposures and numerous blood lead test findings.

Provocative chelation, also known as "challenge" chelation, is a diagnostic procedure in which DMSA (2,3-dimercaptosuccinic acid, succimer) or calcium disodium ethylenediaminetetraacetic acid (EDTA) is administered, followed by the analysis of urinary lead excretion against reference ranges derived from urine samples of a nonchallenged normal population. This mobilization test has been suggested to indirectly assess lead body burden to ascertain the necessity of chelation therapy; however, studies have not demonstrated associations between lead exposure, post-challenge outcomes, and symptoms [149]. The American College of Medical Toxicology (ACMT) does not endorse provocative chelation [150]. Nevertheless, several alternative medical practices evaluate Lead's "high body burden" using provocative chelation, then interpret results and propose treatments devoid of scientific substantiation.

Certain specialists will use provocative chelation to evaluate chronic lead exposure during the diagnostic assessment of lead nephropathy, which is elaborated upon individually.

Abdominal or long-bone radiographs: Abdominal radiographs are often not employed to evaluate lead levels in adults, as exposure is predominantly by inhalation rather than oral ingestion, except in rare instances that may be detectable radiographically. Abdominal radiographs are frequently beneficial in pediatric cases to detect recent oral lead consumption signs. They may even be employed in the rarer instance of suspected oral lead ingestion in adults. Radiographs of long bones are not beneficial in adults, as lead lines manifest at the termini of developing bones.

Diagnosis — Lead exposure or poisoning in adults is diagnosed based on the BLL and 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 (e.g., 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 (e.g., abdominal pain, headache, difficulty concentrating, irritability, weakness, and tremor) or acute biomarker changes.

SPECIFIC POPULATIONS

Elevated blood lead levels (BLLs) are linked to difficulties during pregnancy. Moreover, lead easily traverses the placenta; therefore, even minor increases in blood lead levels during gestation are highly concerning due to the heightened vulnerability of the developing baby to lead's harmful effects.

Clinicians should maintain a low threshold for obtaining a blood lead level in pregnant patients. The screening of pregnant patients or women considering pregnancy for elevated BLL, further testing, management of lead exposure during pregnancy, and the impact of Lead on reproduction and development are elaborated upon individually [151].

Management of Mild to Moderate Lead Toxicity

Patients with mild to moderate exposure can be managed outpatient, focusing on exposure elimination. If symptoms worsen or the BLL is high, further intervention is needed.

Chelation Therapy

• Children: Recommended if BLL is ≥45 mcg/dL

• Adults: Indicated for ≥50 mcg/dL or symptomatic cases

Chelation Agents

• Oral succimer (DMSA): First-line outpatient chelation therapy.

• D-Penicillamine: Second-line therapy if succimer is unavailable.

Additional Interventions

• Regular BLL Monitoring: Re-test after chelation therapy.

• Anemia Management: Treat lead-induced iron deficiency with supplementation.

• Imaging: Abdominal X-ray if acute lead ingestion is suspected.

Management of Severe Lead Toxicity

Severe Lead Toxicity (BLL >40 mcg/dL)

Health Effects of Severe Lead Poisoning

At higher BLLs, multiple organ systems are affected:

Hospitalization Criteria

• Children with BLL ≥70 mcg/dL

• Symptomatic patients

• Neurological involvement (e.g., encephalopathy)

Whole Bowel Irrigation

• Polyethylene glycol solution should be used for enhanced elimination if lead-containing foreign bodies are identified on radiographs.

Chelation Therapy for Severe Cases

• Oral succimer: Used for BLL <70 mcg/dL with no encephalopathy.

• Parenteral Chelation:

  • Dimercaprol (BAL): First-line for encephalopathy or BLL ≥70 mcg/dL.

  • IV Calcium Disodium EDTA (CaNa₂EDTA): Follow BAL for enhanced lead excretion.

Neurological and Supportive Care

• Seizure Control: IV benzodiazepines for seizure management.

• Cerebral Edema Treatment: Mannitol and dexamethasone.

• Avoid lumbar puncture if intracranial pressure is suspected.

When to Seek Immediate Medical Attention

Emergency evaluation is required if:

• Symptoms of severe lead poisoning are present.

• Ingestion of lead-containing objects is suspected.

• BLL is ≥70 mcg/dL.

• Neurological symptoms (confusion, encephalopathy) develop.

