NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.
Prepared by Kowetha A. Davidson, Ph.D., Chemical Hazard Evaluation and Communication Program, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, *, Oak Ridge, Tennessee.
Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under contract No. DE-AC05-84OR21400.
Lead occurs naturally as a sulfide in galena. It is a soft, bluish-white, silvery gray, malleable metal with a melting point of 327.5C. Elemental lead reacts with hot boiling acids and is attacked by pure water. The solubility of lead salts in water varies from insoluble to soluble depending on the type of salt (IARC, 1980; Goyer, 1988; Budavari et al., 1989).
Lead is a natural element that is persistent in water and soil. Most of the lead in environmental media is of anthropogenic sources. The mean concentration is 3.9 ug/L in surface water and 0.005 ug/L in sea water. River sediments contain about 20,000 ug/g and coastal sediments about 100,000 ug/g. Soil content varies with the location, ranging up to 30 ug/g in rural areas, 3000 ug/g in urban areas, and 20,000 ug/g near point sources. Human exposure occurs primarily through diet, air, drinking water, and ingestion of dirt and paint chips (EPA, 1989; ATSDR, 1993).
The efficiency of lead absorption depends on the route of exposure, age, and nutritional status. Adult humans absorb about 10-15% of ingested lead, whereas children may absorb up to 50%, depending on whether lead is in the diet, dirt, or paint chips. More than 90% of lead particles deposited in the respiratory tract are absorbed into systemic circulation. Inorganic lead is not efficiently absorbed through the skin; consequently, this route does not contribute considerably to the total body lead burden (EPA, 1986a).
Lead absorbed into the body is distributed to three major compartments: blood, soft tissue, and bone. The largest compartment is the bone, which contains about 95% of the total body lead burden in adults and about 73% in children. The half-life of bone lead is more than 20 years. The concentration of blood lead changes rapidly with exposure, and its half-life of only 25-28 days is considerably shorter than that of bone lead. Blood lead is in equilibrium with lead in bone and soft tissue. The soft tissues that take up lead are liver, kidneys, brain, and muscle. Lead is not metabolized in the body, but it may be conjugated with glutathione and excreted primarily in the urine (EPA, 1986a,c; ATSDR, 1993). Exposure to lead is evidenced by elevated blood lead levels.
The systemic toxic effects of lead in humans have been well-documented by the EPA (EPA, 1986a-e, 1989a, 1990) and ATSDR (1993), who extensively reviewed and evaluated data reported in the literature up to 1991. The evidence shows that lead is a multitargeted toxicant, causing effects in the gastrointestinal tract, hematopoietic system, cardiovascular system, central and peripheral nervous systems, kidneys, immune system, and reproductive system. Overt symptoms of subencephalopathic central nervous system (CNS) effects and peripheral nerve damage occur at blood lead levels of 40-60 ug/dL, and nonovert symptoms, such as peripheral nerve dysfunction, occur at levels of 30-50 ug/dL in adults; no clear threshold is evident. Cognitive and neuropsychological deficits are not usually the focus of studies in adults, but there is some evidence of neuropsychological impairment (Ehle and McKee, 1990) and cognitive deficits in lead workers with blood levels of 41-80 ug/dL (Stollery et al., 1993).
Although similar effects occur in adults and children, children are more sensitive to lead exposure than are adults. Irreversible brain damage occurs at blood lead levels greater than or equal to 100 ug/dL in adults and at 80-100 ug/dL in children; death can occur at the same blood levels in children. Children who survive these high levels of exposure suffer permanent severe mental retardation.
As discussed previously, neuropsychological impairment and cognitive (IQ) deficits are sensitive indicators of lead exposure; both neuropsychological impairment and IQ deficits have been the subject of cross-sectional and longitudinal studies in children. One of the early studies reported IQ score deficits of four points at blood lead levels of 30-50 ug/dL and one to two points at levels of 15-30 ug/dL among 75 black children of low socioeconomic status (Schroeder and Hawk, 1986).
Very detailed longitudinal studies have been conducted on children (starting at the time of birth) living in Port Pirie, Australia (Vimpani et al., 1985, 1989; McMichael et al., 1988; Wigg et al., 1988; Baghurst et al., 1992a,b), Cincinnati, Ohio (Dietrich et al., 1986, 1991, 1992, 1993), and Boston, Massachusetts (Bellinger et al., 1984, 1987, 1990, 1992; Stiles and Bellinger 1993). Various measures of cognitive performance have been assessed in these children. Studies of the Port Pirie children up to 7 years of age revealed IQ deficits in 2-year-old children of 1.6 points for each 10-ug/dL increase in blood lead, deficits of 7.2 points in 4-year-old children, and deficits of 4.4 to 5.3 points in 7-year-old children as blood lead increased from 10-30 ug/dL. No significant neurobehavioral deficits were noted for children, 5 years or younger, who lived in the Cincinnati, Ohio, area. In 6.5-year-old children, performance IQ was reduced by 7 points in children whose lifetime blood level exceeded 20 ug/dL.
Children living in the Boston, Massachusetts, area have been studied up to the age of 10 years. Cognitive performance scores were negatively correlated with blood lead in the younger children in the high lead group (greater than or equal to 10 ug/dL), and improvements were noted in some children at 57 months as their blood lead levels became lower. However, measures of IQ and academic performance in 10-year-old children showed a 5.8-point deficit in IQ and an 8.9-point deficit in academic performance as blood lead increased by 10 ug/dL within the range of 1-25 ug/dL. Because of the large database on subclinical neurotoxic effects of lead in children, only a few of the studies have been included. However, EPA (EPA, 1986a, 1990) concluded that there is no clear threshold for neurotoxic effects of lead in children.
In adults, the cardiovascular system is a very sensitive target for lead. Hypertension (elevated blood pressure) is linked to lead exposure in occupationally exposed subjects and in the general population. Three large population-based studies have been conducted to study the relationship between blood lead levels and high blood pressure. The British Regional Heart Study (BRHS) (Popcock et al., 1984), the NHANES II study (Harlan et al., 1985; Pirkle et al., 1985; Landis and Flegal, 1988; Schwartz, 1990; EPA, 1990), and Welsh Heart Programme (Ellwood et al., 1988a,b) comprise the major studies for the general population. The BRHS study showed that systolic pressure greater than 160 mm Hg and diastolic pressure greater than 100 mm Hg were associated with blood lead levels greater than 37 ug/dL (Popcock et al., 1984). An analysis of 9933 subjects in the NHANES study showed positive correlations between blood pressure and blood lead among 12-74-year-old males but not females (Harlan et al., 1985; Landis and Flegal et al., 1988), 40-59-year-old white males with blood levels ranging from 7-34 ug/dL (Pirkle et al., 1985), and males and females greater than 20 years old (Schwartz, 1991). In addition, left ventricular hypertrophy was also positively associated with blood lead (Schwartz, 1991). The Welsh study did not show an association among men and women with blood lead of 12.4 and 9.6 ug/dL, respectively (Ellwood et al., 1988a,b). Other smaller studies showed both positive and negative results. The EPA (EPA, 1990) concluded that increased blood pressure is positively correlated with blood lead levels in middle-aged men, possibly at concentrations as low as 7 ug/dL. In addition, the EPA estimated that systolic pressure is increased by 1.5-3.0 mm Hg in males and 1.0-2.0 mm Hg in females for every doubling of blood lead concentration.
The hematopoietic system is a target for lead as evidenced by frank anemia occurring at blood lead levels of 80 ug/dL in adults and 70 ug/dL in children. The anemia is due primarily to reduced heme synthesis, which is observed in adults having blood levels of 50 ug/dL and in children having blood levels of 40 ug/dL. Reduced heme synthesis is caused by inhibition of key enzymes involved in the synthesis of heme. Inhibition of erythrocyte -aminolevulinic acid dehydrase (ALAD) activity (catalyzes formation of porphobilinogen from -aminolevulinic acid) has been detected in adults and children having blood levels of less than 10 ug/dL. ALAD activity is the most sensitive measure of lead exposure, but erythrocyte zinc protoporphyrin is the most reliable indicator of lead exposure because it is a measure of the toxicologically active fraction of bone lead. The activity of another erythrocyte enzyme, pyrimidine-5-nucleotidase, is also inhibited by lead exposure. Inhibition has been observed at levels below 5 ug/dL; no clear threshold is evident.
Other organs or systems affected by exposure to lead are the kidneys, immune system, reproductive system, gastrointestinal tract, and liver. These effects usually occur at high blood levels, or the blood levels at which they occur have not been sufficiently documented.
The EPA has not developed an RfD for lead because it appears that lead is a nonthreshold toxicant, and it is not appropriate to develop RfDs for these types of toxicants. Instead the EPA has developed the Integrated Exposure Uptake Biokenetic Model to estimate the percentage of the population of children up to 6 years of age with blood lead levels above a critical value, 10 ug/dL. The model determines the contribution of lead intake from multimedia sources (diet, soil and dirt, air, and drinking water) on the concentration of lead in the blood. Site-specific concentrations of lead in various media are used when available; otherwise default values are assumed. The EPA has established a screening level of 400 ppm (ug/g) for lead in soil (EPA, 1994a).
Inorganic lead and lead compounds have been evaluated for carcinogenicity by the EPA (EPA, 1989, 1993). The data from human studies are inadequate for evaluating the potential carcinogenicity of lead. Data from animal studies, however, are sufficient based on numerous studies showing that lead induces renal tumors in experimental animals. A few studies have shown evidence for induction of tumors at other sites (cerebral gliomas; testicular, adrenal, prostate, pituitary, and thyroid tumors). A slope factor was not derived for inorganic lead or lead compounds.
Lead occurs naturally as a sulfide in galena. It is a soft, bluish-white, silvery gray, malleable metal that melts at 327.5C. Elemental lead reacts with hot or boiling nitric, hydrochloric, or sulfuric acid; it is attacked by pure water and weak organic acids in the presence of oxygen. The solubility of lead salts in water varies considerably. Lead sulfide, phosphate, carbonate, and oxides are insoluble or practically insoluble in water; lead chloride is slightly soluble; and lead acetate, subacetate, and nitrate are soluble in water (IARC, 1980; Goyer, 1988; Budavari et al., 1989).
