Introduction< ?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

Lead serves no useful purpose in the human body, and 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 1999).

• Acute high lead exposure can cause serious physiologic effects, including death or long-term damage to brain function and organ systems.
• Effects of lead exposure vary according to exposure timing and levels, and other factors, and some effects may be latent.

The blood levels at which health effects have been observed are discussed below. It must be emphasized, however, that these levels are constantly being revised as new data are generated, and that, for children, there may be no threshold for developmental effects. Overt clinical symptoms and health effects that come with high exposure levels can be distinguished on an individual basis by the practicing health care provider. However, lack of overt symptoms doesn’t mean “no lead poisoning.” Lower levels of exposure have been shown, through population studies, to have many subtle health effects. It is important to interdict all lead exposures.

The sections below describe specific physiologic effects associated with major organ systems and functions.

Neurologic Effects

• Lead primarily affects the peripheral and central nervous systems, renal function, blood cells, and the metabolism of vitamin D and calcium. Lead can also cause hypertension, reproductive toxicity, and developmental effects.

The nervous system is the most sensitive target of lead exposure. Fetuses and young children are especially vulnerable to the neurologic effects of lead because their brains and nervous systems are still developing and the blood-brain barrier is incomplete. There may be no lower threshold for some of the adverse neurologic effects of lead in children; some of these effects have been documented at exposure levels once thought to cause no harmful effects (<10 µg/dL) (CDC 1997a). Because otherwise asymptomatic individuals may experience neurologic effects from lead exposure, clinicians should have a high index of suspicion for lead exposure, especially in the case of children.

Children

• Effects in children generally occur at lower BLLs than in adults.

In children, acute exposure to very high levels of lead may produce encephalopathy and its attendant signs (e.g., hyperirritability, ataxia, convulsions, stupor, and coma or death). 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 1999). Even without encephalopathy symptoms, these levels are associated with increased incidences of lasting neurologic and behavioral damage (ATSDR 1999).

• 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 through clinical examination.

Children suffer other neurologic effects at much lower exposure levels. There is a large body of evidence that associates decrement in intelligence quotient (IQ) performance and other neuropsychologic defects with lead exposure. Some studies have found, for example, that for every 10 µg/dL increase in BLL, children’s IQ dropped 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). There is also evidence that the probability of ADHD and hearing impairment in children increases with increasing BLLs, and that lead exposure may disrupt balance and impair peripheral nerve function (ATSDR 1999). These effects may begin at low, more widespread BLLs (at or below 10 µg/dL in some cases), and it may not be possible to detect them on clinical examination.

• There is a wide range of neurologic effects associated with lead exposure, some of which may likely be irreversible.

Some of the neurologic effects of lead in children may persist into adulthood. One study, for example, correlated lead exposure with lower class standing (classroom performance); greater absenteeism; more reading disabilities; and deficits in vocabulary, fine motor skills, reaction time, and hand-eye coordination in young adults more than 10 years after childhood exposure (Needleman et al. 1990).

Adults

There can be a difference in neurologic manifestations or sequelae between an adult exposed to lead as an adult, and an adult exposed as a child when the brain was developing. Childhood neurologic effects, including possibly ADHD, may persist into adulthood. Other than this, many of the neurologic symptoms experienced by children may also be experienced by lead-exposed adults, although the thresholds tend to be higher. Lead encephalopathy may occur at extremely high BLLs, e.g., 460 µg/dL (Kehoe 1961). Precursors of encephalopathy, such as dullness, irritability, poor attention span, muscular tremor, loss of memory, and hallucination, may occur at lower BLLs.

Less severe neurologic and behavioral effects have been documented in lead-exposed workers with BLLs ranging from 40 to 120 µg/dL. These effects include malaise; forgetfulness; irritability; lethargy; impaired concentration; depression and mood changes; increased nervousness; headache; fatigue; impotence; decreased libido; dizziness; weakness; and paresthesia; as well as diminished reaction time, visual motor performance, hand dexterity, IQ scores, and cognitive performance (ATSDR 1999). There is also some evidence that lead exposure may affect adults’ postural balance and peripheral nerve function (ATSDR 1997a, 1997b; Arving et al. 1980; Haenninen et al. 1978; Hogstedt et al. 1983; Mantere et al. 1982; Valciukas et al. 1978). 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

• Lead exposure can lead to renal effects such as Fanconi-like syndromes, chronic nephropathy, and gout.

