Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM) 

Lead Toxicity
What Are the Physiologic Effects of Lead Exposure?

Learning Objectives

Upon completion of this section, you will be able to

• describe how lead affects adults and children
• describe the major physiologic effects of chronic low- level lead exposure
• describe the major physiologic effects of acute high-level lead exposure.

Introduction

Lead serves no useful purpose in the human body, but its presence in the body can lead to toxic effects, regardless of exposure pathway.

• Lead toxicity can affect every organ system.
• On a molecular level, proposed mechanisms for toxicity involve fundamental biochemical processes. These include lead's ability to inhibit or mimic the actions of calcium (which can affect calcium-dependent or related processes) and to interact with proteins (including those with sulfhydryl, amine, phosphate and carboxyl groups) (ATSDR, 2005).

It must be emphasized that there may be no threshold for developmental effects on children.

• The practicing health care provider can distinguish overt clinical symptoms and health effects that come with high exposure levels on an individual basis.
• However, lack of overt symptoms does not mean “no lead poisoning.”
• Lower levels of exposure have been shown to have many subtle health effects.
• Some researchers have suggested that lead continues to contribute significantly to socio-behavioral problems such as juvenile delinquency and violent crime (Needleman 2002, Nevin 2000).
• It is important to prevent all lead exposures.

While the immediate health effect of concern in children is typically neurological, it is important to remember that childhood lead poisoning can lead to health effects later in life including renal effects, hypertension, reproductive problems, and developmental problems with their offspring (see below). The sections below describe specific physiologic effects associated with major organ systems and functions.

Neurological Effects

The nervous system is the most sensitive target of lead exposure.

• There may be no lower threshold for some of the adverse neurological effects of lead in children.
• Neurological effects of lead in children have been documented at exposure levels once thought to cause no harmful effects (<10 µg/dL) (Canfield 2003; CDC 1997a).
• Because otherwise asymptomatic individuals may experience neurological effects from lead exposure, clinicians should have a high index of suspicion for lead exposure, especially in the case of children.

Children

In children, acute exposure to very high levels of lead may produce encephalopathy and other accompanying signs of

• ataxia
• coma
• convulsions
• death
• hyperirritability
• stupor

The BLLs associated with encephalopathy in children vary from study to study, but BLLs of 70-80 µg/dL or greater appear to indicate a serious risk (ATSDR 2005).

• Even without encephalopathy symptoms, these levels are associated with increased incidences of lasting neurological and behavioral damage (ATSDR 2005).

Children suffer neurological effects at much lower exposure levels.

• Neurological effects may begin at low (and, relatively speaking, more widespread) BLLs, at or below 10 µg/dL in some cases, and it may not be possible to detect them on clinical examination.
• Some studies have found, for example, that for every 10 µg/dL increase in BLL, children’s IQ was found to be lower by four to seven points (Yule  et al., 1981; Schroeder  et al., 1985; Fulton  et al., 1987; Landsdown  et al. 1986; Hawk  et al. 1986; Winneke  et al. 1990 as cited in AAP 1993).
• There is a large body of evidence that associates decrement in IQ performance and other neuropsychological defects with lead exposure.
• There is also evidence that attention deficit hyperactivity disorder (ADHD) and hearing impairment in children increase with increasing BLLs, and that lead exposure may disrupt balance and impair peripheral nerve function (ATSDR 2005).
• Some of the neurological effects of lead in children may persist into adulthood.

Adults

There can be a difference in neurological effects between an adult exposed to lead as an adult, and an adult exposed as a child when the brain was developing.

• Childhood neurological effects, including ADHD, may persist into adulthood. Lead-exposed adults may also experience many of the neurological symptoms experienced by children, although the thresholds for adults tend to be higher.

Lead encephalopathy may occur at extremely high BLLs, e.g., 460 µg/dL. (Kehoe 1961 as cited in ATSDR 2005)

• Precursors of encephalopathy, such as dullness, irritability, poor attention span, muscular tremor, and loss of memory may occur at lower BLLs.