In 1990, 80% of lead use in the U.S. was in the production of lead-acid storage batteries; 12.4% was used for production of ammunition, bearing metals, brass and bronze, cable covering, extruded products, sheet lead, and solder; and 7.6% was used in ceramics, type metal, ballast or weights, tubes or containers, oxides, and gasoline additives (U.S. DC. 1992). New environmentally safe uses for lead include radiation protection in computer, television, diagnostic magnetic imaging, and other nuclear medical technology; circuit boards in computers and other electronic equipment; piezoelectric ceramics; superconductor technology; and high purity lead oxides used in optical technology (ATSDR, 1993).
Lead is a natural element that persists in water and soil. Lead particles in the atmosphere have a residence time of about 10 days. Most of the lead in environmental media is of anthropogenic sources. Human exposure to lead occurs primarily through diet, air, drinking water, dust, and paint chips. Levels in air and dust vary with the location [rural, urban, or proximity to point sources (primary and secondary smelter and battery plants)]. Lead concentrations in the various media are presented in Table 1. The mean concentration of lead in surface water is 3.9 ug/L (measured at 50,000 stations); the concentration in sea water is 0.005 ug/L. The average concentration is about 20,000 ug/g in river sediments and about 100,000 ug/g in coastal sediments. The natural lead (galena, PbS) content in soil ranges from less than 10-30 ug/g. However, surface soil concentrations vary depending on point source and automobile exhaust emissions (Table 1) (EPA, 1989b; ATSDR, 1993).
Table 1. Lead Concentrations in Various Media
|Medium||Rural||Urban||Near Point Source|
|Ambient Air (ug/m3)||0.1||0.1-0.3||0.3-3.0|
|Indoor Air (ug/m3)||0.03-0.08||0.03-0.2||0.2-2.4|
|Street Dust (ppm)||80-130||100-5,000||25,000|
|House Dust (ppm)||50-500||50-3,000||100-20,000|
|Drinking Water (ug/L)||5-75||5-75||5-75|
|Paint (mg/cm2)||<1- >5||<1- >5||<1->5|
Lead is absorbed into the body following ingestion and inhalation exposure. Adult humans absorb 10-15% of ingested lead; however, children absorb up to 50% of ingested lead. Gastrointestinal absorption may vary depending on dietary factors and the chemical form of the lead. Lead is more readily absorbed in fasting individuals (up to 45% for adults) than when ingested with food. Absorption is also increased in children suffering from iron or calcium deficiencies. Gastrointestinal absorption in children may be only 30% for lead present in dust and dirt and 17% for lead in paint chips, compared with 50% for lead in food and beverages. Absorption of lead from the respiratory tract is dependent on the size of the particles inhaled and the fraction deposited in the lungs, which is about 30-50% of lead particles depending on size and ventilation rate. Deposition of lead particles in the respiratory tract of children is 1.6-2.7 times that of adults. More than 90% of the lead contained in particles deposited in the lungs is absorbed into the blood. Absorption of inorganic lead through the skin does not contribute considerably to the total (EPA, 1986a).
Gastrointestinal absorption in laboratory animals is similar to that of humans. A higher percentage of the dose is absorbed by young than by adult animals, and dietary and nutritional factors affect the rate of absorption. Fasting and an iron-deficient diet generally increase the absorption rate, whereas zinc and calcium supplements decrease the absorption rate (Conrad and Barton, 1978).
The rate of absorption of different lead compounds may vary considerably. A study in rats showed that relative to lead acetate (100%), lead carbonate was absorbed 164%; lead thallate 121%; lead sulfide, lead naphthenate, and lead octoate 62-67%; lead chromate 44%; and metallic lead 14% (Barltrop and Meek, 1975). Gastrointestinal absorption is similar whether lead is incorporated in dust, dirt, paint chips, or diet. The limited data available indicate that laboratory animals absorb lead from the respiratory tract as efficiently as humans and that the absorption rate is not affected by chemical form or concentration of lead in the air (EPA, 1986a).
The three major compartments for the distribution of lead are blood, soft tissue, and bone. Almost all (99%) blood lead is associated with erythrocytes, and 50% of erythrocyte lead is bound to hemoglobin. The biological half-life of blood lead is 25-28 days when blood lead is in equilibrium with the other compartments. Blood lead levels change rapidly with exposure and are used as an index of recent exposure. The small fraction of lead in the plasma and serum is in equilibrium with soft tissue lead. Soft tissues that take up lead are liver and kidneys, with smaller amounts taken up by brain and muscle. The lead content in the kidney increases with age and may be related to dense inclusion bodies seen in the renal cell nuclei. The greatest amount of lead found in the brain is localized in the hippocampus, followed by the cerebellum, cerebral cortex, and medulla. The largest fraction of lead retained in the body is found in the bone. About 95% of total body lead in adults is in the bone compared with only 73% in children. Although bone lead is a large, relatively inert fraction with a half-life for lead greater than 20 years, there is a "labile" fraction that is in equilibrium with soft tissue lead (EPA, 1986a,c).
Inorganic lead ion is not metabolized in the body; it can be conjugated with glutathione (ATSDR, 1993).
Approximately 75% of inorganic lead absorbed into the body is excreted in urine and less than 25% is excreted in feces. Lead is also excreted in breast milk and therefore, available for intake by infants (Jensen, 1983; EPA, 1989a).
The systemic uptake resulting from exposure to lead in the various media (air, water, diet, soil) contributes to the total body lead burden (tissue uptake), which in turn is linked to the adverse effects. The concentration of lead in blood is used as a measure of exposure. Therefore, effects of lead cannot be described in terms of route specificity. In addition, the effects are considered to be a consequence of exposure to all lead salts absorbed into the systemic circulation, taken up by various tissues, and contributing to the total body lead burden (EPA, 1989a). In addition, the types of lead salt affect the solubility and bioavailability (Goyer, 1988).
The toxic effects of lead in humans have been well documented. The Air Quality Criteria Document for Lead and its addendum (EPA, 1986a-e) and the Supplement to the 1986 Addendum (EPA, 1990) reviewed and assessed the health effects associated with exposure to lead and lead compounds. The carcinogen assessment document, Evaluation of the Potential Carcinogenicity of Lead and Lead Compounds, (EPA, 1989a) evaluated evidence relating the causal association of cancer and exposure to lead and lead compounds.
Nonspecific signs and symptoms of lead intoxication include loss of appetite, metallic taste, constipation, obstipation, pallor, malaise, weakness, insomnia, headache, irritability, pain in muscles and joints, fine tremors, colic, and Burton's lines (purple-blue discoloration of the gums). Specific effects occur in target organs and systems: nervous system (central and peripheral), hematopoietic system, cardiovascular system, kidneys, reproductive system, and fetus.
Irreversible severe brain damage (overt encephalopathic symptoms) occurs after exposure to high concentrations of lead. In adults, lead encephalopathy occurs at blood lead concentrations of 120 ug/dL or more, but it has also been known to occur at concentrations of only 100 ug/dL in some individuals. The onset of encephalopathic symptoms is very rapid; convulsions, coma, and death can occur within 48 hours in individuals appearing to be asymptomatic (EPA, 1986a).
Overt symptoms of subencephalopathic central nervous system (CNS) and peripheral nerve damage are seen at blood lead concentrations ranging from 40-60 ug/dL. Peripheral nerve dysfunction, detected by a slowing of nerve conduction velocities, occurs at blood lead concentrations ranging from 30-50 ug/dL; this effect has shown no clear threshold (EPA, 1986a).
Ehle and McKee (1990) reviewed neuropsychological studies reported in the literature up to 1986. Regarding nonovert neuropsychological impairment, they concluded that there appears to be some evidence of increased irritability and fatigue, suggestive evidence for decreased ability to process information quickly, and suggestive but inconclusive evidence that even low levels of lead impair the ability to input and integrate novel information as well as store information in short-term memory. Stollery et al. (1991) evaluated cognitive performance in lead workers with low (less than 20 ug/dL), medium (21-40 ug/dL), or high (41-80 ug/dL) blood lead levels. Deficits in performance were noted in the high lead group. These included slowing of sensory motor reaction time, impaired decision making and response execution, lapses in concentration, and difficulty in recalling nouns classified in an earlier category search task. These results indicate a slowing of sensory motor reaction time and impairment of short-term memory. Recently, Ogawa et al. (1993) evaluated peripheral nerve function in a cohort of 133 healthy Japanese male workers who had blood lead concentrations of 9.3 ug/dL (control), 19.2 ug/dL (low exposure), and 53.1 ug/dL (high exposure). Nerve function, measured by the latency of the Achilles tendon reflex, was increased by 4-6% in the high exposure group compared with two other groups, indicating that nerve conduction velocities are slowed.
The following information on induction of anemia and erythropoiesis in lead-exposed individuals was summarized from Goyer (1988), EPA (1986a,d), and ATSDR (1993).
Frank anemia, which is a result of reduced hemoglobin production and shortened life span of erythrocytes, is seen in adults at blood lead concentrations of 80 ug/dL and in children at concentrations of 70 ug/dL. The anemia in lead-exposed individuals is of the hypochromic and normocytic (also microcytic) type and is accompanied by reticulocytosis with basophilic stippling. The shortened life span of erythrocytes is due to increased fragility of the blood cell membrane and reduced hemoglobin production is due to decreased levels of enzymes involved in heme synthesis. Reduced heme synthesis is seen at blood lead levels of 50 ug/dL in adults and approximately 40 ug/dL in children.
The key enzymes involved in the synthesis of heme are -aminolevulinic acid synthetase (ALAS), a mitochondrial enzyme that catalyzes the formation of -aminolevulinic acid (ALA), and ALA dehydrase (ALAD), a cytosolic enzyme that catalyzes formation of porphobilinogen. Through a series of steps, coproporphyrin and protoporphyrin are formed from porphobilinogen, and, finally, the mitochondrial enzyme ferrochelatase catalyzes the insertion of iron into protoporphyrin to form heme.