Long-Term Effects of Lead Poisoning and Public Health Measures

Lead toxicity has long-term neurocognitive effects, particularly in children:

• Reduced IQ and learning disabilities

• Behavioral issues and attention deficits

• Peripheral neuropathy (e.g., wrist drop)

• Chronic kidney disease

Lead Poisoning Case Study

Subjective:

• A 4-year-old female with autism and developmental delay.

• Initial capillary BLL: 65 mcg/dL; Confirmed venous BLL: 66 mcg/dL.

• Lives in an older home with suspected lead paint exposure.

• No acute symptoms but has iron deficiency anemia (Hb: 9.3 g/dL).

Objective:

• HR: 141 bpm, RR: 24 breaths/min, Temp: 98.4°F, O2 Sat: 96%

• Lab Results:

  • BLL: 66 mcg/dL

  • Hb: 9.3 g/dL (iron deficiency anemia)

• Abdominal X-ray: No lead-containing foreign bodies; significant stool burden (constipation).

Assessment:

• Severe lead poisoning with confirmed high BLL.

• Iron deficiency anemia, secondary to chronic lead exposure.

• No acute encephalopathy or foreign body ingestion.

Plan:

1. Chelation Therapy:

• Oral succimer (DMSA): 10 mg/kg PO TID x 5 days, then BID for 21 days.

• IV CaNa₂EDTA: 75 mg/kg/day continuous infusion x 5 days.

2. Supportive Care:

• Multivitamins and iron supplementation for anemia.

• Psyllium fiber (Metamucil) wafers for constipation.

• Adequate hydration to support kidney function.

3. Environmental Exposure Management:

• Home lead assessment and public health coordination.

• Family education on lead exposure reduction.

4. Monitoring and Disposition:

• Inpatient admission (5 days) during IV chelation.

• Frequent renal function monitoring.

• Transition to outpatient succimer therapy if stable.

5. Follow-Up:

• Repeat BLL post-chelation.

• Ongoing pediatric toxicology and primary care follow-up.

Lead Toxicity in Pregnancy

During pregnancy, lead crosses the placenta, risking miscarriage, premature birth, low birth weight, and developmental defects, emphasizing the critical need for preventive measures and early intervention.

Preventing Lead Poisoning: Early Intervention, Treatment, and Public Health Strategies

Public Health and Occupational Considerations in Lead Poisoning

• Report childhood lead poisoning cases for home assessment and intervention.

• OSHA notification is required for workplace-related lead poisoning.

• Environmental lead abatement is crucial to prevent re-exposure.

• Educate families on lead-safe practices, including:

  • Lead-safe renovations for homes built before 1978.

  • Frequently wash hands and avoid contaminated surfaces.

  • Use filtered water if lead-contaminated sources exist.

Lead poisoning is preventable, and early intervention is key to minimizing its impact. Long-term complications can be reduced by identifying sources, monitoring BLLs, and providing timely chelation therapy. Public health efforts are crucial in preventing exposure and ensuring safe environments for affected individuals.

Lead exposure and toxicity continue to pose a significant environmental health issue, especially given that the detrimental health impacts of even minimal toxicity levels have been established. A BLL is the primary metric for evaluating an individual's lead exposure. However, the concept of adult lead toxicity based on a precise numeric BLL is evolving as research uncovers detrimental health impacts linked to lower levels of lead exposure in adults.

●Prevalent sources of lead exposure: In adults, most lead exposure occurs in occupational settings. Additional sources include hobbies, environmental exposure, and inadvertent oral intake of lead-contaminated materials.

●Clinical symptoms of lead poisoning – The clinical signs of lead intoxication are diverse and may be vague (Fig 2).

•Acute toxicity — Symptoms of acute toxicity may encompass abdominal pain ("lead colic"), musculoskeletal discomfort, weariness, diminished libido, headaches, impaired concentration, short-term memory loss, and irritability. These symptoms may also manifest during prolonged exposure for more than one year.

Chronic toxicity: Furthermore, prolonged exposure may result in diminished neurocognitive function, nephropathy, tremors, hypertension, and heightened chances of adverse cardiovascular events.

Elevated blood lead levels during pregnancy are linked to problems in pregnant individuals. Lead easily traverses the placenta, rendering the growing fetus more vulnerable to its hazardous effects.

●Management of adults with increased blood lead levels is addressed independently.