Less severe neurological and behavioral effects have been documented in lead-exposed workers with BLLs ranging from 40 to 120 µg/dL. (ATSDR 2005) These effects include

• decreased libido
• depression/mood changes, headache
• diminished cognitive performance
• diminished hand dexterity
• diminished reaction time
• diminished visual motor performance
• dizziness
• fatigue
• forgetfulness
• impaired concentration
• impotence
• increased nervousness
• irritability
• lethargy
• malaise
• paresthesia
• reduced IQ scores
• weakness

There is also some evidence that lead exposure may affect adults’ postural balance and peripheral nerve function. (ATSDR 1997a, b; Arnvig et al. 1980; Haenninen et al. 1978; Hogstedt et al. 1983; Mantere et al. 1982; Valciukas et al. 1978 as cited in ATSDR 1999)

Slowed nerve conduction and forearm extensor weakness (wrist drop), as late signs of lead intoxication, are more classic signs in workers chronically exposed to high lead levels

Renal Effects

Many studies show a strong association between lead exposure and renal effects. (ATSDR 1999)

• Acute high dose lead-induced impairment of proximal tubular function manifests in aminoaciduria, glycosuria, and hyperphosphaturia (a Fanconi-like syndrome). These effects appear to be reversible (ATSDR 1999).
• However, continued or repetitive exposures can cause a toxic stress on the kidney, if unrelieved, may develop into chronic and often irreversible lead nephropathy (i.e., chronic interstitial nephritis).

The lowest level at which lead has an adverse effect on the kidney remains unknown.

• Most documented renal effects for occupational workers have been observed in acute high-dose exposures and high-to-moderate chronic exposures (BLL > 60 µg/dL).
• Currently, there are no early and sensitive indicators (e.g., biomarkers) considered predictive or indicative of renal damage from lead. (ATSDR 2000) Serum creatinine and creatinine clearance are used as later indicators.
• However, certain urinary biomarkers of the proximal tubule (e.g., NAG) show elevations with current exposures, even at BLLs less than 60 µg/dL; and some population-based studies show accelerated increases in serum creatinine or decrements in creatinine clearance at BLLs below 60 µg/dL. (Staessen et al. 1992; Kim et al. 1996; Payton et al. 1994; Tsaih et al. 2004)

Latent effects of lead exposure that occurred years earlier in childhood may cause some chronic advanced renal disease or decrement in renal function.

• In children, the acute lead-induced renal effects appear reversible with recovery usually occurring within two months of treatment. (Chisolm et al. 1976)
• Treatment of acute lead nephropathy in children appears to prevent the progression to chronic interstitial nephritis. (Weeden et al. 1986)

It should be noted that lead-induced end-stage renal disease is a relatively rare occurrence in the U.S. population.

• Renal disease can be asymptomatic until the late stages and may not be detected unless tests are performed.
• Because past or ongoing excessive lead exposure may also be a causative agent in kidney disease associated with essential hypertension (ATSDR 1999), primary care providers should follow closely the renal function of patients with hypertension and a history of lead exposure. (See “Hypertension Effects” section).

Lead exposure is also believed to contribute to “saturnine gout,” which may develop because of lead-induced hyperuricemia due to decreased renal excretion of uric acid.

• In one study, more than 50% of patients suffering from lead nephropathy also suffered from gout. (Bennett 1985 as cited in ATSDR 2000)
• Saturnine gout is characterized by less frequent attacks than primary gout. Lead-associated gout may occur in pre-menopausal women, an uncommon occurrence in non lead-associated gout. (Goyer 1985, as cited in ATSDR 2000)
• A study by Batuman et al (1981) suggests that renal disease is more frequent and more severe in saturnine gout than in primary gout.

Hematological Effects

Lead inhibits the body's ability to make hemoglobin by interfering with several enzymatic steps in the heme pathway.

• Specifically, lead decreases heme biosynthesis by inhibiting d-aminolevulinic acid dehydratase (ALAD) and ferrochelatase activity.
• Ferrochelatase, which catalyzes the insertion of iron into protoporphyrin IX, is quite sensitive to lead.
• A decrease in the activity of this enzyme results in an increase of the substrate, erythrocyte protoporphyrin (EP), in the red blood cells (also found in the form of ZPP—bound to zinc rather than to iron).
• Also associated with lead exposure is an increase in blood and plasma d-aminolevulinic acid (ALA) and free erythrocyte protoporphyrins (FEP) (EPA 1986a as cited in ATSDR 1999).

EPA estimated the threshold BLL for a decrease in hemoglobin to be 50 µg/dL for occupationally exposed adults and approximately 40 µg/dL for children, although other studies have indicated a lower threshold (e.g., 25 µg/dL) for children. (EPA 1986b as cited in ATSDR 1999; ATSDR 1999)

• Recent data indicate that the EP level, which has been used in the past to screen for lead toxicity, is not sufficiently sensitive at lower levels of blood lead and is therefore not as useful a screening test as previously thought (see the “Laboratory Evaluation” section for further discussion of EP testing.).