As erythrocyte ALAD activity is inhibited, ALAS activity is stimulated; therefore, ALA levels in blood are increased, leading also to elevated levels of ALA in urine. The threshold for detecting elevated ALAS activity and blood and urinary ALA levels is 40 ug/dL in both adults and children, but evidence indicates that the threshold may be as low as 15-20 ug/dL. Inhibition of erythrocyte ALAD has been noted at very low blood levels. This enzyme is one of the most sensitive indicators of exposure to lead; the threshold blood lead level for ALAD activity is less than 10 ug/dL in adults and children. Increased coproporphyrin levels are elevated in individuals with blood lead concentrations of 40 ug/dL. Urinary porphobilinogen levels are not elevated in lead-exposed humans.
Although erythrocyte ALAD activity may be the most sensitive measure of lead exposure, detection of erythrocyte zinc protoporphyrin is probably the most reliable indicator of lead exposure, because it is a measure of exposure due to the mobilizable fraction (toxicologically active fraction) of bone lead. In lead-exposed individuals, zinc is inserted into the porphyrin moiety instead of iron. The threshold for detecting elevated zinc protoporphyrin levels is 25-30 ug Pb/dL of blood in adults, 16 ug/dL in 15-16 year old children, and 15.5 ug/dL in one study of children who were 4 years old. The threshold for elevation of total erythrocyte protoporphyrin (zinc and iron) is 25-30 ug/dL in adult males, 15-20 ug/dL in adult females, and 15 ug/dL in children.
The activity of another erythrocyte enzyme, pyrimidine-5-nucleotidase (Py-5-N), is significantly reduced in lead-exposed individuals at blood levels of 30 ug/dL; reduced activity has been detected at levels below 5 ug/dL, with no clear threshold. The consequence of reduced Py-5-N activity is thought to be accumulation of cellular nucleotides, reduced erythrocyte stability and survival, and reduced mRNA and protein synthesis related to production of the globulin chain. Furthermore, inhibition of erythrocyte Py-5-N activity may be indicative of a widespread impact on pyrimidine metabolism in other tissues besides blood. The possibility of generalized effects on pyrimidine metabolism and heme biosynthesis has serious implications regarding the health hazards of very low levels of lead, especially in children.
In an addendum to its Air Quality Criteria for Lead report, the EPA (1986e) evaluated the available data concerning the association of blood lead levels and blood pressure (or hypertension). These data were updated in the Supplement to the 1986 Addendum (EPA, 1990) in which the EPA briefly reviewed the key studies evaluated in its 1986 report and then evaluated studies reported in the literature since 1986.
Lead exposure has also been weakly linked to increased blood pressure and hypertension in the general population and in occupationally exposed subjects. Two large population-based studies, the British Regional Heart Study (BRHS) and the National Health and Nutrition Examination Survey (NHANES II), and a smaller Welsh study (Welsh Heart Programme) comprise the key studies relating blood lead levels with increased blood pressure. The BRHS and NHANES II studies showed weak correlations between blood lead levels and increases in blood pressure or hypertension, but the Welsh study did not show a significant correlation. The BRHS study reported by Pocock et al. (1984) involved a clinical survey of the blood pressure, indicators of renal function, and blood lead concentrations in 7735 men, 40-49 years old, from 24 British towns. Pocock et al. (1984) concluded that increased hypertension (systolic pressure greater than 160 mm Hg, diastolic pressure greater than 100 mm Hg) was suggested at lead concentrations greater than 37 ug/dL of blood.
The NHANES II study was conducted on 9933 persons representative of the general U.S. population at 6 months to 74 years of age; 2372 were 6 months to 5 years old, 1720 were 7-17 years old, and 5841 were 18-74 years old (EPA, 1986c). Harlan et al. (1985) reported that simple linear regression produced a statistically significant linear correlation between blood lead levels and both systolic and diastolic pressure among 12-74-year-old males and females. The correlation remained significant for males, but not for females, after adjusting for pertinent confounders (age, body mass index, etc.). Pirkle et al. (1985) evaluated a subgroup of white males age 40-59 and noted that blood lead levels were significantly correlated with systolic and diastolic blood pressure after adjusting for all known confounders. The correlation was significant for blood lead concentrations ranging from 7-34 ug/dL and showed no obvious threshold. When the data were adjusted for geographical site, the associations between blood lead and blood pressure were weakened but remained significant for both the BRHS group (white males 40-59 years old) and the NHANES II group (males 20-74 or 12-74 years old and white males 40-59 years old) (EPA, 1990).
Landis and Flegal (1988) tested the statistical significance of the association of diastolic blood pressure and blood lead levels among males ages 12-74 evaluated in the NHANES II survey. They noted that, even after adjusting for geographical site, age, and body mass, which resulted in 478 stratifications, diastolic pressure remained positively associated (pless than 0.005) with blood lead levels. Schwartz (1991) conducted regression analyses of data on electrocardiograms and blood pressure from NHANES II males and females greater than 20 years old. This investigator concluded that blood lead is a significant predictor of diastolic blood pressure and left ventricular hypertrophy, even after controlling for race, age, and body mass.
A smaller population-based study conducted on 865 Welsh men and 856 Welsh women whose mean blood lead levels were 12.4 and 9.6 ug/dL, respectively, did not show a significant correlation between blood lead and blood pressure (Ellwood et al., 1988a,b).
Pocock et al. (1988) compared the results of the British, NHANES II, and the Welsh study and concluded that blood pressure increases about 1 mm Hg for every doubling of blood lead concentration.
Other studies have produced results similar to those of the population-based studies. Morris et al. (1990) reported that blood pressure measured in 251 subjects at weekly intervals for 4 weeks was significantly associated with blood lead in males and that 10 ug/dL produced a systolic increase of 5 mm Hg. In an occupational exposure study, Kirby and Gyntelberg (1985) reported that diastolic pressure was significantly associated with blood lead concentrations among Danish lead smelter workers whose blood lead was 51 ug/dL compared with 11 ug/dL for a control group. Among workers processing lead and cadmium compounds, blood pressure was also significantly associated with blood lead levels (average blood lead = 47.4 ug/dL compared with 8.1 ug/dL for controls) and urinary cadmium levels (deKort et al., 1986). Maheswaran et al. (1993) reported that the unadjusted systolic blood pressure was 127 mm Hg in male battery workers who had blood lead levels less than 21 ug/dL (geometric mean) and 133 mm Hg in men who had blood levels greater than 50 ug/dL. After adjusting for several confounders, the correlation was still positive, but not statistically significant. Additional studies showed that systolic pressure was correlated with blood lead levels among male civil service employees (12 to 30 ug/dL) (Moreau et al., 1982) and policemen in Boston, Massachussetts (greater than or equal to 30 ug/dL) (Weiss et al., 1986). Dolenc et al. (1993) reported, however, that systolic blood pressure was negatively correlated with blood lead, and diastolic pressure was not significantly correlated with blood lead in 827 males (10.4 ug/dL); neither systolic nor diastolic pressure was significantly correlated with blood lead in 821 females (6.2 ug/dL).
The EPA (1990) concluded that increased blood pressure is positively associated with blood lead levels in middle-aged men, maybe at concentrations as low as 7 ug/dL. The Agency further noted that for every doubling of blood lead concentrations, the systolic pressure is estimated to increase by 1.5-3.0 mm Hg in males and by 1.0-2.0 mm Hg in females. An association of elevated blood pressure with increased risks for more serious cardiovascular diseases has not been evaluated. However, any increase in blood pressure is likely to predispose individuals to increased risks for heart attacks and strokes (EPA, 1990).
Kidney disease (nephropathy) is a characteristic manifestation of lead toxicity. Two types of nephropathy, acute and chronic nephropathy, have been observed in humans. Acute nephropathy occurs during the early stages of excess exposure, especially in children. The characteristic effects of acute nephropathy are reversible morphological and functional changes in the proximal tubular epithelial cells. The morphological changes include the formation of nuclear inclusion bodies (lead-protein complex), ultrastructural changes in mitochondria, and cytomegaly in the epithelial cells. The functional changes consist of increased aminoaciduria, glucosuria, phosphaturia, and sodium excretion; decreased uric acid excretion and 1,25-dihydroxyvitamin D synthesis; and altered plasma angiotensin II/renin ratio. Glomerular effects are either minimal or absent. Chronic nephropathy occurs after prolonged exposure to lead. It is characterized by sparse or an absence of nuclear inclusion bodies; atrophy or hyperplasia of tubular epithelial cells; and progressive interstitial, glomerular, arterial, and arteriolar sclerosis. Functional characteristics of chronic nephropathy include reduced glomerular filtration rate, azotemia, proportionally greater tubular dysfunction than indicated by the decrease in glomerular filtration rate during the early stage of chronic nephropathy, and the absence of detectable tubular dysfunction accompanying the decrease in glomerular filtration rate at the later stages. Chronic nephropathy does not become clinically apparent until about 50 to 75% of the tubules are destroyed (Goyer, 1985, 1988; Landingran, 1989).
Chronic nephropathy occurs after exposure to high concentrations of lead. In occupational exposure studies, death due to kidney disease has occurred at blood levels exceeding 62 ug/dL. Death rates due to chronic kidney diseases and residual hypertensive diseases (mainly renal) were significantly elevated among cohorts of 2300 smelter workers and 4519 battery workers occupationally exposed to lead (Cooper et al., 1985). The average blood lead concentration was 79.7 ug/dL in the smelter workers and 62.7 ug/dL in the battery workers. Selevan et al. (1975) reported an increased mortality rate due to chronic kidney disease among a cohort of lead smelter workers exposed to airborne levels above 200 ug Pb/m3. In the cohorts studied by Cooper et al. (1985) and Selevan et al. (1975), almost all of the deaths occurred among workers employed more than 20 years, occurred with a latency of 20 years, or occurred among workers hired before 1946. Deaths from chronic azothemic nephritis occurred among battery workers whose exposure exceeded air concentrations of 500 ug/m3 (Lane, 191992) saw no impairment of renal function in 70 active and 30 retired lead smelter workers compared with that of 31 active and 10 retired truck assembly workers who had no known exposure to lead. Kidney function was assessed by the urinary concentration of enzyme markers for renal tubular damage (2-microglobulin and N-acetyl--glucosaminidase) and glomerular damage (albumin). The average employment duration of active and retired smelter workers was 14.3 and 32.6 years, respectively, and the median blood lead concentrations were 31.9 ug/dL (range=5.0-47.4 ug/dL) and 9.9 ug/dL (range=3.3-20.9 ug/dL), respectively. The blood lead concentration for controls ranged from 1.7-12.4 ug/dL.