Many studies show a strong association between lead exposure and renal effects. 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 that, if unrelieved, may develop into chronic and often irreversible lead nephropathy (i.e., interstitial nephritis).

• Most lead-associated renal effects or disease are a result of ongoing chronic or current high acute exposure. They can also be attributable to previous chronic lead exposure.

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, and serum creatinine and creatinine clearance are used as later indicators. However, certain urinary biomarkers of the proximal tubule (e.g., N-acetyl-ß-D-glucosaminidase) show elevations with current exposures, even at BLLs less than 60 µg/dL; and some population-based studies show accelerated (i.e., greater than that for normal aging) 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). Some renal disease or decrement in renal function may be caused by latent effects of lead exposure that occurred years earlier. In children, acute lead-induced renal effects appear reversible, with recovery usually occurring within 2 months of treatment (Chisolm et al. 1976). Treatment of acute lead nephropathy in children appears to prevent progression to chronic interstitial nephritis (Wedeen et al. 1986).

It should be noted that end-stage renal disease is a relatively rare occurrence in the < ?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com:office:smarttags" />U.S. population. Renal disease can be asymptomatic until the late stages and may not be detected without specific testing. If renal disease is detected and treated early, intervention may slow or stop (but not reverse) progression of renal failure. Because past or ongoing excessive lead exposure may also be a causal agent in kidney disease associated with essential hypertension (ATSDR 1999), primary care providers should especially assess and follow closely the renal functions of persons with hypertension with a past history of lead exposure (see Hypertension Effects). Because renal failure can contribute to the severity of hypertension, and vice versa, can contribute to each other’s occurrence and severity, when either health effect presents the other generally should be monitored. Both conditions should be strictly controlled when present. In addition, other known causes of renal disease or damage, such as diabetes mellitus, should be especially well controlled in patients with excess past or current lead exposure.

Lead exposure is also believed to contribute to the onset of “saturnine gout,” which may develop as a result 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). Saturnine gout is characterized by less frequent attacks than primary gout. Lead-associated gout may occur in premenopausal women, an uncommon occurrence in nonlead-associated gout (Goyer 1985). A study by Batuman et al. (1981) suggests that renal disease is more frequent and more severe when associated with saturnine gout than with primary gout.

Hematologic Effects

• Lead inhibits several enzymes critical to the synthesis of heme, causing a decrease in blood hemoglobin.

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  δ-aminolevulinic acid dehydratase 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 zinc protoporphyrin [ZPP]-bound to zinc rather than to iron). An increase in blood and plasma δ-aminolevulinic acid and free EPs is also associated with lead exposure (EPA 1986a). EPA estimates that the threshold BLL for a decrease in hemoglobin is 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, 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 Laboratory Evaluation for further discussion of EP testing.)

• Today, lead exposure in children only rarely results in frank anemia.

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. 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 normocytic or microcytic with associated reticulocytosis. Frank anemia is not an early manifestation of lead exposure and is evident only when the BLL is significantly elevated for prolonged periods.

• Lead’s impairment of heme synthesis can affect other heme-dependent processes in the body outside of the hematopoietic system.

The heme synthesis pathway (including cytochromes), 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 significance and possible sequelae of these biochemical and enzyme changes at lower levels of lead.

Endocrine Effects

• Lead interferes with a hormonal form of vitamin D, which affects multiple processes in the body, including cell maturation and skeletal growth.

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 extracellular and intracellular 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 significantly in children with BLLs > 62 µg/dL) and chronic nutritional deficiency, especially with regard to calcium, phosphorus, and vitamin D (Koo et al. 1991). 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. Minimizing lead exposure, and assuring sufficient calcium and Vitamin D in the diet throughout all stages of life, can help individual patients to ensure peak bone densities and diminish osteoporosis risk factors (ATSDR 1999, 1997b).

The effects of lead exposure on thyroid function have been examined in occupationally exposed adult workers and in children. Lead appears to have a minimal, if any, effect on thyroid function. A weak negative correlation has been reported between duration of exposure and thyroxin and free thyroxin levels (ATSDR, 1999). This suggests that chronic lead exposure could adversely affect the thyroid over time. No effects of lead on thyroid function have been found in children (ATSDR 1999).

Cardiovascular (Hypertension) Effects

• Lead exposure may lead to increased risk for hypertension and its sequelae.