Lead can induce two types of anemia, often accompanied by basophilic stippling of the erythrocytes. (ATSDR 1999)

• Acute high-level lead exposure has been associated with hemolytic anemia.
• Frank anemia is not an early manifestation of lead exposure and is evident only when the BLL is significantly elevated for prolonged periods.
• In chronic lead exposure, lead induces anemia by both interfering with heme biosynthesis and by diminishing red blood cell survival.
• The anemia of lead intoxication is hypochromic, and normo- or microcytic with associated reticulocytosis.

The heme synthesis pathway, on which lead has an effect, is involved in many other processes in the body including neural, renal, endocrine, and hepatic pathways.

• There is a concern about the meaning of and possible sequelae of these biochemical and enzyme changes at lower levels of lead.

Endocrine Effects

Studies of children with high lead exposure have found that a strong inverse correlation exists between BLLs and vitamin D levels.

• Lead impedes vitamin D conversion into its hormonal form, 1, 25-dihydroxyvitamin D, which is largely responsible for the maintenance of extra- and intra-cellular calcium homeostasis.
• Diminished 1, 25-dihydroxyvitamin D, in turn, may impair cell growth, maturation, and tooth and bone development.
• In general, these adverse effects seem to be restricted to children with chronically high BLLs (most striking in children with BLLs > 62 µg/dL) and chronic nutritional deficiency, especially with regard to calcium, phosphorous, and vitamin D (Koo et al. 1991 as cited in ATSDR 1999).
• However, Rosen et al. (1980) noted that in lead-exposed children with blood lead levels of 33-55 µg/dL, 1, 25-dihydroxyvitamin D levels were reduced to levels comparable to those observed in children with severe renal insufficiency.
• Lead appears to have a minimal, if any, effect on thyroid function.

Gastrointestinal Effects

In severe cases of lead poisoning, children or adults may present with severe cramping abdominal pain, which may be mistaken for an acute abdomen or appendicitis.

Cardiovascular (Hypertension) Effects

Hypertension is a complex condition with many different causes and risk factors, including age, weight, diet, and exercise habits.

• Lead exposure is one factor of many that may contribute to the onset and development of hypertension.
• Although low to moderate lead level exposures (BLL<30 µg/dL) show only a low degree of association with hypertension, higher exposures (primarily occupational) increase the risk for hypertensive heart disease and cerebrovascular disease as latent effects.
• One study found that adults who experienced lead poisoning as children had a significantly higher risk of hypertension 50 years later (relative to control adults without childhood lead exposure). (Hu, 1991, as cited in ATSDR 2000) The association has been shown in population-based studies with BLLs below 10 µg/dL. Data supports an association between lead exposure and elevations in blood pressure. (Victery et al. 1988; Schwartz 1995 as cited in ATSDR 2000; Korrick et al. 1999; Hu et al. 1996)
• It is estimated that, on a population basis, blood lead can account for a 1% to 2% variance in blood pressure. (ATSDR 2000) This could increase the incidence of hypertension a substantial amount, due to the high prevalence of hypertension of all causes in general populations.

Reproductive Effects

Reproductive effects examined in the literature include sperm count, fertility, and pregnancy outcomes. While several studies have implicated lead as contributing to reproductive and developmental effects, these effects have not been well-established at low exposure levels.

Male Reproductive Effects

Recent reproductive function studies in humans suggest that current occupational exposures decrease sperm count totals and increase abnormal sperm frequencies (Alexander et al. 1996; Gennart et al. 1992; Lerda 1992; and Lin et al. 1996 as cited in ATSDR 2000; Telisman et al. 2000).

• Effects may begin at BLLs of 40 µg/dL. (ATSDR 2005)
• Long-term lead exposure (independent of current lead exposure levels) also may diminish sperm concentrations, total sperm counts, and total sperm motility (Alexander et al. 1996 as cited in ATSDR 2000).
• It is unclear how long these effects may last in humans after lead exposure ceases.

Fertility

It is not currently possible to predict fertility outcomes based on current BLLs or past lead exposure levels. (ATSDR 2000)

Pregnancy Outcomes

The effect of low-level lead exposures on pregnancy outcomes is not clear. Thus it appears that at higher (e.g., occupational) exposure levels, the evidence is clearer for an association between lead and adverse pregnancy outcomes. This association becomes equivocal when looking at women exposed to lower environmental levels of lead. The data concerning exposure levels are incomplete, probably a result of far greater exposures than are currently found in lead industries.