The effects of exposure to lead on other organs are not as well documented as those described previously in this profile. The following information was summarized from EPA (1986a) and ATSDR (1993).
Gastrointestinal disturbance (colic) is a sign of acute lead intoxication, generally occurring at blood lead levels of 100-200 ug/dL in adults, but it may also occur at levels of 40-60 ug/dL. In children, gastrointestinal disturbances occur at levels greater than or equal to 60 ug/dL Gastrointestinal symptoms include abdominal pain, constipation, cramps, nausea, vomiting, anorexia, and weight loss.
Hepatic effects are manifested by abnormal serum enzyme levels and mild hepatitis. One documented case occurred in a 52-year-old man whose blood lead level was 203 ug/dL.
Data documenting the effect of exposure to lead on the immune system is equivocal. These effects are probably manifested by suppression of cellular immunity. One study showed no significant effects on serum immunoglobulin levels, response to phytohemagglutinin, or natural killer cell activity in workers whose levels were 25-53 ug/dL compared with controls whose levels were 8-17 ug/dL (Kimber et al., 1986). Another study showed that the response of lymphocytes to phytohemagglutinin was depressed in workers exposed to lead oxide (266 mg/m3) and who had blood lead levels of 64 ug/dL (Alomran and Shleamoon, 1988). Coscia et al. (1987) reported that the proportion of B lymphocytes and the absolute number of B lymphocyte and T8 cells were increased in workers exposed to lead.
The most critical effects of lead toxicity occur among children exposed during fetal development, postnatal development, or both. Children are much more sensitive to lead intoxication than adults. In children, encephalopathic symptoms and death occur at blood lead concentrations of 80-100 ug/dL. Those who survive lead encephalopathy, however, may suffer permanent severe mental retardation and other marked neurological deficiencies. Overt subencephalopathic symptoms (peripheral nerve damage) occur at blood levels of 40-60 ug/dL. Nonovert neurotoxic effects [evidenced by slowed nerve conduction velocities and cognitive (IQ), electrophysiological, and neuropsychological defects] were detected in children at levels less than or equal to 40 ug/dL, with no clear threshold being evident (EPA, 1986a).
Studies in children have shown IQ score deficits of approximately five points at blood levels of 50-70 ug/dL, four points at levels of 30-50 ug/dL and one to two points at levels of 15-30 ug/dL. A highly significant (pless than 0.0008) linear relationship between IQ scores and current blood lead levels (average: 21 ug/dL, range: 6-47 ug/dl) was demonstrated in 75 black children 3-7 years old, all of low socioeconomic status (Schroeder and Hawk, 1986). Significant associations between electrophysiological changes (EEG patterns) and IQ deficit with lead exposure were seen in a group of children with estimated average blood lead levels of 30-50 ug/dL (Burchfiel et al.,1980). Another study in children also showed a significant linear relationship between electrophysiological effects (slow wave voltage) and blood lead levels ranging from 6-59 ug/dL (mean=32.5 ug/dl); a dose-response analysis did not show a clear threshold (Otto et al., 1981). A follow-up study showed continued electrophysiological effects (slow wave voltage) 2 and 5 years later, although the mean blood lead level had declined (21.1 ug/dL at 2 years) (Otto et al., 1882, 1985). In a recent cross-sectional study reported by Muñoz et al. (1993), the blood lead concentration (mean = 19.4 ug/dL) was inversely associated with full scale IQ and teachers' rating of performance.
Longitudinal studies in which various manifestations of neurotoxicity are assessed in children relative to lead concentrations in maternal blood, umbilical cord, or the child's blood at different times during postnatal development have provided invaluable information on effects of low lead concentrations. Endpoints of evaluations included various aspects of mental, motor, and behavioral development. These studies are identified by their geographical location. A cohort of children born in or around Port Pirie (located close to a lead smelter in Australia) have been followed from birth through 7 years of age; their blood lead was measured at 6 and 15 months and yearly from age 2 to 7 (Vimpani et al., 1985, 1989; McMichael et al., 1988; Wigg et al., 1988; Baghurst et al., 1992a,b). Mean blood lead concentrations ranged from 6.6 to 13.0 ug/dL in the lowest quartile to 20.0 to 33.5 ug/dL in the highest quartile (Baghurst et al., 1992b). Blood lead concentrations were inversely related to intelligence scores (using various tests) at all ages tested starting at 2 years of age. At 2 years of age, the intelligence score was 1.6 points lower for each 10-ug/dL increase in blood lead concentration measured when the children were 6 months of age (Wigg et al., 1988). At 4 years of age, the scores were reduced by 7.2 points as blood lead increased from 10 to 30 ug/dL (McMichael et al., 1988), and at 7 years of age the score was reduced by 4.4 to 5.3 points for the same increase in blood lead (Baghurst et al., 1992b).
A cohort of inner city children in Cincinnati, Ohio, was assessed from birth to 6.5 years old (Dietrich et al., 1986, 1991, 1992, 1993). Neurobehavioral deficits in 4-year-old children were associated with neonatal blood lead, but not with prenatal maternal blood lead or mean lifetime blood lead (Dietrich et al., 1991). In 5-year-old children (Dietrich et al., 1992), postnatal blood lead concentration was associated with lower cognitive scores, which were not significant after adjusting for developmental covariates. Neonatal blood lead concentrations were inversely associated with covariate-adjusted scores on some aspects of central auditory processing performance. In 6.5-year-old children, deficits in performance IQ were significantly associated with postnatal blood lead before and after covariate adjustment (Dietrich et al., 1993). In addition, a dose-response relationship existed between blood lead and performance IQ. Dietrich et al. (1993) estimated that lifetime blood lead concentrations exceeding 20 ug/dL reduced the intelligence score by 7 points.
Bellinger et al. (1984; 1987) stratified a cohort of middle and upper-middle class Boston, Massachusetts, children into low (less than 3 ug/dL; mean=1.8 ug/dL), medium (6-7 ug/dL; mean=6.5 ug/dL), and high (greater than or equal to 10 ug/dL; mean=14.6 ug/dL) groups based on concentration of lead in the umbilical cord. The overall mental development score for children tested biannually from 6-24 months of age was 4.8 points lower in the high lead group than in the low lead group and 3.8 points lower than in the medium lead group. The deficit was associated with cord blood lead and not with postnatal blood lead. Bellinger et al. (1990) reported later that children showing a deficit at 24 months had cognitive abilities relative to their postnatal blood lead concentrations by 5 years of age (i.e., cognitive scores improved in children who had lower blood lead at 57 months.) Ruff et al. (1993) reported that children treated with chelation therapy to reduce lead levels showed improved cognitive performance after 6 months, but not after only 7 weeks.
Bellinger et al. (1992) used a battery of tests to measure IQ and academic performance in the Boston children when they were 10 years old and noted that a 10-ug/dL increase in blood lead (within the range of 1-25 ug/dL) at 24 months of age was associated with a 5.8-point deficit in IQ and a 8.9-point deficit in academic performance at 10 years of age. Stiles and Bellinger (1993) noted that the IQ deficit could be related to only a few specific measures of neuropsychological performance; the association was generally with broad based measures of performance.
White et al. (1993) evaluated the cognitive ability of adults who had been hospitalized with lead poisoning 50 years earlier. The lead poisoned individuals suffered deficits in cognitive ability and lower lifetime occupational status compared with age- and sex-matched controls.
The EPA (1986a) concluded that there is no clear evidence of a blood lead level at which neurotoxic effects did not occur in children. This conclusion was reiterated in 1990 (EPA, 1990) as more evidence became available.
Historical data on the effect of maternal exposure to lead provide clear evidence of the adverse effect of lead on reproductive outcome, particularly miscarriages and stillbirths. These reports described exposures to high levels of lead, which prompted the exclusion of women from occupational exposure to lead. Therefore, more recent data on low level maternal exposure are scarce and inadequate for establishing exposure levels associated with adverse effects (EPA, 1986d). Recent studies have focused primarily on the effect of low level paternal exposure to lead on male reproductive parameters and reproductive outcome. Early studies reported that a high percentage of males exposed to lead had childless marriages, the rate of miscarriages and stillbirths was increased, and the male:female ratio of offspring was increased (Koinuma, 1926; Nogaki, 1957). Females employed at a smelter were more likely to experience miscarriages in later pregnancies if their husbands were also employed at a smelter, suggesting that long-term exposure of the males was required to affect reproductive outcome (Nordstrom et al., 1979).
Among a cohort of 645 women living in Port Pirie, South Australia, 22 of 23 miscarriages and 10 of 11 stillbirths occurred among women living in Port Pirie where blood lead levels were 10.6 ug/dL compared with blood levels of 7.6 ug/dL for the surrounding area (Baghurst et al., 1987). The rate of spontaneous abortions was not reported. No difference was seen in the rate of spontaneous abortions in another cohort of 304 women living near a lead smelter where blood lead levels were 15.9 ug/dL compared with a cohort of 335 unexposed women whose blood lead levels averaged 5.2 ug/dL (Murphy et al., 1990).