Hypertension is a complex condition with many causes and risk factors, including older age, increased weight, poor diet and exercise habits, and excess alcohol intake. Lead exposure is one factor of many that may contribute to the onset and development of hypertension. Although low-level lead exposures (BLL<30 µg/dL) show only a low magnitude of association with hypertension, studies show that greater 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). Several studies support an association between lead exposure and elevations in blood pressure (Victery et al. 1988, Schwartz 1995, Korrick et al. 1999, Hu et al. 1996). The association has been shown in population-based studies with BLLs below 10 µg/dL. Increased odds of hypertension have been associated with the higher (compared to the lower) end of the range of bone lead levels in studies of veterans and nurses unaware of past lead exposure. It is estimated that, on a population mean basis, systolic blood pressure may rise 1-2 mm with each doubling of blood lead, and that blood lead can account for a 1 to 2% variance in blood pressure. On a population basis, this could increase the incidence of hypertension a substantial amount because of the high prevalence of hypertension of all causes in general populations. Because renal failure and hypertension can exacerbate each other, in general when either health effect presents, the other should be monitored (see Renal Effects). Persons with a history of excessive lead exposure should especially strive to follow standard guidelines to limit controllable risk factors for hypertension.

Reproductive Effects

• Evidence suggests an association between lead exposure and certain reproductive and developmental outcomes.

Male Reproductive Effects

Recent reproductive function studies in humans suggest that current (ongoing) occupational exposures may decrease sperm count totals and increase abnormal sperm frequencies (Alexander et al. 1996; Gennart et al. 1992; Lerda 1992; Lin et al. 1996; Telisman et al. 2000). Effects may begin at BLLs of 40 µg/dL (ATSDR 1999). 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). It is unclear how long reproductive effects may last in humans after lead exposure ceases.

Fertility

Although a few studies have investigated lead’s possible effect on male fertility, results are contradictory and there is at present no body of evidence to address this question. Whether and how lead exposure may affect female fertility remains an even more open question. Many factors can affect female fertility. It is not currently possible to predict fertility outcomes based on current BLLs or past lead exposure levels. A health care provider should approach the work-up and treatment of infertility in a standard fashion whether the patient has a history of lead exposure or not. Persons previously exposed to excessive lead should control those infertility risk factors that they can (e.g., alcohol and reproductive system infections).

Pregnancy Outcomes

An increased frequency of miscarriages and stillbirths among women working in the lead trades was reported as early as the turn of the century. Although the data concerning exposure levels are incomplete, these effects were probably a result of far greater exposures than are currently found in lead industries. The effect of low-level lead exposures on pregnancy outcomes is not clear. 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. Results of another recent retrospective study indicate that women who experienced overt childhood lead poisoning 50 years earlier may have also experienced a higher rate of spontaneous abortions and miscarriages (Hu 1991).

Thus there appears to be an association between higher (e.g., occupational) lead exposure levels and adverse pregnancy outcomes. This association becomes equivocal when looking at women exposed to lower environmental levels of lead.

Developmental Effects

• Maternal blood lead, from exogenous and endogenous sources, can cross the placenta and put the fetus at risk.

Developmental effects examined in the literature include pregnancy issues (e.g., premature births and low birth weights), congenital abnormalities, and postbirth effects on growth or neurologic 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). An association between prenatal lead exposure and major congenital abnormalities appears nonexistent (Ernhart et al. 1985, 1986; McMichael et al. 1986). In a retrospective study (see Pregnancy Outcomes), a higher proportion of learning disabilities was found among school-aged children with biological parents who were lead poisoned as children 50 years previously (Hu 1991). This suggests that the children of parents who experienced overt lead poisoning as children could be at greater risk for neurologic development impairment (Hu 1991).

Carcinogenic Effects

• EPA’s Science Advisory Board has recommended that lead be considered a probable human carcinogen.

Current available data are not sufficient to determine the carcinogenicity of lead in humans. EPA 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 acetate and lead phosphate as “may reasonably be anticipated to be carcinogens.” Information regarding the association of occupational exposure to lead with increased cancer risk is generally limited in its usefulness because the actual compound of lead, the route of exposure, and level of lead to which the workers were exposed were often not reported. In addition, 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).

Challenge

8. What are the major effects of lead on the human body?
9. How do lead’s effects differ in children and adults?
10. Why is physical examination alone often not enough to determine whether or not a child is experiencing potentially harmful lead exposure?