• Some studies of women living near smelters versus those living some distance away did show increased frequency of spontaneous abortions (Nordstrom et al. 1979) and miscarriages and stillbirths (Baghurst et al. 1987; McMichael et al. 1986).
• In contrast, Murphy et al. (1990) evaluated past pregnancy outcomes among women living in the vicinity of a lead smelter and did not find an increase in spontaneous abortion risk among the lead exposed group versus the unexposed group.
• Women with BLL 5-9 µg/dL were two to three times more likely to have a spontaneous abortion than were women with BLL lesser than 5 µg/dL. (Borja-Aburto et al. 1999).

Developmental Effects

Developmental effects examined in the literature include pregnancy outcomes (e.g., premature births and low birth weights), congenital abnormalities, and post birth effects on growth or neurological development.

• Increasing evidence indicates that lead, which readily crosses the placenta, adversely affects fetus viability as well as fetal and early childhood development.
• Prenatal exposure to low lead levels (e.g., maternal BLLs of 14 µg/dL) may increase the risk of reduced birth weight and premature birth (ATSDR 1999).
• Although lead is an animal teratogen, most human studies have not shown a relationship between lead levels and congenital malformations.
• A study by Needleman et al. (1984) correlated increased prenatal lead exposure with increased risk for minor congenital abnormalities (e.g., minor skin abnormalities and undescended testicles).
• No association between prenatal lead exposure and major congenital abnormalities has been found (Ernhart et al. 1985, 1986; McMichael et al. 1986).
• In a retrospective study, a higher proportion of learning disabilities were found among school-aged children with biological parents who were lead poisoned as children 50 years previously (Hu 1991).

Other Potential Effects

Lead has been linked to problems with the development and health of bones. At high levels, lead can result in slowed growth in children.

• Studies have shown increased likelihood of osteoporosis (weakened bones later in life) in animals exposed to lead. A review of this issue can be found in Puzas (1992). Although this link has not been established in humans, it is likely that upon closer examination of lead-exposed individuals, lead will be shown to be a new risk factor for the disease.
• Research currently underway may provide more information about potential impacts of lead on osteoporosis (bone health) in the future.

Current available data are not sufficient to determine the carcinogenicity of lead in humans.

• EPA has classified elemental lead and inorganic lead compounds as Group 2B: probable human carcinogens. (ATSDR 1999) This classification is based in part on animal studies, which have been criticized because the doses of lead administered were extremely high (ATSDR 1999).
• The National Toxicology Program classifies lead and lead compounds as “reasonably anticipated to be a carcinogen” (NTP 2004).
• Information regarding the association of occupational exposure to lead with increased cancer risk is generally limited. This is because these occupational exposure studies, which primarily examined lead smelters, involved confounding exposures to other chemicals, including arsenic, cadmium, antimony, and toxicants from worker smoking habits (Cooper 1976 and IARC 1987).

Researchers are currently investigating the impacts of lead on dental health.

• One study found pre- and perinatal exposure to lead increased prevalence of caries in rat pups by almost 40% (Watson 1997).
• Human epidemiological studies suggesting an association between lead exposure and caries although this has not been well-established (Bowen 2001).

Key Points

• Effects in children generally occur at lower BLLs than in adults.
• The developing nervous system of a child can be affected adversely at BLLs of less than 10 µg/dL. It is often impossible to determine these effects upon clinical examination.
• There is a wide range of neurological effects associated with lead exposure, some of which may likely be irreversible.
• Lead exposure can lead to renal effects such as Fanconi-like syndromes, chronic nephropathy, and gout.
• Most lead-associated renal effects or disease are a result of ongoing chronic or present high acute exposure or can be a latent effect of chronic past lead exposure.
• Lead inhibits several enzymes critical to the synthesis of heme, causing a decrease in blood hemoglobin.
• Today, lead exposure in children only rarely results in frank anemia.
• Lead’s impairment of heme synthesis can affect other heme-dependent processes in the body outside of the hematopoietic system.
• Lead interferes with a hormonal form of vitamin D, which affects multiple processes in the body, including cell maturation and skeletal growth.
• Lead exposure may lead to increased risk for hypertension and its sequelae.
• Evidence suggests an association between lead exposure and certain reproductive and developmental outcomes.
• Maternal blood lead, from exogenous and endogenous sources, can cross the placenta and put the fetus at risk.
• Other potential health effects of lead are currently being studied.

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