Studies have also shown that pregnancy outcome may be affected by paternal exposure to lead. Lancranjan et al. (1975) observed increases in asthenospermia, hypospermia, and teratospermia in two groups of occupationally exposed workers whose mean blood lead levels were 74.5 and 52.8 ug/dL compared with groups that experienced lower exposures (41 and 23 ug/dL). A recent report showed that the frequency distribution of sperm counts among a cohort of battery workers having a mean blood lead level of 61 ug/dL was shifted toward lower counts (median 45 106 sperm/mL) compared with the count (73 106) of the control cohort having a mean blood lead of 18 ug/dL (Assennato et al., 1987). In addition, a threefold increase in the frequency of oligospermia (16.7% compared with 5.5%) was noted. Serum levels of testosterone and pituitary hormones were not affected. Ng et al. (1991) reported an overall significant increase in the serum levels of luteinizing and follicle-stimulating hormone in males exposed to lead (32 ug Pb/dL) compared with unexposed males (8.3 ug/dL). Testosterone levels were not increased significantly, and there was a weak association between hormone level and increasing blood lead. In addition, a case-control study by Lindbohm et al. (1991) showed a significant risk of spontaneous abortions associated with paternal blood lead levels in excess of 1.5 umol/dL during the 80-day period before conception; the risk was exacerbated by paternal consumption of 10 or more alcoholic beverages per week and maternal age below 27.
No LD50 values for inorganic lead or lead compounds were found in the available literature.
No pertinent data on the subchronic toxicity of inorganic lead or lead compounds were located.
The database on chronic toxicity of lead compounds is very large and cannot be adequately reviewed within the scope of this report. Therefore, some of the pertinent studies are summarized in Table 2.
Table 2. Summary: Oral Chronic Toxicity in Laboratory Animals Exposed To Lead Compounds
|Species, Sex, Number||Exposure||Effect||Reference|
|Rat, male & female, 50 each||0, 10, 50, 100, 500, 1000, or 2000 ppm in feed for 2 years||increased mortality at 500 and 1000 ppm, increased number of stippled cells at 10 ppm; effects on RBCs at 50 ppm||Azar et al., 1973|
|Rat, male & female, NR||0, 10, 50, 100, or 1000 ppm in feed for 22 months||transient decrease in food consumption and weight gain at 100 ppm; decreased serum enzymes at 100 and 1000 ppm; effects on RBCs at 100 ppm||API, 1981|
|Rat, Male & female, 60-62 each||0 or 25 ppm in drinking water for lifetime||general life shortening due to nonspecific causes||Schroeder et al., 1965|
|Beagle dog, male & female, 4 each||0, 10, 50, 100, or 500 ppm in feed for 2 years||decreased ALAD activity in RBCs at 100 and 500 ppm; stippled cells at 500 ppm;||Azar et al., 1973|
|Dog, male & female, NR||0, 10, 50, 100, or 1000 ppm in feed for 22 months||decreased hemoglobin and increased urinary ALA at 1000 ppm||API, 1971|
|Rhesus Monkey, NR, NR||1.25 or 25 mg Pb/kg/day by gavage for 22 months||decreased bone marrow activity||API, 1971|
|Rat, male & female, 7-15 each||0, 0.1, or 1% Pb in feed for 29 or 22 months||reduced body weight gain and hematologic effects at both doses||Van Esch et al., 1962|
|Rat, male, 50||0 or 25 ppm in drinking water for lifetime||decreased body weight and glucose levels and glycosuria||Shroeder et al., 1970|
|Rat, male & female, 19-29||463 or 1850 ppm in feed during lactation and after weaning for 120 weeks||reduced food consumption and body weight; lethal bile duct lesions at 1850 ppm||Kroes et al., 1974|
The database on reproductive and developmental effects of lead in animals is very extensive and cannot be adequately reviewed within the scope of this report. Therefore, some of the pertinent studies are summarized in Table 3.
Table 3. Summary: Reproductive/Developmental Toxic Effects of Lead Compounds in Laboratory Animals
|Species, Sex, Number||Exposure||Effect||Reference|
|Rat, male & female, NR||0, 100, or 1000 ppm in feed: 3-generation reproduction study||no effect||API, 1971|
|Rat, male & female, 5 pairs||25 ppm Pb in deionized water (chromium deficient) for 3 generations||breeding failure, death of pups, runting||Schroeder and Mitchener, 1971|
|Mice, male & female, 5 pairs||25 ppm Pb in deionized water for 3 generations||breeding failure, death of pups, runting||Schroeder and Mitchener, 1971|
|Rabbits, male & female, 15 each||0, 54.6, or 546 ppm in feed on gd 7-16||no effect on reproductive paramaters and no malformations||API, 1971|
|Rat, female, NR||0, 7.14, 71.4, 714 mg/kg by gavage on gd 6-16||severe maternal toxicity (CNS and reduced weight gain) and fetal toxicity at 714 ppm, no malformations||Kennedy et al., 1975|
|Mice, female, NR||0, 7.14, 71.4, 714 mg/kg by gavage on gd 5-15||severe maternal toxicity (CNS and reduced weight gain) and fetal toxicity at 714 ppm, no malformations||Kennedy et al., 1975|
|Rat, male, 8-11||0, 0.1, or 0.3% in drinking water for 30 days starting at 42, 52, or 70 days of age||no effect (42 days of age); reduced body weight and prostate weights (0.3% at 52 days); reduced serum testosterone and sperm count (0.1 and 0.3% at 52 days of age and 0.3% at 70 days of age)||Sokol and Berman, 1991|
|Rat, female, ND||0, 1, or 10 ppm in drinking water throughout gestation||fetal toxicity at 10 ppm||Hubermont et al., 1976|
According to the EPA (1994b), the degree of uncertainty regarding the health effects of lead is very low. The critical effects that occur as a result of exposure to lead (changes in levels of certain blood enzymes, elevation of blood pressure, and neurobehavioral deficits in children) occur at exposure levels (measured as blood lead) so low as to be essentially without a threshold. Therefore, the EPA's RfD Work Group considers it inappropriate to develop an RfD for inorganic lead.
The Integrated Exposure Uptake Biokinetic (IEUBK) Model developed by the EPA is a site-specific method for estimating blood lead levels in children 0.5 to 7 years old based on multimedia exposures to lead in air, diet, drinking water, dust, soil, and paint (EPA, 1994c). Children are more sensitive to effects of lead than adults. The source contribution to lead uptake is predicted; mean distribution of lead in blood, bone, liver, and kidney is predicted, and finally, the frequency distribution for lead levels in a population of children is estimated assuming a log-normal distribution and a specified geometric standard deviation, which has a default value of 1.6. This model estimates the risk of blood levels in a child or a population of children exceeding 10 ug/dL, the level of concern. A computer program is used for these calculations. Site-specific concentrations of lead in various media are used when available; otherwise default values are assumed. The EPA has established a screening level of 400 ppm (ug/g) for lead in soil (EPA, 1994a). This is the level above which there may be enough concern to conduct a site-specific study of risk to lead exposure.
The effects of exposure to lead have been characterized much better in humans than in laboratory animals; the following targets have been identified in humans.
Several epidemiologic studies have been conducted on workers exposed to lead. Malcolm and Barnett (1982) studied the causes of death that occurred among a cohort of battery workers between 1926 and 1985. They reported an unexplained excess in deaths due to digestive tract cancer among workers whose urinary lead levels ranged between 100 and 250 ug/L. This excess was observed among deaths occurring only between 1963 and 1966. Fanning (1988) studied the mortality experience of the same cohort until 1985. He established two groups based on blood lead levels: the exposed group had levels of 40-80 ug/dL, and the internal control group had levels less than 40 ug/dL. Statistically nonsignificant excesses in deaths due to cancer of the digestive tract and stomach were observed in the exposed group compared with the control group.
Cooper et al. (1985) updated cohort studies reported by Cooper and Gaffey (1975) and Cooper (1976) on lead battery workers and lead smelter workers. The average urinary lead concentration was 173.2 ug/dL in smelter workers and 129.7 ug/dL in battery workers; the average blood lead levels were 79.7 and 62.7 ug/dL, respectively (Cooper and Gaffey, 1975; Cooper, 1976). In contrast to the earlier reports that showed no significant elevation in the death rate due to cancer at specific anatomical sites, Cooper et al. (1985) observed significantly increased mortality rates for cancer of the stomach and lungs among battery workers but not among smelter workers.
Selevan et al. (1985) conducted a study on two cohorts of smelter workers whose exposure exceeded airborne levels of 200 ug/m3; one cohort was also exposed to other metals and the other cohort had low potential for exposure to other metals. The mortality rate due to kidney cancer was nonsignificantly elevated in all cohorts. Gerhardsson et al. (1986) reported excess deaths due to stomach and lung cancer among a cohort of smelter workers. However, among memonsignificant excess in deaths due to lung cancer was observed.
The results of these studies do not provide evidence for a causal association between exposure to lead and mortality due to cancer at any specific sites. Elevated death rates for stomach and lung cancer were observed in some studies, but the analyses were based on small numbers of deaths, and exposures to other metals confounded interpretation of the results.
The database on the carcinogenicity of lead compound in laboratory animals is very extensive. These data are summarized in Table 4. As noted in the table, the kidney is the primary anatomical site for tumor induction in rats and mice. However, tumors of the pituitary gland, adrenal gland, thyroid gland, prostate, and lungs and cerebral gliomas have also been observed in animals exposed to lead compounds.
Table 4. Summary: Carcinogenic Effects of Lead Compounds in Laboratory Animals
|Species, Sex||Exposure||Tumor Response||Reference|
|Rat, male||10,000 ppm in feed for 12 months||renal tumors||Boyland et al., 1962|
|Rat, male & female||5 ppm Pb in water for life||no tumors (MTD not reached)||Kanisawa and Schroeder, 1969|
|Rat, male||0 or 3 mg in feed for 2 months then 4 mg for 16 months||renal, testicular, adrenal gland, and prostate tumors||Zawirska and Medras, 1968|
|Rat, male & female||0 or 3 mg in feed for 60, 162, 307, or 504 days||pituitary gland, adrenal gland, lung, renal, prostate, and thyroid gland tumors and cerebral gliomas||Zawirska and Medras, 1972|
|Rat, male & female||0, 10, 50, 100, or 1000 ppl Pb in feed for 22 months||renal tumors||API, 1971|
|Rat, male & female||3, 18, 62, 141, 548, 1130, or 2102 ppm in feed for 24 months||renal tumors||Azar et al., 1973|
|Rat, male||0 or 10,000 ppm in feed for 12 months||renal tumors||Tanner and Lipsky, 1984|
|Rat, male||0, 5000, or 10,000 ppm in feed for 6 months||renal tumors||Nogueira, 1987|
|Rat, male||0 or 2600 ppm in water for 18 months||renal tumors||Koller et al., 1985|
|Mouse, female||1, 50, 200, or 1000 ppm in water for 15 weeks with one i.p. injection of urethan||no effect on urethan-induced pulmonary tumors||Blakley, 1987|
|Mouse, female||0, 50, or 1000 ppm in water for 9 months||lymphocytic leukemia||Blakley, 1987|
|Beagle dog||2, 16, 57, 155, or 576 ppm in feed for 24 months||no induction of tumors; duration of exposure inadequate||Azar et al., 1971|
|Beagle dog, male & female||0, 10, 50, 100, or 1000 ppm in feed for 22 months||no induction of tumors; duration of exposure inadequate||API, 1971|
|Rhesus monkey, male & female||0, 1.25, or 25 mg/kg/day by gavage for 22 months||no induction of tumors; duration of exposure inadequate||API, 1981|
|Rat, male & female||0, 1000, or 10,000 ppm in feed for 24 months||renal tumors||Van Esch et al., 1962|
|Rat, male||0 or 10,000 ppm in feed for life||renal tumors||Mao and Molnar, 1967|
|Rat, male||5000 to 10,000 ppm in feed for 7-17 months with or without 2-AAF||renal tumors and cerebral gliomas||Hass et al., 1965|
|Rat, male||10,000 in feed with 0-6% calcium acetate for 18 months||renal tumors||Kasprzak et al., 1985|
|Rat, male||500 or 1000 ppm EHEN in feed for 2 weeks followed by 1000 ppm lead subacetate for 20 weeks, then basal diet for 10 weeks; controls were included||renal tumors||Hiasa et al., 1983|
|1000 ppm EHEN in water for 1 week followed by 1000 ppm lead subacetate in feed for 35 weeks; controls were included||renal tumors||Shirai et al., 1984|
|Mouse, male & female||0, 1000, or 10,000 ppm in feed for 24 months||renal tumors||Van Esch and Kroes, 1969|
|Hamster||0, 1000, or 5000 ppm in feed for 24 months||no tumor response; high mortality, few survivors after 600 days||Van Esch and Kroes, 1969|
|Rabbit, male||500 or 10,000 ppm in feed for 18 months with or without 2-AAF, linseed oil, cholesterol, chloroform, carbon tetrachloride, or vitamin D||no tumor response, duration of exposure inadequate||Hass et al., 1965|
|Rat, male||25 ppm Pb in water for life with 1 ppm trivalent chromium||no tumor response; MTD was not reached||Schroeder et al., 1970|
|Hamster, male & female||1 mg with 1 mg B[a]P ten times intratracheally; controls included||lung tumors||Kobayashi and Okamoto, 1974|
|Rat, male||29, 145, or 450 injected s.c. or i.p. over 8 months||renal tumors||Roe et al., 1965|
|Rat||20 mg by s.c. injection once weekly for up to 16 months||renal tumors||Zollinger, 1953|
|Mouse, male||twice weekly topical applications of 20% solution for a total of 6 mL over 12 months||renal tumors||Baldwin et al., 1964|
|Rat, male & female||0, 25, or 50 ppm in feed for 24 months||no tumor response; MTD was not reached||NCI, 1979|
|Mouse, male & female||4.46 mg/kg/day by gavage for 1 months then 130 ppm in feed for 17 months||no tumor response||BRL, 1968|
|Mouse, male & female||0, 25, or 50 ppm in feed for 24 months||no tumor response; MTD was not reached||NCI, 1979|
|Mouse, male & female||1000 mg/kg once by s.c. injection||no tumor response||BRL, 1968|
Classification--B2 (EPA, 1994b)
Basis--Evidence from human studies is inadequate. Evidence from animal studies is sufficient based on numerous bioassays in laboratory animals showing statistically significant increased incidences of renal tumors with various lead salts. Results from animals were reproducible across strains and different laboratories. Short-term studies showed that lead affects gene expression.
A slope factor was not calculated by the EPA.
Alomran, A.H.; Shleamoon, M.N. (1988) The influence of chronic lead exposure on lymphocyte proliferative response and immunoglobulin levels in storage battery workers. J. Biol. Sci. Res. 19:575-585. (cited in ATSDR, 1993)
API (American Petroleum Institute). (1971). The chronic toxicity of lead. Medical Research Report No. EA7102. Washington, D.C.
Assennato, G.; Paci, C.; Baser, M.E.; et al. (1987) Sperm count suppression without endocrine dysfunction in lead-exposed men. Arch. Environ. Health. 42:124-127.
ATSDR (Agency for Toxic Substances and disease Registry). 1993. Toxicological Profile for Lead. Update. Prepared by Clement International Corporation under contract No. 205-88-0608 for ATSDR, U.S. Public Health Service, Atlanta, GA.
Azar, A.; Trochimowicz, H.J.; Maxfield, M.E. (1973) Review of lead studies in animals carried out at Haskell Laboratory - Two-year feeding study and response to hemorrhage study. In: Environmental Health Aspects of Lead. Proceedings of an International Symposium, Amsterdam, (Nederland) October 2-6, 1972. Luxembourg: Commission of the European Communities Directorate General for Dissemination of Knowledge Center for Information and Documentation. pp. 199-210.
Baghurst, P.A.; Robertson, E.F.; McMichael, A.J.; et al. (1987) The Port Pirie cohort study: Lead effects on pregnancy outcome and early childhood development. Neurotoxicology. 8:395-401. (cited in ATSDR, 1993)
Baghurst, P.A.; Tong, S.-L.; McMichael, A.J.; et al. (1992a) Determinants of blood lead concentrations to age 5 years in a birth cohort study of children living in the lead smelting city of Port Pirie and surrounding areas. Arch. Environ. Health. 47:203-210.
Baghurst, P.A.; McMichael, A.J.; Wigg, N.R.; et al. (1992b) Environmental exposure to lead and children's intelligence at the age of seven years. The Port Pirie Cohort Study. New Eng. J. Med. 327:1279-1284.
Baldwin, R.W.; Cunningham, G.J.; Pratt, D. (1964) Carcinogenic action of motor engine oil additives. Br. J. Cancer 18:503-507.
Barltrop, D.; Meek, F. (1975) Absorption of different lead compounds. Postgrad. Med. J. 51:805-809.
Bellinger, D.C.; Needleman, H.L.; Leviton, A.; et al. (1984) Early sensory-motor development and prenatal exposure to lead. Neurobehav. Toxicol. Teratol. 6:387-402. (cited in EPA, 1986e)
Bellinger, D.; Leviton, A.; Waternaux, C.; (1987a) Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. 316:1038-1043.
Bellinger, D.; Sloman, J.; Leviton, A.; et al. (1987b) Low-level lead exposure and child development: Assessment at age 5 of a cohort followed from birth. In: Int. Conf.; Heavy Metals in the Environment, Vol. 1, Sept, 1987, New Orleans, LA. CEP Consultants, Ltd.; Edinburgh, United Kingdom. pp. 49-53.
Bellinger, D.; Leviton, a.; Sloman, J. (1990) Antecedents and correlates of improved cognitive performance in children exposed in utero to low levels of lead. Environ. Health Perspect. 89:5-11.
Bellinger, D.C.; Stiles, K.M.; Needleman, H.L. (1992) Low-level lead exposure, intelligence and academic achievement: A long-term follow-up study. Pediatrics. 90:855-561. (abstract: BIOSIS/93/07320)
Blakley, B.R. (1987) The effect of lead on chemical- and viral-induced tumor production in mice. J. Appl. Toxicol. 7:167-172.
Boyland, E.; Dukes, C.E.; Grover, P.L.; Mitchley, B.C.V. (1962) The induction of renal tumors by feeding lead acetate to rats. Br. J. Cancer 16:283-288.
Bionetics Research Labs, Incorporated (BRL). 1968. Evaluation of Carcinogenic, Teratogenic, and Mutagenic Activities of Selected Pesticides and Industrial Chemicals. Volume I. Carcinogenic. Report No. NCI-DCCP-CG-1973-1-1. NTIS PB 223 159.
Budavari, S., Ed. 1989. The Merck Index. 11th ed. Merck and Co., Inc., Rahway, NJ.
Burchfiel, J.L., F.H. Duffy, P.H. Bartels and H.L. Neelleman. 1980. The combined discriminating power of quantitative electroencephalography and neuropsychologic measures in evaluating central nervous system effects of lead at low levels. In: Needleman, H.L., Ed. Low Level Lead Exposure: The Clinical Implications of Current Research. Raven Press, New York. pp. 75-89 (as cited in EPA, 1986a,d).
Conrad, M.E.; Barton, J.C. (1978) Factors affecting the absorption and excretion of lead in the rat. Gastroenterology 74:731-740.
Cooper, W.C. (1976). Cancer mortality patterns in the lead industry. Ann. N.Y. Acad. Sci. 271:250-259.
Cooper, C.W.; Gaffey, W.R. (1975) Mortality of lead workers. J. Occup. Med. 17(2):100-107.
Cooper, W.C.; Wong, O.; Kheifets, L. (1985) Mortality among employees of lead battery plants and lead-producing plants, 1947 - 1980. Scand. J. Work Environ. Health 11:331-345.
Coscia, G.C.; Discalzi, G.; Ponzetti, C. (1987) Immunological aspects of occupational lead exposure. Med. Lav. 78:360-364. (cited by ATSDR, 1993)
Dietrich, K.N.; Krafft, K.M.;Bier, M.; et al. (1986) Early effects of fetal lead exposure: neurobehavioral findings at 6 months. Inst. J. Biosoc. Res. 8:151-168. (cited in EPA, 1990)
Dietrich, K.N.; Succop, P.A.; Berger, O.G.; Hammond, P.B.; Bornschein, R.L. (1991) Lead exposure and the cognitive development of urban preschool children: The Cincinnati lead study cohort at age 4 years. Neurotoxicol. Teratol. 13:203-212.
Dietrich, K.N.; Succop, P.A.; Berger, O.G.; Keith, R.W. (1992) Lead exposure and the central auditory processing abilities and cognitive development of urban children: the Cincinnati lead study cohort at age 5 years. Neurotoxicol. Teratol. 14:51-56.
Dietrich, K.N.; Succop, P.A.; Berger, O.G.; Hammond, P.B.; Bornschein, R.L. (1993) The developmental consequences of low to moderate prenatal and postnatal lead exposure: Intellectual attainment in the Cincinnati lead study cohort following school entry. Neurotoxicol. Teratol. 15:37-4.
deKort, W.L.A.M.; Verschoor, M.A.; Wibowo, A.A.E.; van Hemmen, J.J. (1986) Occupational exposure to lead and blood pressure. A study of 105 workers. Am. J. Ind. Med. ? (cited in EPA, 1986e).
Dolenc, P.; Staessen, J.A.; Lauwerys, R.R.; Amery, A. (1993) Short report: low-level exposure does not increase the blood pressure in the general population. Cadmibel Study Group. J. Hypertens. 11:589-593. (cited from abstract)
Ehle, A.L.; McKee, D.C. (1990) Neuropsychological effect of lead in occupationally exposed workers: a critical review. Crit. Rev. Toxicol. 20:237-255.
Elwood, P.C.; Davey-Smith, G.; Oldham, P.D.; Toothill, C. (1988a) Two Welsh surveys of blood lead and blood pressure. Environ. Health Perspect. 78:119-121. (cited in EPA, 1990).
Ellwood, P.C. Yarnell, J.W.G.; Oldham, P.D.; et al. (1988b) Blood pressure and blood lead in surveys in Wales. Am. J. Epidemiol. 127:942-945. (cited in EPA, 1990)
Fanning, D. (1988) A mortality study of lead workers, 1926-1985. Arch. Environ. Health 43:247-51.
Gerhardsson, L; Lundström, N-G.; Nordberg, G; Wall, S. (1986) Mortality and lead exposure: A retrospective cohort study of Swedish smelter workers. Br. J. Ind. Med. 43:707-712.
Gerhardsson, L; Chettle, D.R.; Snglyst, G.F.; et al. (1992) Kidney effects in long term exposed lead smelter workers. Br. J. Ind. Med. 49:186-192.
Goyer, R.A. (1985) Renal changes associated with lead exposure. In: Dietary and Environmental Lead: Human Health Effects. K.R. Mahaffey, Ed., Elsevier, New York, pp. 315-338.
Goyer, R.A. (1988) Lead. In: Handbook on Toxicity of Inorganic Compounds. H.G. Seiler and H. Sigel, eds. Marcel Dekker, Inc.: New York, pp. 359-382.
Harlan, W.R.; Landi, J.R.; Shcmouder, R.L.; Goldstein, N.G.; Harlan, L.C. (1985) Blood lead and blood pressure: relationship in the adolescent and adult US population. J. Am. Med. Assoc. 253:530-534. (cited in EPA, 1986e).
Hass, G.M.; McDonald, J.H.; Oyasu, R.; Battifora, H.A.; Paloucek, J.T. (1965) Renal neoplasia induced by combinations of dietary lead subacetate and N-2-fluorenylacetamide. International Symposium on Renal Neoplasia. Brasilia, pp. 377-412.
Hiasa, Y.; Ohshima, M.; Kitahori, Y.; et al. (1983) Basic lead acetate: Promoting effects on the development of renal tubular cell tumors in rats treated with N-ethyl-N-hydroxyethylnitrosamine. J. Nat. Cancer Inst. 70(4):761-765.
Hubermont, G., J.-P. Buchet, H. Roels and R. Lauwerys. 1976. Effect of short-term administration of lead to pregnant rats. Toxicology. 5: 379-384. (cited in EPA, 1986d; ATSDR, 1990)
International Agency for Research on Cancer (IARC). 1980. Lead and lead compounds, Vol. 23. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Some Metals and Metallic Compounds. IARC, Lyon, France, pp. 325-415.
Jensen, A.A. (1983) Metabolism and toxicokinetics. In: Biological Effects of Organolead Compounds. P. Grandjean and E.C. Grandjean, eds. CRC Press: Boca Raton, FL, pp. 97-115.
Kanisawa, M.; Schroeder, H.A. (1969) Life term studies on the effect of trace elements on spontaneous tumors in mice and rats. Cancer Res. 29:892-895.
Kasprzak, K.S.; Hoover, K.L.; Poirier, L.A. (1985) Effects of dietary calcium acetate on lead subacetate carcinogenicity in kidneys of male Sprague-Dawley rats. Carcinogenesis 6(2):279-282.
Kennedy, G.L., D.W. Arnold and J.C. Calandra. 1975. Teratogenic evaluation of lead compounds in mice and rats. Fd. Cosmet. Toxicol. 13: 629-632.
Kimber, I.; Stonard, M.D.; Gidlow, D.A.; et al. (1986) Influence of chronic low-level exposure to lead on plasma immunoglobin concentration and cellular immune function in man. Int. Arch. Occup. Environ. Health. 57:117-125. (cited in ATSDR, 1993)
Kirby,H.; Gyntelberg, F. (1985) Blood pressure and other cardiovascular risk factors of long-term exposure to lead. Scand. J. Work Environ. Health. 11:15-19. (cited in EPA, 1986e).
Kobayashi, N; Okamoto, T. (1974) Effects of lead oxide on the induction of lung tumors in Syrian hamsters. J. Nat. Cancer Inst. 52(5):1605-1610.
Koinuma, S. (1926) Impotence of workmen. J. Am. Med. Assoc. 86:1924. (cited in EPA, 1986d).
Koller, L.D.; Kerkvliet, N.I.; Exon, J.H. (1985) Neoplasia induced in male rats fed lead acetate, ethyl urea, and sodium nitrite. Toxicol. Pathol. 13(1):50-57.
Kroes, R., M.J. van Logten, J.M. Berkvens, T. De Vries and G.J. van Esch. 1974. Study on the carcinogenicity of lead arsenate and sodium arsenate and on the possible synergistic effect of diethylnitrosamine. F. Cosmet. Toxicol. 12:671-679.
Lancranjan, I.; Popescu, H.I.; Gavanescu, O.; et al. (1975) Reproductive ability of workmen occupationally exposed to lead. Arch. Environ. Health 30:396-401.
Landis, J.R.; Flegal, K.M. (1988) A generalized Mantel-Haenszel analysis of the regression of blood pressure on blood lead using NHANES II data. Environ. Health Prospect. 78:35-41.
Lane, R.E. (1949) The care of the lead worker. Br. J. Ind. Med. 6:125-143. (cited by Cooper et al., 1985)
Lane, R.E. (1965) Health control in inorganic lead industries; a follow-up of exposed workers. Arch. Environ. Health. 8:243-250. (cited by Cooper et al., 1985)
Lindbohm, M.-L.; Sallmen, M.; Anttila, A.; Taskinen, H.; Hemminki, D.; (1991) Paternal occupational lead exposure and spontaneous abortion. Scand. J. Work Environ. Health. 17:95-103.
Maheswaran, R.; Gill, J.S.; Beevers, D.G. (1993) Blood pressure and industrial lead. Am. J. Epidemiol. 137:645-653. (abstract: TOXBIB/93/228062)
Malcolm, D.; Barnett, H.A.R. (1982) A mortality study of lead workers 1925-1976. Br. J. Ind. Med. 39:404-410.
Mao, P.; Molnar, J.J. (1967) The fine structure and histochemistry of lead-induced renal tumors in rats. Am. J. Pathol. 50:571-603.
McMichael, A.J.; Baghurst, P.A.; Wigg, N.R.; et al. (1988) Port Pirie cohort study: environmental exposure to lead and children's ability at the age of four years. N. Engl. J. Med. 319:468-475. (Cited in EPA, 1990)
Moreau, T.; Orssaud, G.; Juguet, B.; Busquet, G. (1982) Plombémie et pression artérielle: premiers résultats d'une enquéte transversale de 431 sujets de sexe masculin 'Blood lead levels and arterial pressure: initial results of a cross sectional study of 431 male subjects] [letter]. Rev. Epidemiol. Sante Publiq 30:395-397. (cited in EPA, 1986e).
Morris, C.; McCarron, D.A.; Benett, W.M. (1990) Low-level lead exposure blood pressure, and calcium metabolism. Am. J. Kidney Dis. 15:568-574. (abstract:TOXBIB/90/313685)
Muñoz, H.; Romieu, I.; Palazuelos, E.; et al. (1993) Blood lead level and neurobehavioral development among children living in Mexico City. Arch. Environ. Health. 48:132-139.
Murphy, M.J.; Graziano, J.H.; Popovac, D.; et al. (1990) Past pregnancy outcomes among women living in the vicinity of a lead smelter in Kosovo, Yugoslavia. Am. J. Public Health. 80:33-35. (cited in ATSDR, 1993)
National Cancer Institute (NCI). 1979. Bioassay of lead dimethyldithiocarbamate for possible carcinogenicity. CAS. No. 19010-66-3. Technical Report Series NO. 151. Carcinogenesis Testing Program, Division of Cancer Cause and Prevention, National Institutes of Health. Bethesda, MD.
Ng, T.P.; Goh, H.H.; Ng, Y.L.; et al. (1991) Male endocrine function in workers with moderate exposure to lead. Br. J. Ind. Med. 48:485-491.
Nogaki, K. (1957) [On the action of lead on the body of lead refinery workers: particularly on the conception, pregnancy and parturition, in the case of females and on the vitality of their newborn]. Igaku Kenkyu. 27:1314-1338. (cited in EPA, 1986d).
Nogueira, E. (1987) Rat renal carcinogenesis after chronic simultaneous exposure to lead acetate and N-nitrosodiethylamine. Virch. Arch. B 53:365-374.
Nordstrom, S. Beckman, L.; Norderson, I. (1979) Occupational and environmental risks in and around a smelter in northern Sweden: VI. congenital malformations. Hereditas. 90:297-302. (cited in EPA, 1986d).
Ogawa, Y.; Hirata, M.; Okayama, A.; Ichikawa, Y.E.; Coto, S. (1993) latency of the Achilles tendon reflex for detection of reduced function of the peripheral nervous system in workers exposed to lead. Br. J. Ind. Med. 50:229-233
Otto, D.A., V.A. Benignus, K.E. Muller and C.N. Barton. 1981. Effects of age and body lead burden on CNS function in young children. I. Slow cortical potentials. Electroencephalogr. Clin. Neurophysiol. 52: 229-239. (as cited in EPA, 1986a,d).
Pirkle, J.L.; Schwartz, J.; Landis, J.R.; Harlan, W.R. (1985) The relationship between blood lead levels and blood pressure and its cardiovascular risk implication. Am. J. Epidemiol. 121:246-258. (cited in EPA, 1986e).
Pocock, S.J.; Shaper, A.G.; Ashby, D. Delves, T.; Whitehead, T.P. (1984) Blood lead concentration, blood pressure, and renal function. Br. Med. J. 289:872-874. (cited in EPA, 1986e).
Pocock, S.J.; Shaper, A.G.; Ashby, D.; Delves, H.T.; Clayton, B.E. (1988) The relationship between blood lead, blood pressure, stroke, and heart attacks in middle-aged British men. Environ. Health Perspect. 78:23-30. (cited in EPA, 1990).
Roe, F.J.C.; Boyland, E.; Dukes, C.E.; Mitchley, B.C.V. (1965) Failure of testosterone or xanthopterin to influence the induction of renal neoplasms by lead in rats. Br. J. Cancer 19:860-866.
Ruff, H.A.; Bijur, P.E.; Markowitz, M.; Ma, Y.-C.; Rosen, J.F.; (1993) Declining blood lead levels and cognitive changes in moderately lead-poisoned children. J. Am. Med. Assoc. 269:1641-1646.
Schroeder, H.A. and Mitchener. 1971. Toxic effects of trace elements on the reproduction of mice and rats. Arch. Environ. Health. 23: 102-106.
Schroeder, H.A.; Balassa, J.J.; Vinton, Jr., W.H. (1965) Chromium, cadmium and lead in rats: Effects of life span, tumors and tissue levels. J. Nutr. 86:51-66.
Schroeder, H.A., M. Mitchener and A.P. Nason. 1970. Zirconium, niobium, antimony, vanadium and lead in rats: Life term studies. J. Nutr. 100: 59-68.
Schroeder, S.R.; Hawk, B.; (1986) Child-caregiver environmental factors related to lead exposure and IQ. In: Toxic Substances and Mental Retardation: Neurobehavioral Toxicology and Teratology, S.R. Schroeder, Ed., Washington, D.C. (AAMD Monograph Series). (cited in EPA, 1986d)
Schwartz, J. (1991) Lead, blood pressure, and cardiovascular disease in men and women. Environ. Health Perspect. 91:71-75.
Selevan, S.G.; Landrigan, P.J. Stern, F.B.; Jones, J.H. (1985) Mortality of lead smelter workers. Am. J. Epidemiol. 122:673-683.
Shirai, T.; Ohshima, M.; Masuda, A.; Tamano, S.; Ito, N. (1984) Promotion of 2-(ethylnitrosamino)ethanol-induced renal carcinogenesis in rats by nephrotoxic compounds: Positive responses with folic acid, basic lead acetate, and N-(3,5-dichlorophenyl)succinimide but not with 2,3-dibromo-1-propanol phosphate. J. Nat. Cancer Inst. 71(2):477-482.
Sokol, R.Z.; Berman, N. (1991) The effect of age of exposure on lead-induced testicular toxicity. Toxicology. 69:269-278.
Stiles, K.M.; Bellinger, D.C. (1993) Neuropsychological correlates of low-level lead exposure in school-age children: A prospective study. Neurotoxicol. Teratol. 15:27-35.
Stollery, B.T.; Broadbent, D.E.; Banks, H.A.; Lee, W.R. (1991) Short-term prospective study of cognitive functioning in lead workers. Br. J. Ind. Med. 48:739-749.
Tanner, D.C.; Lipsky, M.M. (1984) Effect of lead acetate on N-(4'-fluoro-4-biphenyl)acetamide-induced renal carcinogenesis in the rat. Carcinogenesis 5(9):1109-1113.
U.S. DC (U.S. Department of Commerce) (1992) Public comment on the toxicological profile for lead. Submitted to the Agency for Toxic Substances and Disease Registry. Washington, DC: United States Department of Commerce, International Trade Administration. (cited in ATSDR, 1993)
U.S. Environmental Protection Agency (EPA). 1986a. Air Quality Criteria for Lead. Vol. I of IV. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA-600/8-83/028aF. Available from NTIS, Springfield, VA; PB87-142378.
U.S. Environmental Protection Agency (EPA). 1986b. Air Quality Criteria for Lead. Vol. II of IV. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA-600/8-83/028bF. Available from NTIS, Springfield, VA; PB87-142378.
U.S. Environmental Protection Agency (EPA). 1986c. Air Quality Criteria for Lead. Vol. III of IV. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA-600/8-83/028cF. Available from NTIS, Springfield, VA; PB87-142378.
U.S. Environmental Protection Agency (EPA). 1986d. Air Quality Criteria for Lead. Vol. IV of IV. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA-600/8-83/028dF. Available from NTIS, Springfield, VA; PB87-142378.
U.S. Environmental Protection Agency (EPA). 1986e. Lead effects on cardiovascular function, early development, and stature: an addendum to EPA Air Quality Criteria for Lead (1986). In: Air Quality Criteria for Lead, Vol. I. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA-600/8-83/028aF. Available from NTIS, Springfield, VA; PB87-142378. pp. A1-67.
U.S. Environmental Protection Agency (EPA). 1989a. Evaluation of the Potential Carcinogenicity of Lead and Lead Compounds. Office of Health and Environmental Assessment. EPA/600/8-89/045A.
U.S. Environmental Protection Agency (EPA). 1989b. Review of the National Ambient Air Quality Standards for Lead: Exposure Analysis Methodology and Validation. OAQPS Staff Report. Office of Air Quality Planning and Standards, Research Triangle Park, NC. PB89207914/AS.
U.S. Environmental Protection Agency (EPA). 1990. Air Quality Criteria for Lead: Supplement to the 1986 Addendum. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA-600/8-89/049F.
U.S. Environmental Protection Agency (EPA). 1994a. Interim Soil Lead Guidance for CERCLA Sites and RCRA Corrective Action Facilities. OSWER Directive 9355.4-12. Office of Solid Waste and Emergency Response, Washington, D.C.
U.S. Environmental Protection Agency (EPA). 1994b. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. Environmental Protection Agency (EPA). 1994c. Guidance Manual for the Integrated Exposure Uptake Biokinetic Model for Lead in Children. Office of Solid Waste and Emergency Response, Washington, D.C. EPA/540/R-93/081, PB93-963510.
Van Esch, G.J.; Kroes, R. (1969) The induction of renal tumors by feeding basic lead acetate to mice and hamsters. Br. J. Cancer 23:765-771.
Van Esch, G.J., H. Van Genderen and H.H. Vink. 1962. The induction of renal tumors by feeding of basic lead acetate to rats. Br. J. Cancer. 16: 289-297.
Vimpani, G.V.; Wigg, N.R.; Robertson, E.F.; et al. (1985) The Port Pirie cohort study: blood lead concentration and childhood developmental assessment. In: Lead Environmental Health - The Current Issues, L.J. Goldwater, L.M. Wysocki, R.A. Volpe, Eds., Edited proceedings, May, Duke University Press, Durham, NC. pp. 139-155. (cited in EPA, 1990)
Vimpani, G.; Baghurst, P.; McMichael, A.J.; et al. (1989) "The effects of cumulative lead exposure on pregnancy outcome and childhood development during the first four years." Presented at: Conference on Advances in Lead Research: Implications for Environmental Research. Research Triangle Park, NC, National Institute of Environmental Health Sciences, January.
Weiss, S.T.; Muñoz, A.; Stein, A.; Sparrow, D.; Speizer, F.E. (1986) The relationship of blood lead to blood pressure in a longitudinal study of working men. Am. J. Epidemiol. 123:800-808. (cited in EPA, 1986e).
White, R.F.; Diamond, R.; Proctor, S.; Morey, C.; Hu, H. (1993) Residual cognitive deficits 50 years after lead poisoning during childhood. Br. J. Ind. Med. 50:613-622.
Wigg, N.R.; Vimpani, G.V.; McMichael, A.J.; et al. (1988) Port Pirie cohort study: childhood blood lead and neuropsychological development at age two years. J. Epidemiol. Commun. Health. 42:213-219. (cited in EPA, 1990)
Zawirska, B. and Medras, K. (1968) Tumors and disturbances of porphyrin metabolism in rats resulting from chronic experimental lead intoxication. I. Morphological studies. Zentralblatt Allgem. Pathol. Pathol. Anatomie 111:1-12.
Zawirska, B.; Medras, K. (1972) The role of the kidneys in disorders of porphyrin metabolism during carcinogenesis induced with lead acetate. Arch. Immunol. Ther. Exp. 20:257-272.
Zollinger, H.U. (1953) Durch chronische bleivergiftung erzengte nierenadenome und-carcinome bei ratten und ihre beziehungen zu den entsprechenden neubildungen des menshcen. Virch. Arch. Bd. 323:694-710. Retrieve Toxicity Profiles Condensed Version
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